Desferal (Deferoxamine) is an iron-chelating drug that is used in the treatment of acute and chronic iron overload as in patients with thalassemia. It also binds aluminum and is used in patients on hemodialysis with aluminum toxicity.

Indications of Desferal (Deferoxamine):

• Acute iron toxicity:

  • It is used as an adjunct in the treatment of acute iron intoxication.

• Chronic iron overload:

  • It is indicated for the treatment of chronic iron overload secondary to multiple transfusions (often due to the presence of thalassemia major or sickle cell disease).

• Off Label Use of Deferoxamine in Adults:

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

Desferal (Deferoxamine) dose in adults:

Desferal (Deferoxamine) dose in the treatment of Acute iron toxicity:

Note:

• In case of cardiovascular collapse or systemic symptoms (coma, shock, metabolic acidosis, or gastrointestinal bleeding) or potentially severe intoxications (peak serum iron level >500 mcg/dL), therapy is given via IV route.
• The manufacturer states that the IM route 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.
• IM, IV: Initial:
  • 1,000 mg, may be followed by 500 mg every 4 hours for 2 doses;
  • The subsequent doses of 500 mg have been administered every 4 to 12 hours based on clinical response
  • The maximum recommended dose: 6,000 mg/day as per manufacturer.

Desferal (Deferoxamine) dose in the treatment of Chronic iron overload:

• Intramuscular administration:
  • 500 to 1,000 mg/day administered IM.
  • The maximum dose is 1000 mg/day.
• Intravenous administration:
  • 40 to 50 mg/kg/day over 8 to 12 hours for 5 to 7 days per week.
  • The maximum dose is 60 mg/kg/day.
• SubQ administration:
  • 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.

Desferal (Deferoxamine) Dose in the Diagnosis of aluminum-induced toxicity with CKD (off-label use:

• Test dose: 5 mg/kg IV 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.
• Aluminum levels should be checked before administering deferoxamine, remeasure 2 days later (test is positive if serum aluminum increases by ≥50 mcg/L).
• If unstimulated aluminum serum concentrations are >200 mcg/L, therapy should not be used to avoid deferoxamine-induced neurotoxicity.

Desferal (Deferoxamine) dose in the treatment of aluminum toxicity with CKD (off-label use):

• Administer after the diagnostic deferoxamine test dose.

Note:

• If unstimulated aluminum serum concentrations are >200 mcg/L, the risk of deferoxamine neurotoxicity is raised.
• Deferoxamine-stimulation test and administer intensive dialysis should not be done 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.
    • Deferoxamine should be withheld for one month and the deferoxamine-stimulation test should be repeated.
  • 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.
    • Deferoxamine should be withheld for one month and the deferoxamine-stimulation test should be repeated.

Desferal (Deferoxamine) dose in children:

Desferal (Deferoxamine) dose for Acute iron intoxication:

• Children and Adolescents:

Note:

• In case of cardiovascular collapse or systemic symptoms (coma, shock, metabolic acidosis, or gastrointestinal bleeding) or potentially severe intoxications (peak serum iron level >500 mcg/dL), therapy should be given via IV route.
• IM route should be used when symptoms are mild.

• • Continuous IV infusion:
    • Initial: 15 mg/kg/hour and reduce rate as clinically indicated.
    • The maximum daily dose is 80 mg/kg/day and not to exceed 6 g/day.
    • Initial: 20 mg/kg IV (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.
    • The maximum dose is 6 g/day. This dosing may also be used IM if symptoms not severe.
    • 90 mg/kg/dose IM for one dose, then 45 mg/kg/dose every 4 to 12 hours as needed.
    • The maximum single IM dose: Children: 1,000 mg; Adults: 2,000 mg.
    • The maximum daily dose: 6 g/day, others have used 50 mg/kg/dose every 6 hours with maximum daily dose: 6 g/day, intermittent IV dosing may also be used.

Desferal (Deferoxamine) dose in Chronic iron overload:

• General dosing:

  • Manufacturer's labeling: Children ≥3 years and Adolescents:

    • Children and Growing Adolescents:
      • 20 to 40 mg/kg/day IV 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 IV 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.
    • The maximum daily dose: 2,000 mg/day.
    • Doses >60 mg/kg/day have not been shown to provide additional benefit.

Desferal (Deferoxamine) dose for chronic iron overload in patients with Sickle cell disease:

• Children and Adolescents:

  • SubQ infusion: 25 mg/kg/day over 8 hours; dose and duration may be increased as needed.

