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DEFEROXAMINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Deferoxamine is a chelating agent which effectively chelates iron and aluminum. It also has antioxidant effects and may interfere with tumor growth and protazoal survival by limiting iron availability.

Specific Substances

    1) N-Benzoylferrioxamine B
    2) deferoxamine
    3) deferoxaminum
    4) deferrioxamine
    5) Desferal(R)
    6) Desferral
    7) Desferrin
    8) Desferrioxamine
    9) Desferrioxamine B
    10) Df B
    11) DFO
    12) DFOA
    13) DFOM
    14) Ferrioxamine B, N-benzoyl
    15) CAS 70-51-9 (defroxamine)
    16) References: RTECS, 1983
    17) Deferoxamine mesilate (related compound)
    18) Deferoxamine mesylate (related compound)
    19) Deferoxamine methanesulfonate (related compound)
    20) Desferrioxamine B mesylate (related compound)
    21) Desferrioxamine B Methanesulfonate (related compound)
    22) Desferrioxamine methanesulfonate (related compound)
    23) CAS 138-14-7 (deferoxamine mesylate related compound)
    24) DFM

Available Forms Sources

    A) FORMS
    1) Deferoxamine is available as 500 mg/vial and 2 g/vial in powder form to be reconstituted with sterile water for injection (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).
    B) USES
    1) IRON: Deferoxamine is a chelating agent used in the treatment of acute iron poisoning and in chronic iron overload conditions (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012; Kanz et al, 1986; Peck et al, 1983; Westlin, 1966).
    2) ALUMINUM: It has also been used to chelate aluminum in cases of dialysis encephalopathy, dialysis osteomalacia, and aluminum toxicity in renal failure patients (Ackrill et al, 1980; Payton et al, 1984; Brown, 1982).
    3) PORPHYRIA: Deferoxamine has shown some beneficial effects in the treatment of acute intermittent porphyria (Taxay, 1972), and has also been administered to rheumatoid arthritis patients because of a possible anti-inflammatory effect (Blake et al, 1985).
    4) CORNEAL RUST RINGS: Topical ocular administration may be useful in the treatment of corneal rust rings (Valvo, 1967; North, 1970).
    5) MALARIA: Deferoxamine is cytocidal and cytostatic for P. falciparum in vitro. It was shown to increase parasite clearance and reduce the duration of coma in children with cerebral malaria (Voest et al, 1994).
    a) Deferoxamine increased the clearance of P. falciparum almost 10 fold in adults with asymptomatic P. falciparum parisitemia (Gordeuk et al, 1992).
    6) RHEUMATOID ARTHRITIS: Deferoxamine reduced inflammation in a rat model and decreased the acute phase response in patients with rheumatoid arthritis (Voest et al, 1994).
    7) CANCER CHEMOTHERAPY: Deferoxamine reduced the incidence of anthracycline induced cardiomyopathy and bleomycin pulmonary fibrosis in animal models (Voest et al, 1994).
    8) CANCER: Deferoxamine has shown promise as adjunctive therapy for neuroblastoma and leukemias (Voest et al, 1994).
    9) ALZHEIMER'S: Deferoxamine therapy has been associated with a decrease in the rate of deterioration in patients with Alzheimer's disease (Crapper McLachlan, et al, 1994).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Deferoxamine is a parenteral iron chelating agent which is used to treat acute iron overdose and chronic iron overload conditions. It is also used to chelate aluminum in renal failure patients undergoing dialysis.
    B) PHARMACOLOGY: Deferoxamine binds to iron that is not bound to iron-carrying proteins, forming an octahedral iron complex (ferrioxamine). Ferrioxamine is then excreted in the urine and bile, decreasing the overall amount of iron in the serum.
    C) TOXICOLOGY: The mechanism of rate-related hypotension caused by deferoxamine administration is poorly understood, but may be due in part to histamine release.
    D) EPIDEMIOLOGY: Deferoxamine use is relatively uncommon, and acute deferoxamine overdose is extremely rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effect with therapeutic use is hypotension. Hypotension is predominantly rate-related. Less commonly, acute lung injury and ARDS have been described in patients receiving high-dose deferoxamine for more than 24 hours. Deferoxamine therapy has been associated with increased risk of infection with Yersinia enterocolitica; The virulence of the organism is facilitated when ferrioxamine acts as a siderophore for their growth. Zygomycetes, Aeromonas hydrophilia, and mucormycosis appear to also be more common.
    2) CHRONIC THERAPY: Uncommon adverse effects that occur more often in patients on chronic deferoxamine therapy include ocular toxicity (loss of color vision, visual field cuts, and pigmentary retinal degeneration), sensorineural hearing loss, tinnitus, dementia, thrombocytopenia, aplastic anemia, bone dysplasia, and anaphylactic reactions. Acute renal failure and glomerulonephritis have been described in a handful of cases.
    F) WITH POISONING/EXPOSURE
    1) Hypotension is common at high infusion rates. Acute lung injury is common when high-dose continuous infusions are used for 24 hours or more. Pruritus, shortness of breath, chest pain, acute renal failure, and fatal acute lung injury have developed in patients who received inadvertent deferoxamine overdose.
    0.2.20) REPRODUCTIVE
    A) Deferoxamine is classified as US pregnancy category C. Several cases of therapeutic use of deferoxamine have occurred in pregnancy. Serous side effects have not been reported in the fetus. In one case series, of 25 pregnant iron overdose patients treated with deferoxamine (DFO), 20 delivered healthy full-term babies and 1 delivered prematurely. One baby was born malformed. Administration to pregnant experimental animals has caused fetal skeletal abnormalities.

