AHFS Class:

• Heavy Metal Antagonists 64:00

Generic Name(s):

• Deferoxamine Mesylate

Deferoxamine is a heavy metal antagonist that chelates iron118,194 and aluminum.195,196,197

Acute Iron Intoxication

Deferoxamine is used as an adjunct in the treatment of acute iron intoxication;118 the drug is most effective when given early in the treatment of iron poisoning. Deferoxamine is not a substitute for standard measures generally used in iron intoxication including induction of emesis, gastric lavage, whole bowel irrigation, suction and maintenance of airway, correction of acidosis, and control of shock with IV fluids, blood, oxygen, and vasopressors.118,202 Surgical removal of iron tablets (which are visible in abdominal radiographs) may be required if other methods of removing the drug (e.g., gastric lavage, whole bowel irrigation) are unsuccessful.202,204 Many clinicians state that for mild iron intoxication, deferoxamine therapy has little advantage over supportive measures alone;202,204,205 however, when serum iron concentrations exceed 500 mcg/dL and/or patients have severe manifestations of iron intoxication such as metabolic acidosis, repetitive vomiting, lethargy, coma, seizures, hypotension, GI bleeding, or signs of shock, chelation therapy with deferoxamine should be initiated.202,203,204,205

Chronic Iron Overload

Deferoxamine is used to promote iron excretion in patients who have secondary iron overload from the multiple transfusions frequently used in the treatment of thalassemia or other chronic anemias.118,194 Long-term therapy with deferoxamine can slow the accumulation of hepatic iron and retard or eliminate the progression of hepatic fibrosis. Long-term therapy with subcutaneous deferoxamine also can delay and/or prevent the development of cardiac disease induced by iron overload in patients with thalassemia.100,101,128,129,130,132,133,134 Long-term subcutaneous deferoxamine therapy also may improve left ventricular function in asymptomatic patients with thalassemia who have subclinical cardiac dysfunction101,132 and, at least in some patients receiving high dosages of the drug, may improve cardiac function in patients with symptomatic cardiac disease.102 In addition to beneficial effects on the liver and heart, long-term deferoxamine therapy in patients with thalassemia has been shown to improve survival129,133,134,135 and, in the absence of extensive preexisting tissue alterations,134 may prevent and/or delay the development of other abnormalities associated with the disease such as diabetes mellitus.128

Factors influencing cardiac disease-free survival in patients with thalassemia include age at the start of deferoxamine therapy, serum ferritin concentration prior to therapy, mean serum ferritin concentration during treatment, and proportion of ferritin determinations exceeding 2500 ng/mL during treatment; prognosis is excellent for patients who receive adequate regular transfusions and whose serum ferritin concentrations remain below 2500 ng/mL with deferoxamine chelation therapy.129,136 In one study, the estimated 10- and 15-year cardiac disease-free survival rate was 100 and 91%, respectively, if less than 33% of serum ferritin concentrations determined at 1- to 6-month intervals during long-term chelation therapy exceeded this value.129 In this study, the estimated 10- and 15-year rate of such survival was only 38 and 18%, respectively, if more than 67% of serum ferritin determinations exceeded 2500 ng/mL during chelation therapy.129 This study was not designed to determine the optimum serum ferritin concentration required to prevent the development of cardiac disease or other complications of chronic iron overload, and it is possible that maintaining serum concentrations considerably below 2500 ng/mL may be optimal on a long-term basis;129 however, if lower targets are used, the beneficial effects of deferoxamine must be weighed against the toxic effects of the drug in patients with low iron loads.129 Because noncompliance with the prescribed chelation regimen and failure to initiate such therapy prior to the development of irreversible tissue damage are associated with cardiac disease, which is the principal cause of death in this disorder, it is important that deferoxamine therapy be initiated early in the course of thalassemia (i.e., in early childhood) and that compliance be monitored closely.129,130,133 Prepubertal initiation of deferoxamine therapy also can promote attainment of normal sexual maturation.131

Deferoxamine usually should not be used in patients younger than 3 years of age with relatively small degrees of iron overload because iron mobilization by the drug is usually poor in such patients. Deferoxamine should usually be used in such patients only if administration of a test dose of the drug causes the excretion of 1 mg or more of iron daily. To optimize the potential long-term benefits of deferoxamine therapy, some clinicians recommend that such therapy usually be initiated when serum ferritin concentrations reach 1000 ng/mL or a child with thalassemia reaches the age of 3 years old (earlier treatment can result in growth retardation).133

Deferoxamine has been used with some success in the treatment of iron overload secondary to congenital anemias† and in the diagnosis and treatment of primary hemochromatosis†. Although phlebotomy is the treatment of choice for primary hemochromatosis, deferoxamine may be beneficial when phlebotomy is contraindicated.

