Deferoxamine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Injection, as mesylate [preservative free]:

Desferal: 500 mg (1 ea)

Generic: 500 mg (1 ea); 2 g (1 ea)

Pharmacology

Mechanism of Action

Complexes with trivalent ions (ferric ions), primarily in the vascular space, to form ferrioxamine, which is eliminated in the urine by the kidneys. One hundred milligrams of deferoxamine will bind about 8.5 mg of free circulating elemental iron (85 mg per 1,000 mg dose) but does not remove iron from transferrin or hemoglobin. Binding of cytoplasmic free iron reduces the free iron-induced disruption of mitochondrial cell membranes and enzyme systems. Ferrioxamine may create a pink- to red- or orange-colored urine as it is being excreted.

Pharmacokinetics/Pharmacodynamics

Absorption

IM, SubQ: Well absorbed

Distribution

Distributed throughout body fluids

Metabolism

Plasma enzymes; binds with iron to form ferrioxamine (iron complex)

Excretion

Primarily urine (as unchanged drug and ferrioxamine); feces (via bile)

Half-Life Elimination

14 hours; plasma: 20 to 30 minutes (Brittenham 2011)

Protein Binding

<10%

Use: Labeled Indications

Acute iron toxicity: Adjunct in the treatment of acute iron intoxication

Chronic iron overload: Treatment of chronic iron overload secondary to multiple transfusions (often due to the presence of thalassemia major or sickle cell disease [Borgna-Pignatti 2015; Marsella 2015])

Use: Off Label

Diagnosis or treatment of aluminum-induced toxicity associated with chronic kidney disease (CKD)yes

Based on the KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease, deferoxamine is effective and recommended for the diagnosis or treatment of aluminum-induced toxicity in patients with CKD.

Contraindications

Hypersensitivity to deferoxamine or any component of the formulation; patients with severe renal disease or anuria

Dosage and Administration

Dosing: Adult

Acute iron toxicity: Note: The IV route is preferred and is used when severe toxicity is evidenced by cardiovascular collapse or systemic symptoms (coma, shock, metabolic acidosis, or gastrointestinal bleeding) or potentially severe intoxications (peak serum iron level >500 mcg/dL) (Perrone 2015). The IM route may be used (per the manufacturer) but is not preferred and rarely indicated. The use of deferoxamine in situations in which the peak serum iron concentration is <500 mcg/dL or when severe toxicity is not evident is a subject of clinical debate (Howland 2015; Perrone 2015).

IM, IV: Initial: 1,000 mg, may be followed by 500 mg every 4 hours for 2 doses; subsequent doses of 500 mg have been administered every 4 to 12 hours based on clinical response (maximum recommended dose: 6,000 mg/day [per manufacturer])

Chronic iron overload:

IM: 500 to 1,000 mg/day (maximum: 1000 mg/day)

IV: 40 to 50 mg/kg/day (maximum: 60 mg/kg/day) over 8 to 12 hours for 5 to 7 days per week

SubQ: 1,000 to 2,000 mg/day or 20 to 40 mg/kg/day over 8 to 24 hours

Off-label dosing: IV, SubQ: 25 to 50 mg/kg over 8 to 10 hours 5 to 7 days per week (Brittenham, 2011)

Diagnosis of aluminum-induced toxicity with CKD (off-label use) (K/DOQI guidelines 2003): IV: Test dose: 5 mg/kg during the last hour of dialysis if baseline serum aluminum concentrations are 60 to 200 mcg/L, or clinical signs/symptoms of toxicity, or aluminum exposure prior to parathyroid surgery. Measure aluminum just prior to deferoxamine; remeasure 2 days later (test is positive if serum aluminum increases by ≥50 mcg/L). Do not use if unstimulated aluminum serum concentrations are >200 mcg/L to avoid deferoxamine-induced neurotoxicity.

Treatment of aluminum toxicity with CKD (off-label use) (K/DOQI guideline, 2003): IV:

Administer after diagnostic deferoxamine test dose. Note: The risk for deferoxamine-associated neurotoxicity is increased if unstimulated aluminum serum concentrations are >200 mcg/L; do not perform the deferoxamine-stimulation test and administer intensive dialysis until <200 mcg/L.