Laboratory Monitoring

    A) Monitor vital signs and pulse oximetry.
    B) Monitor serum electrolytes, renal function, and urine output.
    C) Deferoxamine concentrations are not widely available or clinically useful.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment of mild to moderate toxicity predominantly consists of symptomatic and supportive care. Acute toxicity with hypotension commonly follows rapid IV infusion of deferoxamine. Administer intravenous fluids and reduce or interrupt the infusion. Reducing the infusion rate to less than 15 mg/kg/hour, with a maximum dose of 50 mg/kg/day, reduces the risk of hypotension. However, in the setting of acute iron overdose, higher doses may be required for adequate treatment.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Patients with severe hypotension may require IV fluid boluses and the addition of pressors (norepinephrine or dopamine) to maintain blood pressure. Severe anaphylaxis should be treated with antihistamines, corticosteroids, and epinephrine. Patients who develop acute lung injury/ARDS should have the deferoxamine discontinued and be treated with intubation and lung-protective ventilation strategies. The risk of acute lung injury/ARDS may be decreased by discontinuing treatment with deferoxamine within 24 hours. Patients who develop severe Yersinia sepsis should discontinue deferoxamine therapy and begin empiric antibiotic treatment with intravenous therapy with a third generation cephalosporin, such as ceftriaxone (2 g/day in adults or 100 mg/kg/day in 1 or 2 divided doses in children, to a maximum dose of 4 g/day) combined with gentamicin (5 mg/kg/day in 1 to 3 divided doses) while awaiting culture results and sensitivities. Less severe Yersinia infections, such as gastroenteritis, may be treated with trimethoprim-sulfa while awaiting culture results.
    C) DECONTAMINATION
    1) PREHOSPITAL/HOSPITAL : Acute toxicity usually follows rapid intravenous administration, and deferoxamine is poorly absorbed from the gastrointestinal tract. Gastrointestinal decontamination is generally not necessary.
    D) AIRWAY MANAGEMENT
    1) Rarely, patients who develop acute lung injury or have anaphylactic reactions may require intubation for airway management.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION
    1) Hemodialysis is effective at removing ferrioxamine in patients with renal failure.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no role for home management.
    2) OBSERVATION CRITERIA: A majority of patients who receive acute deferoxamine therapy will already be admitted to the hospital. Patients on chronic home deferoxamine therapy who receive an inadvertent overdose should be evaluated in a medical facility.
    3) ADMISSION CRITERIA: Patients who develop severe signs and symptoms of deferoxamine toxicity (hypotension, acute lung injury, anaphylaxis, Yersinia sepsis) will likely need to be admitted to an ICU setting.
    4) CONSULT CRITERIA; Contact a medical toxicologist or poison center for any patient with suspected deferoxamine toxicity (hypotension, acute lung injury, anaphylaxis, Yersinia sepsis). Patients with renal failure will benefit from a nephrology consult for possible dialysis. Patients with suspected Yersinia sepsis will benefit from an infectious disease consult to assist in tailoring antibiotic therapy.
    H) PITFALLS
    1) Administering deferoxamine too rapidly, leading to hypotension. Continuing therapy for longer than 24 hours leading to higher risk of acute lung injury.
    I) PHARMACOKINETICS
    1) Deferoxamine is poorly absorbed from the gastrointestinal tract. When given, IV, the initial distribution half-life is 5 to 10 minutes. Deferoxamine is metabolized to ferrioxamine. Volume of distribution for deferoxamine is 0.6 to 1.33 L/kg, while the volume of distribution for ferrioxamine is slightly smaller. Remaining unchanged deferoxamine is excreted both in the urine as well as in bile. The elimination half-life of deferoxamine is approximately 6 hours in healthy patients, but decreases to 3 hours in patients with iron-overload syndromes.

Range Of Toxicity

    A) TOXICITY: Intravenous administration faster than 15 mg/kg/hr may result in hypotension. Acute lung injury has been associated with prolonged (greater than 24 hours) high dose (15 mg/kg/hr or more) infusions in patients with acute iron overdose. A 17-year-old adolescent developed acute renal failure and hypertension after an inadvertent dose of 45 g (700 mg/kg) over 8 hours instead of the intended administration of 96 hours. No permanent sequelae was observed.
    B) THERAPEUTIC DOSE: ACUTE IRON OVERDOSE: ADULTS AND CHILDREN: 15 mg/kg/hour as a continuous IV infusion; a rate of up to 40 mg/kg/hour can be given in patients with life-threatening iron toxicity, although hypotension may occur with higher doses, and the rate should be decreased if this develops. Duration of infusion is up to 24 hours in patients with severe poisoning. CHRONIC IRON OVERLOAD: ADULTS: IM: 500 to 1000 mg IM daily . The maximum daily dose is 1000 mg; IV: 40 to 50 mg/kg/day over 8 to 12 hours 5 to 7 days per week, with the infusion rate not exceeding 15 mg/kg/hour; SubQ: 1000 to 2000 mg (20 to 40 mg/kg/day) administered over 8 to 24 hours. CHILDREN 3 YEARS AND OLDER: 20 to 40 mg/kg/day via slow IV infusion. The average dose should not exceed 40 mg/kg/day until growth has stopped, and the IV infusion rate should not exceed 15 mg/kg/hour. CHILDREN LESS THAN 3-YEARS-OLD: Safety and efficacy not established.

Clinical Effects

Summary Of Exposure

    A) USES: Deferoxamine is a parenteral iron chelating agent which is used to treat acute iron overdose and chronic iron overload conditions. It is also used to chelate aluminum in renal failure patients undergoing dialysis.
    B) PHARMACOLOGY: Deferoxamine binds to iron that is not bound to iron-carrying proteins, forming an octahedral iron complex (ferrioxamine). Ferrioxamine is then excreted in the urine and bile, decreasing the overall amount of iron in the serum.
    C) TOXICOLOGY: The mechanism of rate-related hypotension caused by deferoxamine administration is poorly understood, but may be due in part to histamine release.
    D) EPIDEMIOLOGY: Deferoxamine use is relatively uncommon, and acute deferoxamine overdose is extremely rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effect with therapeutic use is hypotension. Hypotension is predominantly rate-related. Less commonly, acute lung injury and ARDS have been described in patients receiving high-dose deferoxamine for more than 24 hours. Deferoxamine therapy has been associated with increased risk of infection with Yersinia enterocolitica; The virulence of the organism is facilitated when ferrioxamine acts as a siderophore for their growth. Zygomycetes, Aeromonas hydrophilia, and mucormycosis appear to also be more common.
    2) CHRONIC THERAPY: Uncommon adverse effects that occur more often in patients on chronic deferoxamine therapy include ocular toxicity (loss of color vision, visual field cuts, and pigmentary retinal degeneration), sensorineural hearing loss, tinnitus, dementia, thrombocytopenia, aplastic anemia, bone dysplasia, and anaphylactic reactions. Acute renal failure and glomerulonephritis have been described in a handful of cases.
    F) WITH POISONING/EXPOSURE
    1) Hypotension is common at high infusion rates. Acute lung injury is common when high-dose continuous infusions are used for 24 hours or more. Pruritus, shortness of breath, chest pain, acute renal failure, and fatal acute lung injury have developed in patients who received inadvertent deferoxamine overdose.