Aluminum Toxicity

Deferoxamine has been used successfully IV104,105,106,126,148 or intraperitoneally†107,108,109,149 to promote aluminum excretion or removal and provide symptomatic and objective improvement in the treatment of aluminum-associated neurotoxicity (e.g., encephalopathy) and/or bone abnormalities (e.g., osteomalacic osteodystrophy) in patients with chronic renal failure undergoing dialysis†.104,105,106,107,108,109,126,195,196,197,200,201 Humans are exposed to aluminum from a variety of environmental sources, including tap water in municipalities that use aluminum sulfate (alum) as a flocculating agent during purification procedures.126 Most aluminum is excreted in the urine via glomerular filtration; while aluminum is poorly absorbed from the GI tract, absorption is sufficient to result in aluminum accumulation in individuals with renal insufficiency.126,141 Therefore, individuals with impaired renal function are predisposed to developing aluminum toxicity when exposed to increased concentrations of the metal.126 While healthy adults with normal renal function generally can maintain low tissue concentrations despite chronic exposure to increased amounts of aluminum (e.g., chronic consumption of large amounts of aluminum-containing antacids), elevated plasma aluminum concentrations can develop in healthy infants given aluminum-containing antacids.126 Total body aluminum can increase markedly in adults or children with chronic renal failure receiving aluminum-containing antacids or phosphate binders.126 In addition, preparation of dialysate solutions with water that contains high concentrations of aluminum can result in aluminum toxicity in patients with chronic renal failure.126 Aluminum toxicity also has been associated with administration of parenteral products (e.g., casein hydrolysate [no longer used in formulations in the US] in amino acid solutions) and certain blood products (e.g., albumin human) that contained the metal as a contaminant or excipient.126,137,138,139,140,150,151

Recognition of the association between the development of encephalopathy and osteodystrophy in patients with chronic renal failure and accumulation of aluminum as well as the association between aluminum toxicity and exposure to the metal through various sources (e.g., infant formulas, tap water, parenteral and blood products) has resulted in efforts directed at limiting exposure to the metal such as avoiding aluminum-containing antacids and phosphate binders in individuals with renal insufficiency, attention to the aluminum concentration in water, and minimizing the aluminum content in dialysis solutions, infant formulas, parenteral solutions, and blood products.126,137,138,139,140,141 The US Food and Drug Administration (FDA) has proposed that the aluminum content of large volume parenteral solutions be limited to 25 mcg/L and that the content be stated on the label for small volume parenterals and pharmacy bulk packages intended for use in the preparation of, or additive to, total parenteral nutrition (TPN) solutions.139 While such efforts at preventing aluminum toxicity should reduce the need for its treatment, deferoxamine can effectively ameliorate or reverse the manifestations of this toxicity (e.g., neurologic and bone effects) when administered IV or intraperitoneally and is considered the chelating agent of choice.104,105,106,107,108,109,126,138,150,151 Deferoxamine also may improve anemia in patients with chronic renal failure receiving the chelating agent for aluminum toxicity, and may potentiate the activity of epoetin alfa.142,143,144,145,146,147

Deferoxamine also has been used IV to promote mobilization of aluminum from tissue stores as an aid in the diagnosis of aluminum-associated osteodystrophy†.119,127,195,196,200,201

For further information on diagnostic and therapeutic use of deferoxamine in patients with chronic kidney disease, see Aluminum Toxicity under Dosage and Administration: Dosage.

Other Uses

Because of epidemiologic evidence of an association between aluminum consumption (e.g., concentrations of the metal in drinking water) and degenerative dementia of the Alzheimer's type (Alzheimer's disease, presenile or senile dementia),142,152,153,154,155,156 deferoxamine has been studied for potential beneficial effects in patients with this condition†.142,153,154,155 While some evidence suggests that long-term deferoxamine therapy may decrease the rate of functional decline (e.g., loss of ability to perform basic living tasks) in this dementia,142,152,153,154,155,156 the drug currently cannot be recommended for this use since existing support for such therapy is weak and long-term chelation therapy may be associated with potentially serious adverse effects.142,153 Pending further elucidation of the possible association between aluminum exposure and Alzheimer's disease, some experts have recommended that acceptable levels of aluminum in drinking water be reduced to 50 mcg/L in the short term, with a long-term goal of reducing them to 10 mcg/L, both of which are substantially lower than existing guidelines.152,158

Reconstitution and Administration

Deferoxamine mesylate may be administered by IM injection, by slow IV infusion, or by subcutaneous infusion via a portable controlled-infusion device.118 For the treatment of acute iron intoxication, the manufacturer states that IM administration is preferred and should be used for all patients who are not in shock.118 The manufacturer recommends slow IV infusion of the drug only in patients with cardiovascular failure or shock, and states that IM administration should replace IV infusions of the drug as soon as the clinical condition of the patient permits.118 However, most experts recommend IV infusion for acute iron intoxication requiring deferoxamine therapy.202,203,204,205 Rapid IV injection may result in flushing of the skin, generalized erythema, urticaria, hypotension, and shock.118 The maximum safe rate of administration has not been scientifically established.159,203 Subcutaneous infusion is not recommended for the treatment of acute iron intoxication. In the management of chronic iron overload, deferoxamine mesylate may be administered by slow subcutaneous infusion via a small, portable controlled-infusion device118 or by IM injection;118 subcutaneous infusion is reported to be the more effective method of administration of the drug in this condition (e.g., in patients with thalassemia). For the treatment of aluminum toxicity†, deferoxamine generally is administered by slow IV infusion,126,195,196,200,201 but the drug also has been administered by IM injection or intraperitoneally†.107,108,109,149,200,201