If the serum aluminum concentration rises to ≥300 mcg/L two days after the deferoxamine test dose or there are side effects after the deferoxamine-stimulation test: 5 mg/kg once a week 5 hours before dialysis for 4 months. Then discontinue deferoxamine for one month and perform the deferoxamine-stimulation test again.

If the serum aluminum concentration is <300 mcg/L two days after the deferoxamine test dose and there are no side effects after the deferoxamine-stimulation test: 5 mg/kg once a week during the last hour of dialysis for 2 months. The discontinue deferoxamine for one month and perform the deferoxamine-stimulation test again.

Dosing: Geriatric

Refer to adult dosing. May initiate at the lower end of the dosing range.

Dosing: Pediatric

Acute iron intoxication: Limited data available: Children and Adolescents: Note: The IV route is used when severe toxicity is evidenced by cardiovascular collapse or systemic symptoms (coma, shock, metabolic acidosis, or gastrointestinal bleeding) or potentially severe intoxications (peak serum iron level >500 mcg/dL) (Perrone 2011). When severe symptoms are not present, then IM may be used.

Continuous IV infusion: Initial: 15 mg/kg/hour and reduce rate as clinically indicated; maximum daily dose: 80 mg/kg/day and not to exceed 6 g/day (Desferal prescribing information [Canada; UK] 2010)

IV: Initial: 20 mg/kg (maximum dose: 1,000 mg) administered no faster than 15 mg/kg/hour followed by 10 mg/kg (maximum dose: 500 mg) over 4-hour intervals for 2 doses; subsequent doses of 10 mg/kg (maximum dose: 500 mg) over 4 to 12 hours may be repeated depending upon the clinical response; maximum dose: 6 g/day; this dosing may also be used IM if symptoms not severe

IM: 90 mg/kg/dose for one dose, then 45 mg/kg/dose every 4 to 12 hours as needed; maximum single dose: Children: 1,000 mg; Adults: 2,000 mg; maximum daily dose: 6 g/day (Desferal prescribing information [Canada; UK] 2010); others have used 50 mg/kg/dose every 6 hours with maximum daily dose: 6 g/day (Chang 2011); may also use intermittent IV dosing (see above)

Chronic iron overload:

General dosing: Manufacturer's labeling: Children ≥3 years and Adolescents:

IV:

Children and Growing Adolescents: 20 to 40 mg/kg/day over 8 to 12 hours, 5 to 7 days per week, usual maximum daily dose: 40 mg/kg/day

Adolescents once growth has ceased: 40 to 50 mg/kg/day over 8 to 12 hours, 5 to 7 days per week, usual maximum daily dose: 60 mg/kg/day

SubQ infusion via a portable, controlled infusion device: 20 to 40 mg/kg/day over 8 to 12 hours 3 to 7 days per week; maximum daily dose: 2,000 mg/day. Doses >60 mg/kg/day have not been shown to provide additional benefit (Vlachos 2008).

Sickle cell disease, chronic iron overload: Children and Adolescents: SubQ infusion: 25 mg/kg/day over 8 hours; dose and duration may be increased as needed (NHLBI 2005)

Thalassemia, chronic iron overload: Note: A lower dose may be required if the ferritin levels are low. In general, the therapeutic index should be kept <0.025 at all times. Therapeutic index = mean daily deferoxamine dose (mg/kg)/ferritin (mcg/L) (Cappellini 2008):

Children and Growing Adolescents: SubQ infusion: 20 to 40 mg/kg/day over 8 to 12 hours, 6 to 7 nights per week, maximum daily dose: 40 mg/kg/day

Adolescents once growth has ceased:

SubQ infusion (preferred): 40 to 60 mg/kg/day over 8 to 12 hours, 6 to 7 nights per week, maximum daily dose: 2,000 mg/day

SubQ bolus: 45 mg/kg/dose, 5 times per week

Aluminum-induced bone disease in chronic renal failure: Limited data available: Children and Adolescents: Note: Intended for predialysis serum aluminum concentration of 60 to 200 mcg/L; do not start chelation therapy if serum aluminum concentration >200 mcg/L; intensive dialysis (6 days per week with a high flux dialysis membrane) should be used until serum aluminum concentration decreases below 200 mcg/L (National Kidney Foundation 2003):

Test (diagnostic) dose: IV: 5 mg/kg as a single dose infused over the last hour of dialysis; measure serum aluminum concentration 2 days later; depending upon the change in serum aluminum concentration, treatment with deferoxamine may be indicated (see Treatment below)

Treatment: Monitor serum aluminum levels closely. See National Kidney Foundation guidelines for additional details on treatment algorithms.

