A7: Antidotes in Depth

Deferoxamine (DFO) is the parenteral chelator of choice for treatment of acute iron poisoning. Considering that DFO has been used to treat patients with acute iron overdose for more than 40 years,³³ there is still much that is unknown. No controlled studies have evaluated the efficacy or dosing of DFO. Animal studies and case series from the 1960s and 1970s form the basis for current use of DFO. This information has been supplemented since then by case reports and clinical experience. DFO is also used for chelation of aluminum in patients with chronic kidney failure. The merits of DFO as a treatment strategy for acute iron overdose is discussed in Chap. 46 and for aluminum toxicity in Chap. 87.

The development of DFO (or desferrioxamine B) resulted from an analysis of the iron containing metabolites of a species of actinomycetes. Ferrioxamine is a brownish-red compound containing trivalent iron (ferric, Fe³⁺) and three molecules of trihydroxamic acid isolated from the organism Streptomyces pilosus.³⁸ DFO is the colorless compound that results when the ­trivalent iron is chemically removed from ferrioxamine B (Fig. A7–1).³⁸

Chemistry

DFO is a water-soluble hexadentate chelator with a molecular weight of 561 Da. The commercial formulation is the mesylate salt with a ­molecular weight of 657 Da. One mole of DFO binds 1 mole of Fe³⁺; therefore, 100 mg DFO as the mesylate salt theoretically can bind 8.5 mg Fe³⁺.

DFO has a much greater affinity constant for iron (10³¹) and aluminum (10²²) than for zinc, copper, nickel, magnesium, or calcium (10²–10¹⁴).³⁸ Thus, at physiologic pH, DFO complexes almost exclusively with ferric iron.^28,84

Related Chelators

Deferiprone, a bidentate oral iron chelator with a molecular weight of 139 Da, was approved by the US Food and Drug Administration (FDA) in 2011 for the treatment of iron overload in patients with thalassemia in whom current treatment is inadequate.²⁴ Three moles of deferiprone are required to bind one mole of ferric ion to form a stable complex, which is excreted in the urine.³² Inappropriate ratios of drug to iron may be ineffective or even harmful because of the formation of potentially toxic intermediates.³² Preliminary animal studies of the use of deferiprone in acute iron toxicity are contradictory.^10,23,36,39 A dose of 75 mg/kg deferiprone produces 60% of the total iron excretion that can be achieved with 50 mg/kg DFO. All of the iron eliminated with deferiprone occurs in the urine, while DFO eliminates iron in the urine and feces.⁴² It has been proposed that deferiprone is less likely to cause toxicity in patients with low iron stores because it can exchange iron with transferrin. Adverse events include QT prolongation, elevation of hepatic enzymes, gastrointestinal effects, arthralgia, chromaturia. Because of embryofetal toxicity in animals studies it is given an FDA pregnancy category D; DFO also carries a boxed warning for agranulocytosis.²⁴ Deferiprone is now being combined with DFO because studies demonstrate additive or synergistic effects in chronic iron overload syndromes. It is hypothesized that deferiprone, because of its smaller size, can enter and chelate cardiac iron and then transfer it to DFO for elimination.⁴²

Deferasirox, an oral iron chelator that was FDA approved in 2005, is indicated to treat chronic iron overload caused by blood transfusions or in patients with thalassemia and elevated liver iron concentrations. Deferasirox, a tridentate ligand with a molecular weight of 373 Da, binds ferric iron in a 2:1 ratio. Deferasirox is lipid soluble with high protein binding (~99%). Once bound to iron, the complex is predominantly eliminated in the feces. The serum half-life (19 ± 6.5 hours) is considerably longer than DFO and deferiprone (47–137 minutes). Preliminary studies demonstrate a comparable efficacy to DFO in patients with chronic iron overload.⁸⁰ One study utilizing deferasirox in a human model of supraphysiologic iron ingestion demonstrated a reduction in serum iron concentrations when compared with placebo.²⁹ However, the dose of iron ingested was 5 mg/kg, and concerns about achieving the effective dose ratio of deferasirox to iron of 2:1 and the effects of acidemia on the binding of deferasirox to iron in a large overdose limit its use in acute iron poisoning at this time.⁵⁶ In addition, similar to other oral chelators, concerns exist about increasing oral absorption of the deferasirox iron complex, and the toxicity of this complex in the setting of an acute iron overdose.^22,63,72 Adverse events include boxed warnings for gastrointestinal hemorrhage, kidney failure, and hepatic failure. Advanced age increases these risks.²²