For IV administration, deferoxamine mesylate sterile powder is reconstituted by adding 5 mL of sterile water for injection to a vial labeled as containing 500 mg of the drug or 20 mL of sterile water for injection to a vial labeled as containing 2 g of the drug to provide a solution containing 95 mg/mL.118 The reconstituted solution should be further diluted prior to IV infusion.118 For IM administration, deferoxamine mesylate sterile powder is reconstituted by adding 2 mL of sterile water for injection to a vial labeled as containing 500 mg of deferoxamine mesylate or 8 mL of sterile water for injection to a vial labeled as containing 2 g of the drug to provide a solution containing 210 or 213 mg/mL, respectively.118 For subcutaneous administration, deferoxamine mesylate sterile powder is reconstituted by adding 5 mL of sterile water for injection to a vial labeled as containing 500 mg of deferoxamine mesylate or 20 mL of sterile water for injection to a vial labeled as containing 2 g of the drug to provide a solution containing 95 mg/mL.118 For IM or subcutaneous administration, the reconstituted solution may be administered undiluted. Reconstituted solutions of the drug are for single use only, and any unused portions should be discarded.118

For IV infusion, the required amount of reconstituted solution is added to 0.9% sodium chloride, 0.45% sodium chloride, dextrose, or lactated Ringer's injection and administered at a rate not exceeding 15 mg/kg per hour for the first 1000 mg.118,159,167,169,176 Subsequently, the rate of administration of IV deferoxamine mesylate should not exceed 125 mg/hour.118 For subcutaneous infusion, the rate of infusion must be individualized but ranges from 20-40 mg/kg per 8-24 hours;118 when an 8- to 12-hour subcutaneous infusion is used, it generally is most convenient to administer the drug overnight. In some patients, iron excretion will be as high following an 8- to 12-hour infusion as it is when the same dose is administered over a 24-hour period.118

Dosage

Acute Iron Intoxication

The optimal dosage and duration of deferoxamine therapy for the treatment of acute iron intoxication have not been established.202,203,204,205 In severe iron intoxication, consultation with poison control experts is recommended.204,205 The usual IM or IV dose of deferoxamine mesylate recommended by the manufacturer for the treatment of acute iron intoxication in adults and children is 1 g followed by 500 mg at 4-hour intervals for 2 doses.118 Depending on the clinical response of the patient, subsequent doses of 500 mg may be administered every 4-12 hours.118 Alternatively, children may be given an initial dose of 20 mg/kg or 600 mg/m² IM or by slow IV infusion, followed by 10 mg/kg or 300 mg/m² at 4-hour intervals for 2 doses. Subsequent doses of 10 mg/kg or 300 mg/m² may be administered every 4-12 hours if needed. The manufacturer states that dosages of deferoxamine mesylate exceeding6 g should not be given to adults or children in a 24-hour period.118 However, some experts suggest that larger dosages may be required in severe intoxications.202,203,204

Chronic Iron Overload

When deferoxamine mesylate is used in the management of chronic iron overload resulting from multiple transfusions, the usual IM dosage for adults and children is 0.5-1 g daily.118 In addition, 2 g of the drug should be administered by slow IV infusion with, but separate from, each unit of blood transfused.118 The total daily dose should not exceed 1 g in the absence of transfusion, or 6 g with transfusion (even if 3 or more units of blood or packed red blood cells have been transfused).118 When deferoxamine mesylate is administered by subcutaneous infusion in the management of chronic iron overload, the usual dosage for adults and children is 1-2 g (20-40 mg/kg) daily.118 The duration of infusion must be individualized. (See Dosage and Administration: Reconstitution and Administration.)118

When deferoxamine has been administered in the management of various iron storage diseases†, the dose and frequency of administration have usually been individualized depending on the severity of the disease and the rate of urinary iron excretion. Patients with various iron storage diseases (including primary hemochromatosis) have received 1-4 g of deferoxamine mesylate daily, administered by subcutaneous infusion. When deferoxamine mesylate was used in the diagnosis of primary hemochromatosis†, 0.5-1 g or 10 mg/kg was administered IM and 24-hour urinary excretion of iron was determined. Patients with primary hemochromatosis excreted more than 10 mg of iron in urine in 24 hours.