Vital Signs

    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) Hypotension and shock may occur with rapid intravenous administration (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012; Westlin, 1966; Westlin, 1971; Whitten et al, 1966) .

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) ELDERLY: Postmarketing reports suggest that patients over the age of 65 years may be at increased risk for developing color blindness, maculopathy, and scotoma from administration of deferoxamine. It is unknown if these adverse ocular effects are dose related (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).
    2) RISK FACTORS: It appears that continuous intravenous administration of deferoxamine, often in the presence of low iron stores, has produced visual toxicity. Visual toxicity has also been associated in patients with rheumatoid arthritis and chronic renal failure (Howland, 1996b).
    3) MECHANISM: The mechanism remains unclear. One report has postulated that an altered blood retinal barrier allows access of deferoxamine and results in toxicity (Howland, 1996b).
    4) CHILDREN: In a retrospective case series of 84 children treated with deferoxamine (doses, 25 to 50 mg/kg/day subcutaneously) for transfusional hemochromatosis, ocular toxicity (central blurriness and retinal pigmentary changes, and decreased central responses measured by electroretinography) was observed only in one patient (1.2%) who was receiving deferoxamine 50 mg/kg/day intravenously as a continuous 24-hour infusion. Following the discontinuation of deferoxamine, all symptoms improved 3 days later. The patient did not experience any ocular toxicity after treatment with a lower dose of deferoxamine (40 mg/kg/day subcutaneously) was started (Baath et al, 2008).
    5) Administration of high-dose deferoxamine for the treatment of iron overload conditions has been associated with ocular toxicity including loss of vision, decreased visual acuity, visual field loss, color vision loss, pigment retinopathy, and optic neuropathy (Davies et al, 1983; Olivieri et al, 1986; Blake et al, 1985; Simon et al, 1983; Rubinstein et al, 1985; Mehta et al, 1994).
    a) Most of these changes are reversible upon discontinuation of deferoxamine therapy (Davies et al, 1983; Cohen et al, 1990), but some may be permanent (Olivieri et al, 1986; Lai et al, 2006).
    6) CASE SERIES: In one case, acute visual loss followed a single two gram deferoxamine injection (Simon et al, 1983). Ocular toxicity was reported in two hemodialysis patients following a single intravenously infused dose of 2.7 g of deferoxamine (40 mg/kg) (Pengloan et al, 1987).
    7) CASE REPORT: Bene et al (1989) reported irreversible visual loss in a 63-year-old woman on chronic ambulatory peritoneal dialysis for 4 years. She had received 40 mg/kg of deferoxamine intravenously (2 g and 1.8 g) over 2 hours on 2 occasions about 1 year apart. Generalized blurring and color distortion occurred 2 days after the first challenge dose. Vision subsequently returned to normal (Bene et al, 1989).
    8) CASE REPORT: A 75-year-old man with myelodysplasia reported a dramatic decrease in his vision in dim light after 20 months of deferoxamine at 38 mg/kg (Cohen et al, 1990). His acuity with best correction was unchanged and retinal examination was normal. Complete resolution occurred after deferoxamine was discontinued.
    9) One study showed the visual loss to be of retinal origin and characterized by a tritan-type dyschromatopsy and sometimes pigmentary retinal deposits (Cases et al, 1990).
    10) CATARACTS have also been observed in animals and (very rarely and after long-term treatment) in men (Halliday & Powell, 1982; Bloomfield et al, 1978; Losowsky, 1966).
    11) CASE REPORT: A 25-year-old woman with Diamond-Blackfan syndrome had a mild amount of macular stippling 24 months after beginning daily intravenous deferoxamine at 108 mg/kg (Cohen et al, 1990). The ocular findings did not change even after shifting to subcutaneous therapy for 20 months.
    12) CASE REPORT: A 58-year-old man undergoing hemodialysis who had a deferoxamine test (dose 10 mg/kg) to rule out aluminum overload developed visual acuity loss and color vision disturbances 2 hours later. Fundoscopy showed dull appearance of the macular pigmentary epithelium in both eyes; computerized campimetry revealed bilateral central scotomata. Visual acuity was measured at 20/200 in both eyes on the Snellen scale, which improved to 20/30 3 months later (Rodriguez et al, 1999).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) Patients administered high-dose deferoxamine for iron overload conditions have developed symptomatic or asymptomatic high frequency sensorineural hearing loss (Olivieri et al, 1986; Baratt & Toogood, 1987; Gallant et al, 1987; Cases et al, 1988). Reducing the dose is usually associated with clinical improvement (Olivieri et al, 1986a).
    2) CHILDREN: In a retrospective case series of 84 children treated with deferoxamine (25 to 50 mg/kg/day subcutaneously) for transfusional hemochromatosis, significant sensorineuronal auditory toxicity developed in only one (1.2%) patient (Baath et al, 2008).
    3) CASE SERIES: One of a series of regularly transfused patients receiving deferoxamine had mild, bilateral, high-frequency sensorineural hearing loss (Cohen et al, 1990). This patient did not receive higher doses of deferoxamine nor did she have lower serum ferritin levels than those without such abnormality.
    4) CASE SERIES: In another series of 309 children aged 3 to 18 with thalassemia major receiving chronic deferoxamine, 48 (16%) developed sensorineural hearing loss (Argiolu et al, 1991).
    5) CASE SERIES: Thirty transfusion-dependent patients with beta-thalassemia major (n=25), thalassemia intermedia (n=3), or other hereditary hemolytic anemias (n=2) were given deferoxamine therapy, 40 to 50 mg/kg/dose subcutaneously for 8 to 10 hours for 4 to 7 days/week, when their ferritin level increased to greater than 1,000 ng/mL. Six patients (20%) developed deferoxamine-related high-frequency hearing loss. The frequencies involved were from 3,000 to 12,500 Hertz (Hz), with the majority of hearing impairment occurring at a frequency of 6,000 Hz or higher. Because the risk of hemochromatosis outweighed the possible adverse effects of deferoxamine administration, therapy was neither decreased or withdrawn. A follow-up 2 years later showed that all affected patients remained stable, with no further auditory deterioration (Chen et al, 2005).
    6) CASE REPORT: One patient has been reported who developed tinnitus during deferoxamine therapy for iron overload in thalassemia major (Marsh et al, 1981). The tinnitus cleared after discontinuance of deferoxamine therapy, but recurred when another course of deferoxamine was administered and was then not reversible following withdrawal of the drug (Marsh et al, 1981).
    7) ELDERLY: Postmarketing reports suggest that patients over the age of 65 years may be at increased risk for developing hearing loss or deafness from administration of deferoxamine (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).