Aluminum serum concentration rise to ≥300 mcg/L or adverse effects with test dose: IV: 5 mg/kg once a week 5 hours before dialysis for 4 months

Aluminum serum concentration rise to <300 mcg/L: IV: 5 mg/kg once a week during the last hour of dialysis for 2 months

Reconstitution

IM: Reconstitute with sterile water for injection (500 mg vial with 2 mL SWFI; 2000 mg vial with 8 mL SWFI) to a final concentration of 213 mg/mL

IV: Reconstitute with sterile water for injection (500 mg vial with 5 mL SWFI; 2000 mg vial with 20 mL SWFI) to a final concentration of 95 mg/mL; further dilute for infusion in sodium chloride 0.9%, sodium chloride 0.45%, D5W, or LR.

SubQ: Reconstitute with sterile water for injection (500 mg vial with 5 mL SWFI; 2000 mg vial with 20 mL SWFI) to a final concentration of 95 mg/mL

Administration

IV: Urticaria, flushing of the skin, hypotension, and shock have occurred following rapid IV administration; limiting infusion rate to 15 mg/kg/hour may help avoid infusion-related adverse effects.

Acute iron toxicity: The IV route is generally preferred in patients with severe toxicity (ie, patients in shock). For the first 1,000 mg, infuse at 15 mg/kg/hour (although rates up to 40 to 50 mg/kg/hour have been given in patients with severe iron intoxication). Subsequent doses may be given over 4 to 12 hours at a rate not to exceed 125 mg/hour.

Chronic iron overload: Administer over 8 to 12 hours for 5 to 7 days per week; rate not to exceed 15 mg/kg/hour. In patients with poor compliance, deferoxamine may be administered on the same day of blood transfusion, either prior to or following transfusion; do not administer concurrently with transfusion. Longer infusion times (24 hours) and IV administration may be required in patients with severe cardiac iron deposition (Brittenham, 2011).

Diagnosis or treatment of aluminum-induced toxicity with CKD: Administer dose over 1 hour, during the last hour of dialysis (K/DOQI guidelines, 2003).

SubQ: When administered for chronic iron overload, administration over 8 to 12 hours using a portable infusion pump is generally recommended; however, longer infusion times (24 hours) may also be used. Topical anesthetic or glucocorticoid creams may be used for induration or erythema (Brittenham, 2011).

IM: IM administration may be used for patients with acute iron toxicity that do not exhibit severe symptoms (per the manufacturer), but the IV route is preferred (Perrone 2015); may also be used in the treatment of chronic iron toxicity.

Dietary Considerations

Vitamin C supplements may need to be limited. The manufacturer recommends a maximum ascorbic acid dose of 200 mg/day in adults (given in divided doses), 100 mg/day in children ≥10 years of age, or 50 mg/day in children <10 years of age. Avoid concurrent use with ascorbic acid in patients with heart failure.

Storage

Prior to reconstitution, store at ≤25˚C (≤77°F). Following reconstitution, may be stored at room temperature for 24 hours, although the manufacturer recommends use begin within 3 hours of reconstitution. Do not refrigerate reconstituted solution. When stored at 30˚C in polypropylene infusion pump syringes, deferoxamine 250 mg/mL in sterile water for injection retained 95% of initial concentration for 14 days (Stiles 1996).