Aluminum Toxicity

For diagnosis of aluminum toxicity in adults and children with chronic kidney disease†, the test dose of deferoxamine mesylate is 5 mg/kg administered by slow IV infusion during the last hour of a dialysis session.200,201 The test dose is recommended for use in patients with clinical signs and symptoms of aluminum toxicity, those with serum aluminum concentrations of 60-200 mcg/L, or prior to parathyroidectomy in children with aluminum exposure for 4 months or longer and in adults who have had aluminum exposure.200,201 The test is considered positive for aluminum toxicity if the increase in serum aluminum above baseline is 50 mcg/L or greater 2 days later at the start of the next dialysis session.200,201 If the baseline serum aluminum concentration exceeds 200 mcg/L, appropriate measures (including discontinuance of all aluminum intake and performance of dialysis 6 days per week) should be instituted to reduce the aluminum concentration to less than 200 mcg/L and thereby decrease the risk of acute aluminum-associated neurotoxicity prior to administering the deferoxamine test dose.200,201

Use of deferoxamine for the treatment of aluminum toxicity in patients with chronic kidney disease† is recommended in symptomatic adults and children with serum aluminum concentrations greater than 60 but less than 200 mcg/L and those with an increase in serum aluminum concentration of 50 mcg/L or greater following the deferoxamine test dose.200,201 To avoid deferoxamine-induced neurotoxicity in patients with serum aluminum concentrations exceeding 200 mcg/L, initiation of deferoxamine therapy should be delayed until the predialysis serum aluminum concentration is reduced to less than 200 mcg/L (e.g., by intensive dialysis [6 days per week with high-flux membrane; dialysate aluminum concentration less than 5 mcg/L], elimination of other sources of aluminum intake).200,201

Deferoxamine treatment is considered optional in asymptomatic children receiving maintenance hemodialysis and having serum aluminum concentrations of 60-200 mcg/L, unless the desired serum aluminum concentration is not achieved with discontinuance of aluminum-containing gels and intensive dialysis.201

Treatment recommendations for adults and children are based on results of the deferoxamine diagnostic testing (see table).

Adverse Effects

Data regarding frequency of adverse events in patients receiving deferoxamine are lacking.118 Deferoxamine is relatively nontoxic when administered as recommended in acute iron intoxication. Pain, irritation, burning, swelling, and induration at the site of injection may occur.118 Following rapid IV injection, flushing of the skin, generalized erythema, urticaria, hypotension, and shock may occur; these reactions may be manifestations of a histamine-liberating property of the drug. Deferoxamine should be administered IM or by slow subcutaneous or IV infusion to avoid these reactions.

Adverse effects reported in patients receiving long-term deferoxamine therapy for chronic iron storage disease include allergic-type reactions, such as cutaneous wheal formation, pruritus, rash, and anaphylactoid reactions. Successful desensitization in a few patients who experienced anaphylactoid reactions has been reported.110,111,112 Adverse ocular and otic effects, abdominal discomfort, diarrhea, nausea, vomiting, leg cramps, tachycardia, and fever also may occur. Adverse effects reported in patients receiving subcutaneous deferoxamine therapy include localized pain, pruritus, erythema, skin irritation, and swelling.

Adverse neurologic effects reported in patients receiving deferoxamine include dizziness, paresthesia, and peripheral sensory, motor, and mixed neuropathy; precipitation of aluminum-related dialysis encephalopathy also can occur.118 Dysuria and impaired renal function have been reported in patients receiving the drug.118 Although a causal relationship to the drug has not been established, blood dyscrasias, including thrombocytopenia and/or leukopenia, have been reported in patients receiving deferoxamine.118

Although a causal relationship to the drug was not established, myasthenia gravis characterized by diplopia and ophthalmic muscle weakness, a positive edrophonium test, and the presence of serum anti-acetylcholine receptor antibodies developed 2 years after initiating iron chelation therapy with deferoxamine in a 33-year-old man.187 Because of continued need for chelation therapy to treat iron overload associated with sideroblastic anemia, deferoxamine therapy was continued and pyridostigmine was initiated; subsequently, manifestations of myasthenia gravis were mild.187 It was postulated that deferoxamine and penicillamine may share a common mechanism of inducing myasthenia gravis that is related to chelation.187

Ocular and Otic Effects

Cataracts have occurred in a few patients who received prolonged deferoxamine therapy for chronic iron storage disease.118 Serious, usually acute, ocular112,113,114,115,116,118,119,120,133,154,155,156,158,159,160,161,163 and/or otic116,117,118,120,133,159,160,162 toxicity has occurred in patients receiving IV or subcutaneous deferoxamine therapy for chronic iron overload, almost exclusively at dosages exceeding 50 mg/kg daily,112,113,116,133,160 or in patients with low ferritin levels118,133,159,160 or chronic renal disease.119,120 Ocular toxicity also has been associated with low-dose deferoxamine therapy in patients with rheumatoid arthritis or chronic renal failure,159,160 and occasionally has occurred in patients with chronic renal failure after a single IV aluminum mobilization test dose (e.g., 40 mg/kg [smaller test doses of 5 mg/kg currently are recommended195,196,200,201 ]) of deferoxamine.119,159