Mechanism of Action

DFO binds Fe³⁺ at the 3 N–OH sites, forming an octahedral iron complex (Fig. A7–1). Once bound, the resultant ferrioxamine is very stable. DFO appears to benefit iron-poisoned patients by chelating free iron (non–transferrin plasma iron), iron in transit between transferrin and ferritin (labile chelatable iron pool),^32,46,65 and hemosiderin and ferritin, while not directly affecting the iron of transferrin, hemoglobin, and cytochromes.^20,38 Although in vitro studies suggest that DFO removes iron from ferritin and transferrin with only very little from hemosiderin,⁵¹ in vivo experiments demonstrate that DFO cannot remove iron after the iron is bound to transferrin.⁴ DFO does bind “free iron,” now referred to as non transferrin bound iron found in the plasma after transferrin saturation, which only occurs acutely after overdose or chronically in iron overload syndromes.³² In vitro studies demonstrate that DFO chelates and inactivates cytoplasmic, lysosomal, and probably mitochondrial iron, preventing disruption of mitochondrial function and injury.^27,46 An in vitro study suggests that DFO gains access to cytosol and endosomes through endocytosis rather than passive diffusion.²⁷ In chronic iron overload, DFO chelates iron deposited in the reticuloendothelial cells found in the spleen, liver, and bone marrow and excretes iron in the urine as ferrioxamine.³² Whether DFO actually chelates the iron within the reticuloendothelial cells or after liberation into the plasma is unclear. In vitro studies demonstrate that the liver can donate iron to DFO; thus, chelation may also subsequently lead to biliary iron excretion and fecal elimination.^32,50

Pharmacokinetics/Pharmacodynamics

The volume of distribution of DFO ranges from 0.6 to 1.33 L/kg.^38,43,59 Because DFO is water soluble, entry into most cells is limited except for hepatocytes, in which facilitated uptake takes place.^62a,63 The initial distribution half-life of DFO is 5 to 10 minutes.^41,71 The terminal elimination half-life of DFO is approximately 6 hours in healthy patients² but approximately 3 hours in patients with thalassemia. DFO is metabolized in the plasma to several metabolites (A–F), of which metabolite B is believed to be toxic.^38,43,59,61 Unchanged DFO undergoes glomerular filtration and tubular secretion.⁵⁰

By comparison, ferrioxamine has a smaller volume of distribution than DFO. In nephrectomized dogs, the volume of distribution of ferrioxamine was calculated to be 19% of body weight compared with 50% of body weight for DFO.³⁸ This finding implies that DFO has a more extensive tissue distribution. The different pharmacokinetic patterns may be related to the potential for facilitated penetrance of the straight-chain molecule DFO compared with that of the octahedral ferrioxamine.⁶¹ Experiments in dogs with normal kidney function demonstrate that intravenous (IV) ferrioxamine is entirely eliminated by the kidney within 5 hours via glomerular filtration and partial reabsorption.^36,50

The pharmacokinetics of DFO and ferrioxamine differ in healthy compared with iron overloaded patients. Whereas plasma DFO concentrations in healthy patients are approximately twice the concentrations noted in patients with thalassemia major, ferrioxamine concentrations are five times greater in patients with thalassemia major compared with healthy patients.^38,73

The metabolism of DFO is unclear but occurs in the plasma by plasma enzymes and in the liver.²⁰

DFO is hemodialyzable. Some investigators suggest that DFO can be administered during hemodialysis to remove ferrioxamine.⁸⁵ Hemodialysis,^14,71 particularly high flux hemodialysis⁷⁸ and hemoperfusion,¹⁴ are effective in ferrioxamine removal and are indicated in patients with renal failure.

Due to the limitations in the amount of iron which DFO can chelate, aggressive gastrointestinal decontamination and supportive measures should accompany its use in iron overdose, as discussed in Chap. 46.