    8) In a study of thalassemia patients who were receiving deferoxamine, 25% had abnormal audiograms with some requiring hearing aids (Howland, 1996b).
    a) RISK FACTORS include deferoxamine dose, duration of therapy, and the presence of a low serum ferritin (Howland, 1996b).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension and shock may occur with rapid intravenous administration of deferoxamine (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012; Westlin, 1966).
    b) Hypotension appears to be rate related (Howland, 1996b).
    c) These effects can usually be prevented by not infusing the drug at a rate faster than 15 milligrams per kilogram per hour to a maximum dose of 50 milligrams per kilogram per day (Westlin, 1971; Prod Info DESFERAL(R) injection, 2007; Whitten, 1965).
    d) One patient who developed hypotension also had a seizure (Westlin, 1966). Associated tachycardia and flushing have also been noted (Westlin, 1971; Whitten, 1965).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DISORDER OF RESPIRATORY SYSTEM
    1) WITH THERAPEUTIC USE
    a) A "pulmonary syndrome" developed in high-dose IV deferoxamine therapy for several days for acute and chronic iron overloaded patients (Freedman et al, 1990; Scanderbeg et al, 1990; Benson & Cheney, 1992). Features included severe tachypnea, hypoxemia, fever, eosinophilia, preceding urticaria, and pulmonary infiltrates. This evidence seemed to suggest a hypersensitivity type reaction (Freedman et al, 1990; Scanderbeg et al, 1990).
    b) ONSET: Usually 3 to 9 days after initiating deferoxamine infusion (Anderson & Rivers, 1992).
    c) RISK FACTORS: Adult respiratory distress syndrome has been reported in patients receiving prolonged high dose deferoxamine infusions (15 mg/kg/hour for 45 to 98 hours) for acute iron poisoning (Tenenbein et al, 1992a).
    d) Pulmonary toxicity has been suggested to be related to the duration of infusion and high daily doses (Macarol & Yawalkar, 1992).
    e) MECHANISM: The etiology of pulmonary toxicity remains unknown. Hypersensitivity as a cause appears unlikely in patients with acute iron poisoning (Howland, 1996b). It has been suggested that pulmonary toxicity induced by deferoxamine in iron-poisoned mice resulted from free radical destruction (Adamson et al, 1993).
    f) Pulmonary toxicity has been suggested to be related to the duration of infusion. Four adults treated with 15 mg/kg/hour for 65 to 92 hours developed fatal adult respiratory distress syndrome, with the onset of respiratory difficulty between 32 and 72 hours. Pulmonary edema was also noted on necropsy of 3 additional patients who died of iron-induced cardiac failure after deferoxamine infusions lasting 45 to 98 hours. A chart review of 29 iron overdose patients who received infusions of less than 24 hours showed no evidence of pulmonary complications. Slow entry of ferrioxamine into mitochondria causing free-radical damage was suggested as the mechanism (Tenenbein et al, 1992a).
    g) Following 193 courses administered to 13 children at rate of 15 mg/kg/hour for 48 hours, no pulmonary toxicity occurred (Chan et al, 1992).
    h) CASE REPORT: Pulmonary toxicity developed in a 22-month-old child treated with deferoxamine 2 grams orally followed by intramuscular injection every 6 to 8 hours and a 6 hour trial of subcutaneous infusion for a total parenteral dose of 553 milligrams/kilogram over 64 hours (Anderson & Rivers, 1992a).
    i) CASE SERIES: Chan et al (1992) reported that in 193 courses of deferoxamine therapy administered to 13 children with thalassemia at a rate of 15 milligrams/kilogram/hour for 48 hours pulmonary toxicity did not develop (Chan et al, 1992).
    j) CASE SERIES: Pulmonary toxicity was reported in 2 of 4 children receiving deferoxamine infusions (9 and 12.5 milligrams/kilogram/hour in 5 day courses separated by 2 weeks) (Weitman et al, 1991).
    B) ACUTE LUNG INJURY
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Pulmonary toxicity has been suggested to be related to the duration of infusion. Four adults treated with 15 mg/kg/h for 65 to 92 hours developed fatal adult respiratory distress syndrome, with the onset of respiratory difficulty between 32 and 72 hours. Pulmonary edema was also noted on necropsy of 3 additional patients who died of iron-induced cardiac failure after deferoxamine infusions lasting 45 to 98 hours. A chart review of 29 iron overdose patients who received infusions of less than 24 hours showed no evidence of pulmonary complications. Slow entry of ferrioxamine into mitochondria causing free-radical damage was suggested as the mechanism (Tenenbein et al, 1992).
    b) CASE REPORT: Acute respiratory distress syndrome (ARDS) developed in an 11-month-old girl treated with high dose deferoxamine (45 mg/ kg/hour for 12 hours, then 15 mg/kg/hour for 17 hours) following severe iron poisoning. At 49 hours postingestion, intravenous N-acetylcysteine (NAC) (140 milligrams/kilogram, then 70 mg/kg every 4 hours) was started and continued for 6 days. The patient was extubated 9 days after admission and recovered fully (Douglas & Smilkstein, 1995a). Further study is needed before an absolute recommendation can be made.
    c) It is unclear whether pulmonary toxicity in these cases was due to severe iron poisoning or prolonged deferoxamine therapy (Shannon, 1992). The safety of deferoxamine infusions may be dependent upon the iron burden. Further study is needed before an absolute recommendation can be made.
    d) CASE REPORT: An 18-month-old girl presented after an inadvertent ingestion of 30 tablets of an iron preparation (110 mg/kg of elemental iron ingested). She was treated with a desferrioxamine IV infusion of 15 mg/kg/hour continuously for 3 days, recovered and was discharged on hospital day 4. Three days after discharge, the patient was readmitted with tachycardia and tachypnea with subcostal and intercostal retractions. A chest radiograph demonstrated bilateral widespread infiltrates and decreased inflation, and an echocardiogram revealed mild pulmonary hypertension. She was readmitted and treated with antibiotics, prednisolone, furosemide, and the deferoxamine infusion was resumed at 10 mg/kg/hr. She continued to deteriorate and subsequently died on the fourth day of readmission, likely from acute lung injury secondary to deferoxamine overdose (Atas et al, 2005).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RESPIRATORY DISORDER
    a) MICE: Adamson et al (1993) suggested that the mechanism of pulmonary toxicity induced by deferoxamine in iron poisoned mice is a result of free radical destruction (Adamson et al, 1993).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: One patient who developed hypotension during rapid intravenous deferoxamine infusion also had a seizure (Westlin, 1966).