Adverse ocular effects of deferoxamine have included decreased visual acuity (e.g., blurred vision, visual loss),112,116,118,119,120,133 visual field defects (e.g., scotoma, loss of central or peripheral vision),112,114,115,116,118,133,160 night blindness (defective dark adaptation),112,114,115,118,120,133,161 impairment or loss of color vision,112,114,115,116,118,119,120,160 delayed visual evoked potentials,114,115,116,160 decreased electroretinographic amplitudes,161 corneal opacities,118 optic neuropathy,115,116,118,133 optic atrophy (with thinning of the nerve-fiber layer and asymmetric pallor and translucent swelling of the optic disk),160 eccentric fixation,160 and retinal pigmentation changes.112,115,116,118,133,160 Visual disturbances usually partially or completely resolve following discontinuance of the drug, but adverse ocular signs may persist.112,113,114,115,116,120,133,159 Deferoxamine therapy usually can be resumed if necessary at a reduced dosage, with close electroretinographic monitoring.133 Risk factors for the development of acute ocular toxicity appear to be high dosages and/or continuous IV infusion of the drug and low iron stores.118,159,160,161 It has been suggested that patients with diabetes mellitus or other factors affecting the blood-retinal barrier may be at increased risk of deferoxamine-induced ocular toxicity, and more careful monitoring of these patients has been recommended.133,163 Although the mechanism of this ocular toxicity remains to be elucidated, it has been suggested that alterations in the blood-retinal barrier allow intraocular access of deferoxamine with resultant toxicity.159 It also has been suggested that deferoxamine-induced mobilization of copper (translocation) may result in oxidative damage within neural tissue, including the retina,160 and depletion in zinc, copper, and/or iron (affecting critical iron-dependent enzyme systems) also has been suggested as a possible mechanism.160,161

Adverse otic effects of deferoxamine have included tinnitus;118 audiogram abnormalities, with or without clinical hearing loss; and occasionally deafness.116,117,118,120,133,159,160,162 Audiogram abnormalities generally are characterized by high-frequency sensorineural hearing loss, but losses may also occur at lower frequencies.116,117,118,160,162 Hearing loss may partially or completely resolve following discontinuance of deferoxamine,116,117 but may also persist and in some cases a hearing aid may be necessary.116,159 Risk factors for the development of ototoxicity appear to be dose, duration of therapy, and low iron stores.159,162,164 Patients should be monitored regularly for body iron burden and hemoglobin, as well as with otolaryngologic and audiometric examinations.118,162 (See Cautions: Precautions and Contraindications.) It has been suggested that maintaining a therapeutic index below 0.025 may reduce the risk of ototoxicity.133,160,164 The therapeutic index is determined by dividing the mean daily dosage of deferoxamine in mg/kg by the serum ferritin concentration in mcg/L.133,164

Susceptibility to Infection

Iron overload increases the susceptibility of patients to infection with Yersinia enterocolitica and Y. pseudotuberculosis. Rarely, deferoxamine therapy has enhanced the susceptibility to such infection by providing the bacteria with a siderophore otherwise missing; generalized Y. enterocolitica or Y. pseudotuberculosis infections have resulted. The possibility of Y. enterocolitica or Y. pseudotuberculosis infection should be reasonably excluded by appropriate stool samples, blood testing, and/or serologic testing and the drug withheld in patients who develop unexplained diarrhea, abdominal pain, and/or fever during deferoxamine therapy.133 If Y. enterocolitica or Y. pseudotuberculosis infection is confirmed or strongly suspected during deferoxamine therapy, the drug should be discontinued until the infection resolves118 and anti-infective therapy should be initiated as appropriate. Fungal infections (e.g., mucormycosis, including infections caused by Rhizopus ) have been reported rarely in patients receiving deferoxamine, and occasionally the infections were fatal.118,200,201 The mechanism of enhanced susceptibility to certain fungal infections during deferoxamine therapy is not known but may involve siderophores. If signs or symptoms suggestive of mucormycosis occur during deferoxamine therapy, the drug should be discontinued, mycologic tests performed, and appropriate anti-infective therapy initiated as appropriate.118

Respiratory Effects

An adult respiratory distress syndrome (ARDS)-like condition with dyspnea, cyanosis, and/or interstitial infiltrates, which can be fatal, has occurred in pediatric and adult patients receiving deferoxamine.118,133,159,165,170,171,172,173 The ARDS-like condition described in association with deferoxamine therapy meets the clinical, physiologic, radiographic, and/or necropsy criteria used to define the syndrome.133,159,165,170,171,172,173 Although some clinicians have postulated that rather than being associated with excessive deferoxamine dosages, this pulmonary toxicity may result instead from prolonged inadequate dosages of the drug,166 most clinicians consider high dosages (including total daily and cumulative doses) and prolonged (more than 24 hours) continuous IV infusion to be risk factors for the development of this toxicity.118,133,159,165,167,173,202,203 Low serum ferritin concentrations also have been suggested as a risk factor.159,173 In one series of case reports, the risk of ARDS appeared to be increased with IV deferoxamine dosages exceeding 15 mg/kg per hour for periods exceeding 24 hours.133,165 Other clinicians have suggested that the increased risk becomes prominent as the duration of such dosages exceeds 48 hours.168 The manufacturer suggests that the risk of pulmonary toxicity may increase with daily doses exceeding 6 g and/or when the initial maximum infusion rate of 15 mg/kg per hour is not reduced as soon as the clinical condition permits.167 Although the mechanism of this pulmonary toxicity remains to be elucidated, it has been suggested that deferoxamine-induced intracellular iron chelation may acutely decrease the synthesis of catalase and heme, and that pulmonary morbidity may result from the catalase decrease, intracellular heme entry, scission, iron release, and catalysis of oxidative degeneration of cells.159,171 A hypersensitivity reaction as the mechanism is unlikely.159