Animal Studies

Guinea pigs given oral lethal doses of ferrous sulfate and oral DFO in a dose calculated to bind most of the iron showed dramatically improved survival rates.⁵¹ Mortality rates in this study and in a swine study¹⁹ directly correlated with the delay to DFO administration.⁵¹

In two canine studies, dogs that received the iron–DFO complex orally had a 40% to 100% mortality.^84,85 When both oral and IV DFO were administered, the mortality rate was 67%.⁸³ A similar follow-up study demonstrated a 50% mortality rate in dogs given a lethal dose (225 mg/kg) of iron, followed by oral DFO (2.6 g) and IV DFO (0.75–1.5 mg/kg/min for 8–12 hours).⁸⁵ These studies discouraged further investigation in the use of oral DFO despite the more favorable results in other animal models.^5,34,51,77

Early Human Use and History of Dosing Recommendations

In one of the earliest case series, 172 hemodynamically stable children who were not severely poisoned were treated with 5 to 10 g oral DFO and either 1 or 2 g intramuscular (IM) DFO every 3 to 12 hours.⁸³ Patients who were in shock or severely ill received 1 g of DFO IV at a maximum of 15 mg/kg/h every 4 to 12 hours for 2 to 3 days as necessary. Of the 28 patients who developed coma, shock, or both, three died. One of the three patients who died had received late treatment with DFO.

This case series was expanded to 472 patients, and guidelines for DFO dosing were formulated as a result of this clinical experience.⁸² The recommended initial dose of DFO was suggested as 1 g IM followed by 0.5 g at 4 and 8 hours later and then every 4 to 12 hours as necessary, not to exceed 6 g in 24 hours. For patients in shock, DFO was recommended at an initial dose not to exceed 1 g IV and a rate not to exceed 15 mg/kg/h followed 4 and 8 hours later by two 0.5-g doses for a total dosage not to exceed 6 g in 24 hours. These recommendations for total dosages were not scientifically developed and appear to be based on arbitrary assumptions. However, the manufacturer continues to recommend these doses.²⁰

Intramuscular Versus Intravenous Administration

Prior to 1976, IM DFO was the preferred route of administration, and IV DFO was reserved for patients in shock. However, when transfusion-induced iron overload was studied and IM and IV DFO administration were compared, IV DFO significantly enhanced urinary iron elimination.⁶⁶ This study provided compelling arguments against IM dosing, as did data showing higher peak and more stable DFO concentrations with IV infusions. A single patient was given 425 mg/kg IV over 24 hours without incident, although the increase in urinary iron excretion seen when the DFO dose increased from 4 to 16 g/day appeared to be of limited consequence.

Duration of Dosing

The optimum duration of DFO administration is unknown. In canine ­models, serum iron concentrations peak within 3 to 5 hours and then decrease quickly as iron is transported out of the blood into the tissues.^79,86 In one human study, initial iron concentrations of approximately 500 µg/dL decreased to approximately 100 µg/dL within 12 hours.⁴⁴ Other case reports also suggest that most of the easily accessible iron is distributed out of the blood compartment by 24 hours.²¹ Although severely poisoned patients have received DFO for more than 24 hours, pulmonary toxicity is associated with prolonged DFO infusions.^31,57,75 Intuitively, in patients with acute iron overdose, DFO should be administered early and for a shorter duration while the iron is easily accessible in the blood. In patients with chronic iron overload, prolonged infusions of smaller DFO doses are necessary to act as a sink and to slowly remove iron from the limited labile pool and tissue stores.³⁵

Patients with severe chronic kidney disease are at high risk for aluminum toxicity.⁸⁸ Acute aluminum toxicity resulting from bladder irrigations with alum for hemorrhagic cystitis is also reported.⁶⁰ Chronic aluminum toxicity is reported from administration of aluminum salts as phosphate binders or from hemodialysis with a water source containing aluminum. DFO binds aluminum to form aluminoxamine, analogous to iron and ferrioxamine. The chelate is a 1:1 octahedral complex with aluminum.⁸⁸ Aluminoxamine is renally excreted. In patients with kidney insufficiency, hemodialysis (especially with a high-flux membrane) is effective in removing the aluminoxamine and should be used to prevent aluminum redistribution to the central nervous system and other tissues.⁵³ The dosing of DFO is unclear but should be tailored to the patient’s serum aluminum concentrations, symptoms, and response.⁵³ Electroencephalography monitoring is recommended. DFO doses of 5 to 15 mg/kg/day, infused over several hours and 6 to 8 hours before a 3 to 4 hour run of high flux hemodialysis, have been successful and maximize aluminoxamine removal without exacerbating adverse events.^53,68 The appropriate duration of this DFO dosing with hemodialysis is unknown and should be based on central nervous system symptoms, serum aluminum concentrations, and kidney function. The correlation of serum aluminum concentrations with toxicity is poorly defined and may depend on the chronicity of aluminum exposure. Patients are treated for days to weeks, with one holiday per week (Chap. 87).