    B) APHASIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A six-year-old girl receiving intravenous deferoxamine at home for the treatment of transfusion-related iron overload received an overdose of deferoxamine when the intravenous solution infused too rapidly.
    1) Ten minutes later she developed sudden onset of headache, nausea, agitation, loss of vision, and inability to speak (Dickerhoff, 1987). The patient recovered fully after about 8 hours.
    C) DEMENTIA
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Hemodialysis patients receiving deferoxamine for aluminum overload developed dementia in 5 cases with 3 fatalities, the other two improved when chelation therapy was decreased or discontinued, and/or extracorporeal elimination techniques were employed (Sherrard et al, 1988).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) GLOMERULONEPHRITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 16-year-old patient with thalassemia major and secondary hemosiderosis was treated with IV deferoxamine (up to 3 g/day). Impairment in cardiac and hepatic status followed; he developed acute renal failure on day 12 and died 30 hours later. Histologic examination of the kidneys demonstrated a mild diffuse proliferative glomerulonephritis with no evidence of tubular necrosis (Batey et al, 1979).
    B) ACUTE RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) Acute renal failure may occur when deferoxamine is infused in patients with decreased intravascular volumes. Adequate hydration is necessary to preserve renal hemodynamics when administering parenteral deferoxamine (Tenenbein, 1996a).
    b) Elevated creatinine levels and decreased creatinine clearances have been reported (Koren et al, 1989).
    c) CASE SERIES: Three cases of acute renal failure were reported in two thalassemic adolescents and a 3-year-old child. One of the adolescents had received high doses (10 mg/kg/hr for 18 hours/day for 7 days); the other one was dehydrated. The young child had received a massive overdose (Bentur et al, 1988).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 17-year-old with severe iron overload and sickle cell-beta thalassemia undergoing home iron chelation therapy was inadvertently given ten times the recommended dose of intravenous deferoxamine (a scheduled dose of 45 g over 96 hours {700 mg/kg} was accidentally given over 8 hours). The following morning the patient had symptoms of an allergic response (ie, itching, shortness of breath and chest pain) along with oliguria. Despite IV hydration and supportive measures, the oliguria progressed and hypertension developed. Hemodialysis was then initiated and the patient's urine output increased to 2,050 mL/8 hours (a tenfold increase). One year after exposure, laboratory parameters and blood pressure remained normal (Prasannan et al, 2003).
    1) It has been suggested that the acute renal failure described in this case was likely because of tubular damage due to deferoxamine toxicity (Li Volti et al, 2003).
    b) CASE REPORT: A 19-year-old man, with thalassemia major, developed acute renal failure (persistent oliguria, and peak BUN and serum creatinine concentrations of 28.2 mmol/L and 540 mcmol/L, respectively) after inadvertently receiving a desferrioxamine overdose of 39 mg/kg/hour (33.7 g over an 18-hour period) instead of the intended desferrioxamine infusion of 4.3 mg/kg/hour. Oliguria persisted despite intravenous hydration and diuretics, so hemodialysis was performed for 2 hours and repeated for the next 3 days. Oliguria resolved after the first dialysis session, and renal function returned to normal (Cianciulli et al, 1992).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RENAL FUNCTION ABNORMAL
    a) In DOGS, a 2-hour infusion of 10 mg/kg/hr resulted in acute decreases in glomerular filtration rate (GFR) and renal blood flow (RBF). Preliminary observations in dogs suggest that deferoxamine nephrotoxicity may be dependent on hydration status (Bentur et al, 1988).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: One patient developed thrombocytopenia while receiving deferoxamine therapy (5 doses of 6 grams each) for osteomalacia secondary to aluminum toxicity during chronic hemodialysis treatment of renal failure (Walker et al, 1985). The thrombocytopenia resolved after the drug was discontinued (Walker et al, 1985).
    B) APLASTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Bone marrow aplasia was reported in a 16-year-old with homozygous beta-Thalassemia (Sofroniadou et al, 1990). The aplasia was characterized by megakaryocytic thrombocytopenia (Bentur et al, 1991).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) LEUKOPENIA
    a) WITH THERAPEUTIC USE
    1) Deferoxamine inhibits human lymphocyte (B and T cell) proliferation in vitro, but has relatively little effect on RNA or protein synthesis (Lederman et al, 1984).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) DISORDER OF BONE
    1) WITH THERAPEUTIC USE
    a) Long term deferoxamine therapy in children with thalassemia has been associated bone dysplasia (Chan et al, 2000; Brill et al, 1991; Olivieri et al, 1992; Miller et al, 1993; Orzincolo et al, 1992) Falik Borenstein et al, 1993).
    b) CHILDREN: In a retrospective case series of 84 children treated with deferoxamine (25 to 50 mg/kg/day subcutaneously) for transfusional hemochromatosis, bone dysplasia developed in 17 (20.2%) patients (Baath et al, 2008).
    c) Abnormalities of the metaphyseal growth plate, particularly in the distal ulnar, radial, tibial and femoral metaphyses have been described in several case series (Brill et al, 1991; Olivieri et al, 1992; Miller et al, 1993; Orzincolo et al, 1992) Falik Borenstein et al, 1993).
    d) Flattening, osteoporosis and sclerosis of the vertebral bodies and calcification and narrowing of the intravertebral disc have also been described in several case series (Brill et al, 1991) Falik Borenstein et al, 1993; (Hartkamp et al, 1993).
    e) These bone dysplasias are generally associated with shortened stature (Chan et al, 2000; Olivieri et al, 1992) Falik Borenstein et al, 1993; (Hartkamp et al, 1993).
    f) Chan et al (2000) reported that deferoxamine-induced bone dysplasia in the distal femur and patella of pediatric patients and young adults, is represented by a spectrum of changes in the epiphysis, physis, metaphysis, and metadiaphysis on MR imaging (Chan et al, 2000) .
    g) CASE SERIES: Significant deficits in longitudinal growth were noted in 36 children chelated with 10 mg/kg/day for thalassemia, with a dose-related response (De Virgiliis et al, 1988).
    h) CASE SERIES: In two studies deferoxamine treated children who developed bone dysplasia had received higher deferoxamine doses than those who did not develop bone anomalies (Olivieri et al, 1992; Hartkamp et al, 1993).
    i) CASE REPORT: A 59-year-old woman with chronic renal insufficiency and aluminum intoxication was treated with deferoxamine 2 grams intravenously followed by 0.5 grams intravenously twice weekly for 4 weeks (Davie et al, 1993). Serum osteocalcin levels rose 8-fold in conjunction with deferoxamine therapy.