Hypotension

Hypotension is the most alarming acute adverse effect of deferoxamine therapy.160 Hypotension, with associated tachycardia, has occurred following rapid IV administration of relatively large dosages of deferoxamine (e.g., 800-1500 mg over 15 minutes in children).118,159,160,174,177 Blood pressure usually returns to normal within 1 hour after discontinuance of the infusion.160 In animals, administration of the drug at a rate of 3-30 mg/kg per minute resulted in hypotension and increased plasma histamine concentrations; however, pretreatment with diphenhydramine did not prevent the development of hypotension.159,160,175

Although the risk of hypotension is thought to be related to the rate of deferoxamine administration and probably the release of histamine,159,175 a maximum safe rate of administration has not been scientifically established.159 Instead, an empiric maximum rate of 15 mg/kg per hour has been recommended for the first 1 g administered.118,159,167,169,176 Subsequently, the rate of administration of IV deferoxamine should not exceed 125 mg/hour.118 If hypotension occurs during deferoxamine infusion, the drug generally should be discontinued and the infusion reinitiated at a slower rate once blood pressure recovers; however, caution should be exercised in attributing the decrease in blood pressure to the drug in acute iron intoxication, especially when therapy with the drug is considered urgent.160

Effects on Bone Development and Growth

The use of deferoxamine in children with thalassemia usually improves growth (e.g., height) by decreasing iron overload.131,133 However, if excessive dosage is given or therapy is initiated prior to accumulation of a clinically important iron load (e.g., commencing therapy at younger than 3 years of age), growth retardation can occur.118,133,178,179,183,185 Delaying the initiation of deferoxamine therapy too long also has been associated with an increased risk of growth retardation secondary to the thalassemia.180,181 The strongest prognostic factor for growth retardation identified to date has been an inverse relationship between height (e.g., sitting height) and serum ferritin concentrations (i.e., lower levels of transfusion iron overload).133,178,180,181,183 Short stature associated with deferoxamine therapy appears to be mainly due to a disproportion between upper and lower segments.179 A progressive decline in growth velocity usually can be detected 2-3 years before the appearance of rickets-like radiologic lesions, which can be severe.179 A variety of bone and growth abnormalities has been observed,133,178,179,180,181,182,183,184,185,186 including marked abnormalities in the metaphyseal growth plate in the distal ulnar, radial, and tibial metaphyses,118,183,185 changes in long bones similar to rickets and scurvy,133,184 and vertebral abnormalities.133,181,182,185

The growth and body weight of children receiving long-term deferoxamine therapy should be monitored regularly (i.e., every 3 months) and documented on appropriate charts to detect early changes in their growth pattern and to establish an appropriate plan for further investigation and treatment.118,133,181 The assessment may be complicated by the adverse effects on growth of both inadequately treated thalassemia and excessive deferoxamine therapy.181,182 However, some evidence suggests that spinal changes (decreased spinal height, increased thoracic kyphosis, vertebral flattening and elongation anteriorly, disk calcification) induced by excessive deferoxamine therapy differ morphologically and pathogenetically from vertebral deformities associated with inadequately treated thalassemia.182 Growth velocity may partially resume to pretreatment rates following a reduction in deferoxamine dosage.118,133,186

Cardiovascular Effects

Impairment of cardiovascular function has occurred in patients with severe chronic iron overload receiving deferoxamine and high dosages of ascorbic acid (greater than 500 mg daily in adults).118 The cardiac dysfunction was reversible following discontinuance of ascorbic acid.118 (See Drug Interactions: Ascorbic Acid.)

Precautions and Contraindications

The risk for development of ocular118,159,160,161 and otic toxicities159,162,164 associated with deferoxamine increases with high dosages, prolonged therapy, and/or low iron stores. Since cataracts have occurred rarely in patients receiving long-term deferoxamine therapy, the possibility of this effect occurring in patients receiving short-term therapy should be considered. Slit-lamp examinations should be performed periodically in patients treated for chronic iron overload. Because of the ocular and otic toxicities of deferoxamine, visual acuity tests, funduscopic examinations, and audiometry should be performed periodically in patients receiving prolonged deferoxamine therapy.118,162 To minimize the risk of irreversible toxicity, early detection of abnormalities is important.118 Some clinicians recommend that complete ophthalmologic examinations, studies of visual evoked potentials, and audiometry be performed every 3 months in patients treated for chronic iron overload, particularly when dosages greater than 50 mg/kg daily are employed.116 Immediate discontinuance of deferoxamine generally results in reversal of ocular and otic effects.118 If ocular and/or otic toxicities develop during deferoxamine therapy, dosage should be markedly reduced or the drug temporarily discontinued.116 Ocular and otic effects may partially or completely resolve following discontinuance of the drug.116,117 However, in some cases, ocular and otic effects may persist.112,113,114,115,116,120,133,159

The potential risk of Yersinia enterocolitica or Y. pseudotuberculosis infection during deferoxamine therapy should be considered.118 (See Cautions: Adverse Effects.)