DFO administration to patients with acute iron overdose is associated with rate related hypotension, hypersensitivity reactions and systemic allergic reactions, pulmonary toxicity, and infection. DFO administration to patients with chronic iron overload is associated with auditory, ocular, and pulmonary toxicity and infection.^9,35

Significant hypotension was first noted in 1965 in two children who were administered approximately 80 to 150 mg/kg DFO IV over 15 minutes.⁸⁴ The mechanism for rate-related hypotension is not fully understood, although histamine release is at least partially implicated. Although elevated histamine concentrations were documented in a canine experiment, pretreatment with diphenhydramine was not protective.⁸⁵ Intravascular volume depletion caused by iron toxicity also contributes to hypotension. No experiment has determined the maximum safe rate of DFO administration. Adverse events of DFO, including tachycardia, hypotension, and shock, were reported with rapid infusion.⁸³ These complications resulted in the current recommendations for less rapid IV infusions of DFO not to exceed 15 mg/kg/h.^{83, 84, and 85} Currently suggested IV infusion rates are somewhat empirical because of the lack of robust evidence. Higher rates were administered successfully in critically ill patients when time was of the essence.^11,15,21

Acute respiratory distress syndromes (ARDS) occur in patients with acute iron overdoses who have received IV administration of DFO (15 mg/kg/h) therapy for more than 24 hours.^3,37,75 Usually, iron concentrations are normal in these patients within 24 hours, and the rationale for continued administration of DFO was not reported. Examination of the nontoxicologic literature reveals other instances of ARDS occurring in patients receiving continuous IV DFO for hemosiderosis and malignancies.^13,25,81 Administration of continuous IV doses of DFO for prolonged (>24 hours) periods was common to all of these patients. The mechanism for development of pulmonary toxicity after DFO is unknown. Pulmonary toxicity may result from excessive DFO chelation of intracellular iron and depletion of catalase, resulting in oxidant damage,³⁰ or generation of free radicals.¹

DFO therapy may lead to infection with a number of unusual organisms, including Yersinia enterocolitica, Zygomycetes spp, and Aeromonas hydrophilia. The virulence of these organisms is facilitated when the DFO–iron complex acts as a siderophore for their growth.^45,49,52 Most cases of septicemia occurred when DFO was used for treatment of aluminum toxicity in patients receiving chronic hemodialysis.⁵⁰ Several cases of ­Yersinia sepsis were reported after acute iron overdose and treatment with DFO.^49,52

Ocular toxicity characterized by decreased visual acuity and peripheral visual fields, night blindness, color blindness, and retinal pigmentary abnormalities has occurred in patients who received continuous IV DFO for thalassemia and other nonacute iron and aluminum excess conditions.^{8,12,18,55,58} Ototoxicity documented by abnormal audiograms indicating partial or total deafness is reported.^61,62 However, neither ocular toxicity nor ototoxicity is reported in the setting of acute overdose treatment. When DFO is used in the absence of iron overload, zinc deficiency and decreases in serum ferritin, mean corpuscular volume and hemoglobin may develop.⁴⁰

Infusion pump malfunctions have occasionally led to acute kidney injury (AKI) due to IV DFO overdose. This has been successfully treated with hemodialysis after failure of medical management.¹⁶ One inadvertent overdose of IV DFO in a patient with severe iron overload associated with sickle cell β thalassemia resulted in AKI within 12 to 18 hours of IV DFO administration. The patient received a planned 45 g (700 mg/kg) 96 hour infusion over 8 hours due to incorrect programming of the infusion pump. High efficiency hemodialysis, instituted after an 8 hour trial of intravenous hydration and mannitol were unsuccessful in restoring kidney function.⁶⁴

A review of the literature identified 61 cases of intentional iron overdose in pregnant women.⁷⁶ Serious iron toxicity with organ involvement was associated with spontaneous abortion, preterm delivery, and maternal death. There is no evidence to indicate that DFO is teratogenic.⁷⁶ Neither iron nor DFO appears to cross the ovine placenta.¹⁷ A case report of a pregnant woman with thalassemia and a review of 40 other pregnant patients with thalassemia treated extensively with DFO found no evidence of teratogenicity.⁶⁹ Thus, DFO should be administered to pregnant women with acute iron overdose for the same indications as for nonpregnant women and is listed as FDA pregnancy category C. Excretion in breast milk is not reported.