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) Anaphylactic and anaphylactoid reactions have occurred in patients with thalassemia major treated with deferoxamine (Athanasiou et al, 1977; Bousquet et al, 1983). These patients developed tachycardia, laryngospasm, cyanosis, hypotension, generalized pruritus, and loss of consciousness (Athanasiou et al, 1977; Bousquet et al, 1983).

Reproductive

    3.20.1) SUMMARY
    A) Deferoxamine is classified as US pregnancy category C. Several cases of therapeutic use of deferoxamine have occurred in pregnancy. Serous side effects have not been reported in the fetus. In one case series, of 25 pregnant iron overdose patients treated with deferoxamine (DFO), 20 delivered healthy full-term babies and 1 delivered prematurely. One baby was born malformed. Administration to pregnant experimental animals has caused fetal skeletal abnormalities.
    3.20.2) TERATOGENICITY
    A) MALFORMATION
    1) CASE SERIES: Of 25 pregnant iron overdose patients treated with deferoxamine (DFO), 20 (80%) delivered healthy full-term babies and 1 delivered prematurely. One baby was born malformed, and 3 were electively aborted (of these 1 was anencephalic with no data on the other 2). Six patients treated with DFO had serum iron levels of greater than or equal to 90 mcmol/L, and all six delivered healthy, full-term babies after gastric decontamination and deferoxamine therapy (McElhatton et al, 1991).
    B) LACK OF EFFECT
    1) Several cases of therapeutic use of deferoxamine have occurred in pregnancy. Serious side effects have not been reported in the fetus.
    2) CASE REPORT: A 27-year-old woman, at 27 weeks gestation, ingested 24 mg/kg of elemental iron and had an initial serum iron level of 603 mcg/dL (normal range 50-170 mcg/dL). Chelation therapy included deferoxamine started at 1 gram/hour (15 mg/kg/hour) and was continued for 2 hours; ferritin levels dropped to normal within 48 hours. At 32 weeks, a 2420 gram infant with normal Apgar scores was delivered. The infant was discharged to home on day 7 with no further follow-up reported (Tran et al, 1998).
    3) CASE REPORT/CHRONIC THERAPY: An 18-year-old with a history of thalassemia, chronic hepatitis, and iron overload became pregnant and stopped her DFO therapy. By 16 weeks gestation her ferritin level had reached 6000 ng/mL. At 18 weeks gestation DFO was restarted at a dose of 40 mg/kg via SQ infusion 4 days/week and intravenous treatment of 50 mg/kg every 2 weeks. At 26 weeks, the subcutaneous dose was increased to 50 mg/kg/day and intravenous dose to 80 mg/kg. A MediPort was inserted at 30 weeks to administer DFO at 50 mg/kg/day. The patient gave birth at 38 weeks gestation. At 10 month follow-up, the child was developmentally age-appropriate, and evaluation for DFO toxicity (ie, audiogram, skeletal survey for bone dysplasia, and ophthalmology exam) was negative (Singer & Vichinsky, 1999).
    4) CASE REPORT: Intramuscular and nasogastric tube administration was reported in one 24-year-old patient with a ferrous sulfate overdose at 34 weeks gestation. Admission serum iron level was 1,380 micrograms per deciliter. Spontaneous labor began 8 hours following iron ingestion. The infant had an uneventful clinical course, with the exception of low serum iron levels requiring iron supplementation. The authors felt it possible that transplacental transfer of deferoxamine may have resulted in iron chelation in the fetus, resulting in postnatal iron deficiency (Rayburn et al, 1983).
    5) CASE REPORT: A 15-year-old female at fifteen weeks of gestation with an acute iron overdose was administered an initial dose of two grams of deferoxamine followed by one gram 8 hours later. This patient later had a normal spontaneous delivery of a healthy infant with no evidence of congenital malformation (Blanc et al, 1984).
    6) CASE REPORT: A patient treated in the third trimester for iron overdose had a normal fetal outcome (Lovett, 1986).
    7) CASE SERIES: In three other cases of women treated during pregnancy with deferoxamine for iron overdose, the outcomes were normal (Strom et al, 1976).
    8) CASE REPORT: A thalassemia patient who received 2 g every 12 hours for the first 16 weeks of pregnancy by continuous subcutaneous infusion pump had a Cesarean section at 33 weeks, with delivery of a normal preterm infant. No adverse effects were attributed to deferoxamine (Thomas & Skalicka, 1980).
    9) CASE SERIES: A healthy infant was delivered by Cesarean section at 36 weeks in a 30-year-old woman acutely intoxicated with iron and treated with deferoxamine infusion. The patient subsequently died. A 26-year-old woman at 15 weeks of gestation was treated with deferoxamine for iron overdose; she recovered, had a normal pregnancy and delivered a full-term normal infant (Olenmark et al, 1987).
    C) ANIMAL STUDIES
    1) Administration to pregnant experimental animals has caused fetal skeletal abnormalities (Reynolds & Prasad, 1982; Prod Info Desferal(R), deferoxamine mesylate(R), 1987).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Deferoxamine is classified as US pregnancy category C (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF EFFECT
    1) BREAST MILK
    a) It is not known whether deferoxamine is excreted in human breast milk. Until more data is available, use caution when considering the use of deferoxamine in lactating women (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).