The potential risk of adult respiratory distress syndrome (ARDS) during deferoxamine therapy, particularly at high dosages, should be considered.118,133,159,165,170,171,172,173 (See Respiratory Effects under Cautions: Adverse Effects.)

The possibility of growth retardation during chronic deferoxamine therapy in pediatric patients should be considered.118,133,178,179,180,181,182,183,184,185,186 (See Effects on Bone Development and Growth under Cautions: Adverse Effects.)

Because impaired cardiovascular function has occurred in patients with severe chronic iron overload receiving deferoxamine and high dosages of ascorbic acid (greater than 500 mg daily in adults), ascorbic acid supplements should not be administered to deferoxamine-treated patients with cardiac failure.118 Ascorbic acid supplements should be initiated only after the initial month of regular deferoxamine therapy and only in patients receiving regular deferoxamine therapy.118 Ascorbic acid generally is given in divided doses; dosage in adults should not exceed 200 mg daily.118 Clinical monitoring of cardiac function is advised in patients receiving deferoxamine and ascorbic acid.118 (See Drug Interactions: Ascorbic Acid.)

High dosages of deferoxamine may exacerbate neurologic dysfunction (i.e., cause seizures) in patients with aluminum-related encephalopathy, probably due to an acute increase in circulating aluminum.118 The risk of acute, potentially fatal neurotoxicity increases in those with serum aluminum concentrations greater than 200 mcg/L; initiation of deferoxamine therapy should be delayed until predialysis serum aluminum concentrations are reduced to less than 200 mcg/L by other means.200,201 In addition, deferoxamine may precipitate the onset of dialysis dementia.118 Pretreatment with deferoxamine in the presence of aluminum overload may result in decreased serum calcium concentrations and aggravate hyperparathyroidism.118

Patients should be warned of the possibility of nervous system effects (e.g., dizziness) or impairment of vision or hearing and should be advised to avoid driving or operating machinery if such effects occur.118 Patients also should be advised that deferoxamine may cause a reddish discoloration of urine.118

Deferoxamine is contraindicated in patients with severe renal disease or anuria because deferoxamine and ferrioxamine are excreted principally by the kidneys.118 However, the drug may be used for diagnosis119,127,195,196,200,201 or treatment of aluminum toxicity in patients with chronic renal failure undergoing dialysis†.104,105,106,107,108,109,126,195,196,197,200,201 When used for treatment of aluminum toxicity, deferoxamine should be administered in a manner that maximizes removal of chelated aluminum and iron (e.g., 3 or 4 dialysis sessions scheduled between doses, appropriate intervals between drug administration and the next dialysis session, use of highly permeable dialyzer membrane).200,201

Urinary excretion of parenterally administered iron has been reported to exacerbate latent pyelonephritis; this may also occur with deferoxamine therapy. The drug, therefore, should be used with caution in patients with pyelonephritis.

Pediatric Precautions

Safety and efficacy of deferoxamine in pediatric patients younger than 3 years of age have not been established.118 Iron mobilization with deferoxamine is relatively poor in children younger than 3 years of age with relatively little iron overload.118 Therefore, the drug should generally not be used in such patients unless mobilization of 1 mg or more of iron can be demonstrated.118 The risk of adverse effects of deferoxamine on bone development and growth should be considered in children receiving long-term therapy (e.g., those with thalassemia).118,133,178,179,180,181,182,183,184,185,186 Growth and body weight of children receiving long-term deferoxamine therapy should be monitored every 3 months.118,133,181 Growth measurements should be documented in these children to detect early changes in growth patterns and establish appropriate plans for further treatment.118,133,181 (See Effects on Bone Development and Growth under Cautions: Adverse Effects.)

Geriatric Precautions

Clinical studies of deferoxamine did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.118 Postmarketing experience suggests a possible increased risk of ocular disorders (e.g., color blindness, maculopathy, scotoma) and ototoxicity (e.g., deafness, hearing loss) in geriatric patients;118 it remains to be determined whether the ocular disorders reported were dose related.118 Drug dosage should be selected with caution in geriatric patients, usually initiating therapy at the low end of the dosage range.118 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.118

Carcinogenicity

Long-term carcinogenicity studies in animals have not been performed with deferoxamine.118 Because the drug has been shown to inhibit DNA synthesis in vitro, cytotoxicity may occur.118

Pregnancy and Lactation

Pregnancy

In teratogenicity studies, deferoxamine mesylate appeared to cause delayed ossification and skeletal anomalies in 2 animal species at dosages up to 4.5 times the maximum dosage recommended for humans.118 For this reason, the drug should not be administered to pregnant women (especially during early pregnancy) or women who may become pregnant unless the potential benefits outweigh the possible risks to the fetus.118

Lactation

It is not known whether deferoxamine is distributed into milk.118 Because many drugs are distributed into milk, caution should be exercised when deferoxamine is used in nursing women.118

Ascorbic Acid

Patients with iron overload usually become ascorbic acid deficient, most likely because iron oxidizes the vitamin.118 Ascorbic acid is given as an adjunct to deferoxamine therapy in patients with iron overload; ascorbic acid increases availability of iron for chelation.118 Ascorbic acid in dosages up to 200 mg daily in divided doses in adults may be initiated after the initial month of regular deferoxamine therapy.118 A dosage of 50 mg daily has been suggested for children younger than 10 years of age, and a dosage of 100 mg daily has been suggested for children 10 years of age and older.118