Drug Interactions

Ascorbic Acid: May enhance the adverse/toxic effect of Deferoxamine. Left ventricular dysfunction is of particular concern. Management: Avoid ascorbic acid doses greater than 200 mg/day. Lower doses may be given to patients without cardiac failure, after one month of regular treatment with deferoxamine alone, ideally soon after setting up the infusion pump. Monitor cardiac function. Consider therapy modification

Multivitamins/Fluoride (with ADE): May enhance the adverse/toxic effect of Deferoxamine. Management: Avoid ascorbic acid doses greater than 200 mg/day. Lower doses may be given to patients without cardiac failure, after one month of regular treatment with deferoxamine alone, ideally soon after setting up the infusion pump. Monitor cardiac function. Consider therapy modification

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the adverse/toxic effect of Deferoxamine. Left ventricular dysfunction is of particular concern. Management: Avoid ascorbic acid doses greater than 200 mg/day. Lower doses may be given to patients without cardiac failure, after one month of regular treatment with deferoxamine alone, ideally soon after setting up the infusion pump. Monitor cardiac function. Consider therapy modification

Multivitamins/Minerals (with AE, No Iron): May enhance the adverse/toxic effect of Deferoxamine. Management: Avoid ascorbic acid doses greater than 200 mg/day. Lower doses may be given to patients without cardiac failure, after one month of regular treatment with deferoxamine alone, ideally soon after setting up the infusion pump. Monitor cardiac function. Consider therapy modification

Prochlorperazine: Deferoxamine may enhance the adverse/toxic effect of Prochlorperazine. Specifically, prolonged loss of consciousness has been reported. Consider therapy modification

Test Interactions

TIBC may be falsely elevated with high serum iron concentrations or deferoxamine therapy. Imaging results may be distorted due to rapid urinary excretion of deferoxamine-bound gallium-67; discontinue deferoxamine 48 hours prior to scintigraphy.

Adverse Reactions

Frequency not defined.

Cardiovascular: Flushing, hypotension, shock, tachycardia

Central nervous system: Brain disease (aluminum toxicity/dialysis-related), dizziness, headache, neuropathy (peripheral, sensory, motor, or mixed), paresthesia, seizure

Dermatologic: Skin rash, urticaria

Endocrine & metabolic: Growth suppression (children), hyperparathyroidism (aggravated), hypocalcemia

Gastrointestinal: Abdominal distress, abdominal pain, diarrhea, nausea, vomiting

Genitourinary: Dysuria, urine discoloration (pink, orange, or reddish color)

Hematologic & oncologic: Dysplasia (metaphyseal; children <3 years; dose related), leukopenia, thrombocytopenia

Hepatic: Hepatic insufficiency, increased serum transaminases

Hypersensitivity: Anaphylaxis (with or without shock), angioedema, hypersensitivity

Infection: Infection (Yersinia, mucormycosis)

Local: Injection site reaction (burning, crust, edema, erythema, eschar, induration, infiltration, irritation, pain, pruritus, swelling, vesicles, wheal formation)

Neuromuscular & skeletal: Arthralgia, muscle spasm, myalgia

Ophthalmic: Blurred vision, cataract, chromatopsia, corneal opacity, decreased peripheral vision, decreased visual acuity, nocturnal amblyopia, optic neuritis, retinal pigment changes, scotoma, vision loss, visual field defect

Otic: Hearing loss, tinnitus

Renal: Acute renal failure, increased serum creatinine, renal tubular disease

Respiratory: Acute respiratory distress (dyspnea, cyanosis, and/or interstitial infiltrates), asthma

Miscellaneous: Fever

Warnings/Precautions

Concerns related to adverse effects:

• Acute respiratory distress syndrome (ARDS): Deferoxamine has been associated with ARDS following excessively high-dose IV treatment of acute iron intoxication or thalassemia; has been reported in children and adults.
• Auditory effects: Auditory disturbances (tinnitus and high frequency hearing loss) have been reported following prolonged administration, at high doses, or in patients with low ferritin levels; effects are generally reversible with early detection and immediate discontinuation. Elderly patients are at increased risk for hearing loss. Audiology exams are recommended with long-term treatment.
• Growth retardation: High deferoxamine doses and concurrent low ferritin levels are also associated with growth retardation. Growth velocity may partially resume to pretreatment rates after deferoxamine dose reduction.
• Infection: Patients with iron overload are at increased susceptibility to infection with Yersinia enterocolitica and Yersinia pseudotuberculosis; treatment with deferoxamine may enhance this risk; if infection develops, discontinue therapy until resolved.
• Infusion reactions: Flushing of the skin, hypotension, urticaria, and shock are associated with rapid IV infusion; administer by slow IV infusion, IM, or slow subcutaneous infusion only.
• Mucormycosis: Rare and serious cases of mucormycosis (including fatalities) have been reported with use; withhold treatment with signs and symptoms of mucormycosis.
• Ocular effects: Ocular disturbances (blurred vision; cataracts; corneal opacities; decreased visual acuity; impaired peripheral, color, and night vision; optic neuritis; retinal pigment abnormalities; retinopathy; scotoma; visual loss/defect) have been reported following prolonged administration, at high doses, or in patients with low ferritin levels; effects are generally reversible with early detection and immediate discontinuation. Elderly patients are at increased risk for ocular disorders. Periodic ophthalmic exams are recommended with long-term treatment.
• Renal effects: Increases in serum creatinine, acute renal failure and renal tubular disorders have been reported; monitor for changes in renal function. Deferoxamine is readily dialyzable. When iron is chelated with deferoxamine, the chelate is water-soluble and is excreted renally.
• Urine discoloration: Patients should be informed that urine may have a pink, reddish, or orange discoloration (often referred to as vin rosé discoloration).

Disease-related concerns:

• Aluminum toxicity: Treatment with deferoxamine in patients with aluminum toxicity may cause hypocalcemia and aggravate hyperparathyroidism. Deferoxamine may cause neurological symptoms (including seizure) in patients with aluminum-related encephalopathy receiving dialysis and may precipitate dialysis dementia onset.
• Hemochromatosis: Deferoxamine is not indicated for the treatment of primary hemochromatosis (treatment of choice is phlebotomy).

Concurrent drug therapy issues:

• Ascorbic acid: Combination treatment with ascorbic acid (>500 mg/day in adults) and deferoxamine may impair cardiac function (rare), effects are reversible upon discontinuation of ascorbic acid. If combination treatment is warranted, initiate ascorbic acid only after one month of regular deferoxamine treatment, do not exceed ascorbic acid dose of 200 mg/day for adults (in divided doses), 100 mg/day for children ≥10 years of age, or 50 mg/day in children <10 years of age; monitor cardiac function. Do not administer deferoxamine in combination with ascorbic acid in patients with preexisting cardiac failure.

Monitoring Parameters

Serum iron, ferritin, total iron-binding capacity, CBC with differential, renal function tests (serum creatinine), liver function tests, serum chemistries; ophthalmologic exam (visual acuity tests, fundoscopy, slit-lamp exam) and audiometry with long-term treatment; growth and body weight in children (every 3 months). When deferoxamine complexes with iron it forms a water-soluble compound (ferrixoamine) that imparts discoloration of the urine; often described as vin rosé (dark pink) discoloration to the urine (Fernández 2014). However, other than being aware of that it may occur, its presence or absence should not be used as a therapeutic endpoint.

Dialysis patients: Serum aluminum (yearly; every 3 months in patients on aluminum-containing medications)

Aluminum-induced bone disease: Serum aluminum concentration 2 days following deferoxamine test dose; test is considered positive if the serum aluminum increases ≥50 mcg/L

Pregnancy

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Toxic amounts of iron or deferoxamine have not been noted to cross the placenta; however, the metabolic effects of a maternal overdose may adversely affect the fetus. In case of acute iron toxicity, treatment during pregnancy should not be withheld (Chang 2011).

Patient Education

What is this drug used for?

• It is used to get rid of iron when too much is in the body.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Urine discoloration
• Headache
• Nausea
• Vomiting
• Diarrhea
• Muscle spasms
• Joint pain
• Muscle pain
• Abdominal pain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Severe pulmonary disorder like lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse.
• Fast heartbeat
• Severe dizziness
• Passing out
• Flushing
• Blue/gray skin discoloration
• Burning or numbness feeling
• Seizures
• Bruising
• Bleeding
• Severe injection site irritation
• Vision changes
• Trouble hearing
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.