Carcinogenicity

    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential carcinogenicity of deferoxamine.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and pulse oximetry.
    B) Monitor serum electrolytes, renal function, and urine output.
    C) Deferoxamine concentrations are not widely available or clinically useful.
    4.1.2) SERUM/BLOOD
    A) Monitor serum electrolytes and renal function.
    B) Deferoxamine concentrations are not widely available or clinically useful.
    C) LABORATORY INTERFERENCE
    1) The presence of deferoxamine may interfere with several widely used serum iron analytical procedures, resulting in falsely low reports of serum iron levels (Gevirtz & Wasserman, 1966).
    4.1.3) URINE
    A) Monitor urine output.
    B) OTHER
    1) Deferoxamine therapy may produce a reddish discoloration of the urine from the ferrioxamine complex formed with chelatable iron (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs and pulse oximetry.
    b) Patients receiving deferoxamine should be monitored for signs of ocular toxicity.

Radiographic Studies

    A) RADIOGRAPHIC-OTHER
    1) Radiographs of the spine, wrists and knees may help identify children with bone dysplasia from chronic deferoxamine therapy (Brill et al, 1991; Olivieri et al, 1992; Miller et al, 1993; Orzincolo et al, 1992).
    B) MRI
    1) MRI has also been used (Miller et al, 1993).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients who develop severe signs and symptoms of deferoxamine toxicity (hypotension, acute lung injury, anaphylaxis, Yersinia sepsis) will likely need to be admitted to an ICU setting.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no role for home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Contact a medical toxicologist or poison center for any patient with suspected deferoxamine toxicity (hypotension, acute lung injury, anaphylaxis, Yersinia sepsis). Patients with renal failure will benefit from a nephrology consult for possible dialysis. Patients with suspected Yersinia sepsis will benefit from an infectious disease consult to assist in tailoring antibiotic therapy.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) A majority of patients who receive acute deferoxamine therapy will already be admitted to the hospital. Patients on chronic home deferoxamine therapy who receive an inadvertent overdose should be evaluated in a medical facility.

Monitoring

    A) Monitor vital signs and pulse oximetry.
    B) Monitor serum electrolytes, renal function, and urine output.
    C) Deferoxamine concentrations are not widely available or clinically useful.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Acute toxicity usually follows rapid intravenous administration, and deferoxamine is poorly absorbed from the gastrointestinal tract. Gastrointestinal decontamination is generally not necessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Acute toxicity usually follows rapid intravenous administration, and deferoxamine is poorly absorbed from the gastrointestinal tract. Gastrointestinal decontamination is generally not necessary
    6.5.3) TREATMENT
    A) GENERAL TREATMENT
    1) See the PARENTERAL EXPOSURE treatment section for further information.

Enhanced Elimination

    A) HEMODIALYSIS
    1) CASE REPORT: A 17-year-old adolescent with sickle cell-beta thalassemia inadvertently received 45 g (700 mg/kg) over a period of 8 hours instead of the intended 96 hours, and developed oliguria and acute renal failure. Despite intravenous hydration and forced diuresis with mannitol, the patient remained oliguric with progressive azotemia, and had a new onset of hypertension. Hemodialysis using a standardized flow rate and blood flow rate of 400 mL/minute was initiated, and a gradual improvement in urine output and color was observed, along with a decrease in creatinine level. Deferoxamine clearance was not calculated. No residual alterations in renal function or blood pressure were observed up to one year after exposure (Prasannan et al, 2003).
    2) CASE REPORT: A 19-year-old man, with thalassemia major, developed acute renal failure (persistent oliguria, and peak BUN and serum creatinine concentrations of 28.2 mmol/L and 540 mcmol/L, respectively) after inadvertently receiving a desferrioxamine overdose of 39 mg/kg/hour (33.7 g over an 18-hour period) instead of the intended desferrioxamine infusion of 4.3 mg/kg/hour. Oliguria persisted despite intravenous hydration and diuretics, so hemodialysis was performed for 2 hours and repeated for the next 3 days. Oliguria resolved after the first dialysis session, and renal function returned to normal (Cianciulli et al, 1992).

Abstracts

Case Reports

    A) CHRONIC EFFECTS
    1) Davies et al (1983) reported loss of vision and abnormal electrophysiological retinal tests following high-dose deferoxamine (up to 235 milligrams per kilogram per day intravenously) for treatment of iron overload induced by transfusion therapy of thalassemia major. Two patients complained of night blindness and visual field losses. Except for pigmentary retinopathy in one patient, these manifestations resolved almost completely on withdrawal of deferoxamine. The authors recommended gradually increasing the intravenous dose to a maximum of 125 milligrams per kilogram per day (Davies et al, 1983).

