Deferoxamine

V03A - All other therapeutic products ATC V03AC01 Small molecule approved 1968 Parenteral Natural product

JFDA label: Noferal

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.

Indications

Approved

Acute iron toxicity
Chronic iron overload

Off-label

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

Contraindications

Source: Lexicomp

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

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (4)

Not Known Flushing · hypotension · shock · tachycardia

Nervous system disorders (6)

Not Known Brain disease (aluminum toxicity/dialysis-related) · dizziness · headache · neuropathy (peripheral, sensory, motor, or mixed) · paresthesia · seizure

Renal and urinary disorders (5)

Not Known Acute renal failure · Dysuria · increased serum creatinine · renal tubular disease · urine discoloration (reddish color)

Blood and lymphatic system disorders (1)

Not Known Dysplasia (metaphyseal; children Hepatic: Hepatic insufficiency, increased serum transaminases

Immune system disorders (3)

Not Known Anaphylaxis (with or without shock) · angioedema · hypersensitivity

Metabolism and nutrition disorders (3)

Not Known Growth suppression (children) · hyperparathyroidism (aggravated) · hypocalcemia

Gastrointestinal disorders (5)

Not Known Abdominal distress · abdominal pain · diarrhea · nausea · vomiting

Skin and subcutaneous tissue disorders (2)

Not Known Skin rash · urticaria

Musculoskeletal and connective tissue disorders (3)

Not Known Arthralgia · muscle spasm · myalgia

Eye disorders (12)

Not Known 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

Ear and labyrinth disorders (2)

Not Known Hearing loss · tinnitus

Infections and infestations (1)

Not Known Infection (Yersinia, mucormycosis)

General disorders and administration site conditions (2)

Not Known Fever · Injection site reaction (burning, crust, edema, erythema, eschar, induration, infiltration, irritation, pain, pruritus, swelling, vesicles, wheal formation)

Respiratory, thoracic and mediastinal disorders (2)

Not Known Acute respiratory distress (dyspnea, cyanosis, and/or interstitial infiltrates) · asthma

Dosing

Source: Lexicomp

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 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 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 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.

(For additional information see "Deferoxamine: Pediatric drug information") Acute iron toxicity: Children and Adolescents: 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 IM: 90 mg/kg/dose every 8 hours (maximum: 6,000 mg/24 hours) IV: 15 mg/kg/hour (maximum: 6,000 mg/24 hours) Chronic iron overload: Children ≥3 years and Adolescents: IV: 20 to 40 mg/kg/day over 8 to 12 hours for 5 to 7 days per week; dose should not exceed 40 mg/kg/day until growth has ceased SubQ: 20 to 40 mg/kg/day over 8 to 12 hours (maximum: 1,000 to 2,000 mg/day) Off-label dosing: IV, SubQ: 25 to 30 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): Children and Adolescents: 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 guidelines 2003): Children and Adolescents: 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 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 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.

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

Severe renal disease or anuria: Use is contraindicated in the manufacturer's US labeling. The following adjustments have been used by some clinicians (Aronoff 2007): Adults: CrCl >50 mL/minute: No adjustment required CrCl 10 to 50 mL/minute, CRRT: Administer 25% to 50% of normal dose CrCl

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Warnings & Precautions

Source: Lexicomp

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. 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

Pregnancy & Lactation

Pregnancy

FDA category C

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).

Lactation

It is not known if deferoxamine is excreted in breast milk. The manufacturer recommends that caution be exercised when administering to nursing women.

Monitoring

Clinical pearl	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

Clinical pearl

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

Chemistry & Properties

Formula	C25H48N6O8
Molecular weight	560.69 g/mol
IUPAC name	N-[5-[[4-[5-[acetyl(hydroxy)amino]pentylamino]-4-oxobutanoyl]-hydroxyamino]pentyl]-N'-(5-aminopentyl)-N'-hydroxybutanediamide
CAS	70-51-9
PubChem CID	2973
InChIKey	`UBQYURCVBFRUQT-UHFFFAOYSA-N`
logP	0.92 (XLogP -2.1)
Polar surface area	205.84 Å²
H-bond acceptors / donors	9 / 6
Drug-likeness (QED)	0.06
Lipinski violations	2

SMILES

CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2C19	Substrate	—
CYP3A4	Inhibitor	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (18, DDInter)

Interacting drug	Severity	Management
Cidofovir	major
Diatrizoate	major
Inotersen	major
Iodipamide	major
Iodixanol	major
Iohexol	major
Iopamidol	major
Iopromide	major
Iothalamic acid	major
Ioversol	major
Ioxilan	major
Vigabatrin	major
Ascorbic acid	moderate
Busulfan	moderate
Clofarabine	moderate
Gallium chloride Ga-67	moderate
Prochlorperazine	moderate
Remdesivir	moderate

Registered Products (2)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Froxa	Vial 500 mg	10 vial	MS PHARMA/JORDAN	—
Noferal	Vial 500 mg	10 vial	Hikma Pharmaceuticals Co.Ltd/Jordan	—