Because impaired cardiovascular function has occurred in patients with severe chronic iron overload receiving deferoxamine and high dosages of ascorbic acid (greater than 500 mg daily in adults), ascorbic acid supplements should not be administered to deferoxamine-treated patients with cardiac failure.118 Clinical monitoring of cardiac function is advised in patients receiving deferoxamine and ascorbic acid.118 Cardiovascular dysfunction is reversible following discontinuance of ascorbic acid therapy.118

Other Drugs

Temporary loss of consciousness has been reported in patients receiving deferoxamine concomitantly with prochlorperazine.118,188 EEG showed abnormalities that are usually associated with metabolic disturbances.188 In one patient, pyramidal features and subsequent optic neuropathy and pigmentary retinopathy were observed.188 Analysis of CSF indicated a decrease in loosely-bound (catalytic) iron and an increase in loosely-bound (catalytic) copper, total iron, and products of lipid peroxidation; such values approached normal levels as symptoms resolved.188 In vivo and in vitro studies indicate that concomitant use of deferoxamine and prochlorperazine may synergistically increase adverse neurologic effects of the drugs, probably associated with abnormal fluxes of intracellular and/or extracellular iron and/or copper that may have deleterious effects on noradrenergic and serotonergic systems.188

Laboratory Test Interferences

In patients undergoing gallium scintigraphy, imaging results may be distorted because of rapid urinary excretion of deferoxamine-bound gallium.118,189,190,191 Therefore, the manufacturer recommends that deferoxamine be discontinued 48 hours prior to such procedures.118

Pharmacology

Deferoxamine chelates iron by binding ferric ions to the 3 hydroxamic groups of the molecule.118 Ferrioxamine, the resulting octahedral iron complex, is formed in many tissues, but mainly in plasma; this complex prevents iron from entering into further chemical reactions and is stable, water soluble, and readily excreted by the kidneys.118 Deferoxamine is a hexadentate ligand with high binding affinity for iron in a 1:1 ratio.198 Theoretically, 1 g of deferoxamine mesylate is capable of sequestering 85 mg of iron (as the ferric ion);118 however, the rate of complex formation seems to be pH dependent and is most rapid at acid pH. Increased excretion of electrolytes and other trace metals has not been demonstrated in patients receiving deferoxamine. The main effect is probably on loosely bound stored iron; in vitro studies have shown that deferoxamine removes iron from ferritin, hemosiderin, and, to a lesser extent, transferrin, but not from cytochromes or hemoglobin. However, decreases in plasma iron concentration, which may have been caused by a shift of the iron from blood to tissues, have been observed both in control patients with iron intoxication and in deferoxamine-treated patients. Limited evidence indicates that concomitant administration of deferoxamine and ascorbic acid increases iron excretion more than deferoxamine alone.

Deferoxamine also chelates aluminum104,105,106,107,108,109 and increases its excretion by the kidneys106 and/or removal by dialysis.104,105,106,107,108,109

Pharmacokinetics

Absorption

Deferoxamine is poorly absorbed from the GI tract in the presence of intact mucosa; however, absorption of the drug may occur in patients with acute iron intoxication.

Distribution

Animal studies have shown that deferoxamine is widely distributed in body tissues and fluids following parenteral administration.

Elimination

Deferoxamine is metabolized principally by plasma enzymes, but the exact pathways remain to be determined.118

The elimination half-life of deferoxamine reportedly is 20 minutes.198,199

Deferoxamine is excreted principally in urine as unchanged drug and ferrioxamine; ferrioxamine gives urine a characteristic reddish color which is indicative of elevated iron concentrations in urine.118 Ferrioxamine is also excreted in feces via bile.118 The amount of iron excreted as ferrioxamine varies considerably from patient to patient. Iron excretion tends to be maximal at the beginning of treatment, suggesting that only the more accessible metal is chelated. Unlike iron, deferoxamine and ferrioxamine can be removed by hemodialysis.118,195 Deferoxamine-iron and deferoxamine-aluminum chelates are also removed by dialysis.195,200,201

Chemistry and Stability

Chemistry

Deferoxamine is a siderochrome produced as the ferric complex by Streptomyces pilosus. The iron is chemically removed and the metal-free ligand is purified for use as the mesylate salt. Deferoxamine mesylate occurs as a white to off-white powder and is freely soluble in water and soluble in alcohol.

Stability

Vials of lyophilized deferoxamine mesylate powder should be stored at temperatures of 25°C or less.118 Reconstituted solutions of deferoxamine mesylate are chemically and physically stable for 1 week at room temperature. However, the manufacturer recommends that reconstituted deferoxamine solutions be used immediately (within 3 hours) for microbiologic safety.118 When solutions are reconstituted under aseptic conditions, deferoxamine solutions may be stored at room temperature for up to 24 hours before use; the solutions should not be refrigerated.118 Turbid solutions of the drug should not be used.118

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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