Range Of Toxicity

Summary

    A) TOXICITY: Intravenous administration faster than 15 mg/kg/hr may result in hypotension. Acute lung injury has been associated with prolonged (greater than 24 hours) high dose (15 mg/kg/hr or more) infusions in patients with acute iron overdose. A 17-year-old adolescent developed acute renal failure and hypertension after an inadvertent dose of 45 g (700 mg/kg) over 8 hours instead of the intended administration of 96 hours. No permanent sequelae was observed.
    B) THERAPEUTIC DOSE: ACUTE IRON OVERDOSE: ADULTS AND CHILDREN: 15 mg/kg/hour as a continuous IV infusion; a rate of up to 40 mg/kg/hour can be given in patients with life-threatening iron toxicity, although hypotension may occur with higher doses, and the rate should be decreased if this develops. Duration of infusion is up to 24 hours in patients with severe poisoning. CHRONIC IRON OVERLOAD: ADULTS: IM: 500 to 1000 mg IM daily . The maximum daily dose is 1000 mg; IV: 40 to 50 mg/kg/day over 8 to 12 hours 5 to 7 days per week, with the infusion rate not exceeding 15 mg/kg/hour; SubQ: 1000 to 2000 mg (20 to 40 mg/kg/day) administered over 8 to 24 hours. CHILDREN 3 YEARS AND OLDER: 20 to 40 mg/kg/day via slow IV infusion. The average dose should not exceed 40 mg/kg/day until growth has stopped, and the IV infusion rate should not exceed 15 mg/kg/hour. CHILDREN LESS THAN 3-YEARS-OLD: Safety and efficacy not established.

Therapeutic Dose

    7.2.1) ADULT
    A) ACUTE IRON INTOXICATION
    1) Administer deferoxamine by continuous IV infusion at a rate of 15 mg/kg/hour. It can be titrated up to a rate of 40 mg/kg/hour for patients with life-threatening iron toxicity, although hypotension may occur with higher doses, and the rate should be decreased if this develops (Seifert, 2004).
    2) Duration of infusion is 12 hours in patients with moderate poisoning, up to 24 hours in patients with severe poisoning. The patient should be titrated off the infusion, if clinically improving. If the patient worsens as the deferoxamine is titrated off, it should be restarted. Infusions of greater than 24 hours have been associated with acute lung injury and should be avoided (Seifert, 2004).
    B) CHRONIC IRON OVERLOAD
    1) SUBCUTANEOUS ADMINISTRATION
    a) Slow subcutaneous infusion is the standard recommended method of administration for treatment of patients with chronic iron overload (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).
    b) DOSAGE REGIMEN: 1000 to 2000 mg (20 to 40 mg/kg/day) administered over 8 to 24 hours, although the recommended duration of infusion is 8 to 12 hours (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).
    1) It has been determined that, in some patients, the amount of iron excreted after a short infusion of 8 to 12 hours, is the same as with the same deferoxamine dose administered over a 24-hour period (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).
    2) INTRAMUSCULAR ADMINISTRATION
    a) The recommended dose is 500 to 1000 mg IM daily . The maximum daily dose is 1000 mg (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).
    3) INTRAVENOUS ADMINISTRATION
    a) DOSAGE REGIMEN: 40 to 50 mg/kg/day over 8 to 12 hours 5 to 7 days per week. The average dose should not exceed 60 mg/kg/day and the infusion rate should not exceed 15 mg/kg/hour (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).
    b) Maximum daily doses of 6 to 12 g (administered IV at 15 mg/kg/hr over 12 hours) for up to 25 months were well tolerated and effective for patients requiring frequent transfusional blood replacement due to sickle cell disease or thalassemia major (Cohen et al, 1989).
    7.2.2) PEDIATRIC
    A) ACUTE IRON INTOXICATION
    1) Administer deferoxamine by continuous IV infusion at a rate of 15 mg/kg/hour (Seifert, 2004).
    2) Infusion rates up to 35 mg/kg/hour have been used in children with severe overdoses without adverse effects (Boehnert et al, 1985a), although hypotension may occur with higher doses, and the rate should be decreased if this develops (Seifert, 2004).
    B) CHRONIC IRON OVERLOAD
    1) 3 YEARS OF AGE AND OLDER
    a) INTRAVENOUS: The recommended dose is 20 to 40 mg/kg/day via slow IV infusion. The average dose should not exceed 40 mg/kg/day until growth has stopped, and the IV infusion rate should not exceed 15 mg/kg/hour (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).
    2) LESS THAN 3 YEARS OF AGE
    a) The safety and efficacy in children younger than 3 years of age have not been established (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Intravenous bolus or infusion rates exceeding 15 mg/kg/hr may cause hypotension (Howland, 1996a; Pagliaro & Levin, 1979); however higher infusion rates, up to 35 mg/kg/hr, have been tolerated in severely poisoned patients (Boehnert et al, 1985).
    2) CASE SERIES: Pulmonary toxicity has been suggested to be related to the duration of infusion. Four adults treated with 15 mg/kg/h for 65 to 92 hours developed fatal adult respiratory distress syndrome, with the onset of respiratory difficulty between 32 and 72 hours. Pulmonary edema was also noted on necropsy of 3 additional patients who died of iron-induced cardiac failure after deferoxamine infusions lasting 45 to 98 hours. A chart review of 29 iron overdose patients who received infusions of less than 24 hours showed no evidence of pulmonary complications (Tenenbein et al, 1992).
    B) CASE REPORTS
    1) A 17-year-old adolescent with sickle cell-beta thalassemia developed acute renal failure and a new onset of hypertension after an inadvertent dose of 45 g (700 mg/kg) over 8 hours instead of the intended administration of 96 hours. Following supportive care including hemodialysis, renal function and blood pressure improved. Up to one year after exposure, no permanent sequelae was observed (Prasannan et al, 2003).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Deferoxamine forms a chelate complex (ferrioxamine) with iron not bound to iron-carrying proteins, which is then excreted in the urine and bile (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).
    B) One hundred milligrams of deferoxamine can chelate 8.5 to 9.5 milligrams of elemental iron (Tenenbein, 1996; Howland, 1996).

Toxicologic Mechanism

    A) Rapid intravenous administration causes hypotension. The mechanism of rate-related hypotension caused by deferoxamine administrations is poorly understood, but may be due in part to histamine release (Howland, 1996).
    B) OCULAR TOXICITY: Pall et al (1989) hypothesized that the ocular toxicity seen with deferoxamine therapeutically was due to copper or zinc binding in patients with low iron stores (Pall et al, 1989).

Physicochemical

Physical Characteristics

    A) Deferoxamine mesylate is a white to cream colored odorless or nearly odorless powder with a bitter taste (Reynolds & Prasad, 1982).

Ph

    A) 3.5-5.5 (10% solution) (Reynolds & Prasad, 1982)

Molecular Weight

    A) 656.8

References

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