The indications and dosage schedules for DFO administration are largely empirical.^6,67 Systemic toxicity associated with acute iron poisoning manifested by coma, shock, or metabolic acidosis warrants IV infusion of DFO. The duration of therapy probably should be limited to 24 hours to maximize effectiveness while minimizing the risk of pulmonary toxicity. Some investigators have suggested that more than the recommended dose of 15 mg/kg/h be infused during the first 24 hours for life-threatening iron toxicity, but this recommendation remains to be validated experimentally.³⁵ We recommend starting with 5 mg/kg/h and increasing after 15 minutes if tolerated to 15 mg/kg/h to minimize the risk of hypotension. In adults, after the first 1000 mg is infused, the subsequent doses can be adjusted to infuse the remainder of the 6 to 8 g during the next 23 hours. How exactly this should be done is not clear. Theoretically, an adult patient with significantly elevated serum iron concentrations (>1000 µg/dL) who is severely symptomatic, might do better with continuing at a rate of 15 mg/kg/h if tolerated for the first several hours and then reducing the dose to limit the total 24 hours dose to 6 to 8 g. If after the first 1000 mg the patient improved clinically then consideration might be given to administering the remainder of the 5 g over the next 23 hours. In a 70 kg patient, this would be about 3 to 4 mg/kg/h for the next 23 hours. Dosing in obese patients is unknown; however, because DFO is water soluble, limiting the hourly dose in obese adults to 1000 mg is reasonable. The manufacturer recommends not exceeding 125 mg/h after the first 1000 mg has been infused. Although patients with mild toxicity can be treated with IM injections of 90 mg/kg of DFO (maximum of 1 g in children or 2 g in adults), this volume of antidote cannot be given IM with ease or painlessly in children. Therefore, few clinicians administer IM DFO, with most preferring the IV route (Chap. 46). The total daily parenteral dose is limited by the infusion rate in children (if the manufacturer’s recommendations are followed). Conservative recommendations in adults limit the dose to 6 to 8 g/day, although doses as high as 16 g/day with diverse dosing regimens have been administered without incident.^{15,21,47,57,66,74}

To further define the role of DFO and the quantitative excretion of urinary iron, investigators studied urinary samples.⁵¹ Several reviews of patients with acute iron poisoning who had received DFO^48,87 investigated the correlation between urinary iron concentrations and systemic toxicity. Most data suggest that the absence of a urine color change, often referred to as a vin rose color, after DFO administration indicates very little renal excretion of ferrioxamine.²⁶ However, unless a baseline urine color is obtained before DFO administration, post–DFO administration comparisons of urine color are unreliable. DFO administration may not yield a vin rose color despite severe iron toxicity and/or high serum iron concentrations.⁷⁰ No relationship between urinary iron excretion, clinical iron toxicity, and the effectiveness of DFO has been established.

DFO mesylate (Desferal) is available in vials containing 500 mg or 2 g of sterile, lyophilized powder.²⁰ Adding 5 or 20 mL of sterile water for injection to either the 500 mg or the 2 g vial, respectively, results in an approximately 100 mg/mL solution. The drug must be completely dissolved before using. The resulting solution is isotonic, clear, and colorless to slightly yellowish²⁰ and can be diluted further with 0.9% NaCl solution, glucose in water, or Ringer lactate solution for IV administration. For IM administration, a smaller volume of solution is preferred. Adding 2 or 8 mL of sterile water for injection to the 500 mg or 2 g vial, respectively, results in a stronger yellow-colored solution containing approximately 200 mg/mL.

• DFO is the parenteral chelator of choice for treatment of iron poisoning.

• No controlled studies have evaluated its efficacy or dosing.

• IV is the preferred route of administration.

• Early administration captures iron still in the blood compartment.

• Administration for more than 24 hours after ingestion may predispose to acute respiratory distress syndrome.

• DFO is also used for chelation of aluminum in patients with chronic kidney failure.

References