Desferal (Deferoxamine) dose in chronic iron overload in patients with Thalassemia:

Note:

• In the case of low ferritin levels, a smaller dose is needed.
• In general, the therapeutic index should be kept <0.025 at all times.
• Therapeutic index = mean daily deferoxamine dose (mg/kg)/ferritin (mcg/L).

• Children and Growing Adolescents:

  • SubQ infusion: 20 to 40 mg/kg/day over 8 to 12 hours, 6 to 7 nights per week.
  • The maximum daily dose is 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.
  • The maximum daily dose: 2,000 mg/day.
  • SubQ bolus: 45 mg/kg/dose, five times per week.

Desferal (Deferoxamine) dose in the treatment of aluminum-induced bone disease in chronic renal failure:

• Children and Adolescents:

Note:

• Intended for predialysis serum aluminum concentration of 60 to 200 mcg/L.
• Chelation therapy should not be initiated 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.
  • Test (diagnostic) dose:
    • 5 mg/kg IV as a single dose infused over the last hour of dialysis;
    • Measure serum aluminum concentration 2 days later.
    • Treatment with deferoxamine depends on the changes in serum aluminum levels.
  • Treatment:
    • Monitor serum aluminum levels closely.
    • See National Kidney Foundation guidelines for additional details on treatment algorithms.

Desferal (Deferoxamine) dose if Aluminum serum concentration rises to ≥300 mcg/L or adverse effects with test dose:

• 5 mg/kg IV once a week 5 hours before dialysis for 4 months.

Desferal (Deferoxamine) dose if Aluminum serum concentration rises to <300 mcg/L:

• 5 mg/kg IV once a week during the last hour of dialysis for 2 months.

Pregnancy Risk Factor C

• Studies on animal reproduction have shown negative results.
• The amount of iron or deferoxamine that crosses the placenta is not greater than what was recommended. 
• However, maternal overdose can have adverse effects on the fetus.
• Acute iron toxicemia should not be treated during pregnancy.

Deferoxamine use during breastfeeding:

• It is unknown if breast milk secretes deferroxamine.
• One patient with beta-thalassemia who was lactating had normal iron levels in breast milk.
• Breastfed infants showed no adverse effects.
• It is important to follow the manufacturer's instructions when prescribing deferoxamine for breastfeeding women.

Desferal (Deferoxamine) Dose adjustment in renal disease:

• Severe renal disease or anuria:

  • Use is contraindicated in the manufacturer's US labeling.

• The following adjustments have been used by some clinicians:

• Adults:

  • CrCl >50 mL/minute:
    • No adjustment required.
  • CrCl 10 to 50 mL/minute, CRRT:
    • Administer 25% to 50% of the normal dose.
  • CrCl<10 mL/minute, hemodialysis, peritoneal dialysis:
    • Avoid use.

Desferal (Deferoxamine) Dose adjustment in liver disease:

There are no dosage adjustments provided in the manufacturer's labeling.

Side effects of Desferal (Deferoxamine):

• Cardiovascular:

  • Flushing
  • Hypotension
  • Shock
  • Tachycardia

• Central Nervous System:

  • Brain Disease (Aluminum Toxicity/Dialysis-Related)
  • Dizziness
  • Headache
  • Neuropathy
  • 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
  • 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

Contraindications to Desferal (Deferoxamine):

• Hypersensitivity to deferoxamine and any component of the formulation
• Anuria or severe renal disease

Warnings and precautions

• Acute respiratory distress syndrome (ARDS).

  • Higher doses of deferoxamine administered via IV can lead to ARDS in children and adults when used for the treatment of severe iron toxicity.

• Auditory effects

  • Higher doses or chronic therapy can cause auditory disturbances (tinnitus, high-frequency hearing loss), which can be reversed by stopping the drug.
  • This is especially true for patients with low ferritin or older age.
  • An audiology exam is required for prolonged therapy.

• Growth Retardation

  • High doses of deferoxamine and low levels of ferritin can cause growth retardation.
  • Deferoxamine dose reductions can partially restore growth velocity at pretreatment rates.

• Infection

  • Iron overload patients on deferoxamine therapy have a higher risk of infection with Yersinia pseudotuberculosis and Yersinia enterocolitica.
  • You should not start treatment until the infection has subsided.

• Infusion reactions

  • Rapid intravenous infusions can cause hypotension, skin flushing, urticaria, shock, and even skin rashes.
  • Slow IV infusions, IM or subcutaneous infusions should be used for all types of therapy.

• Mucormycosis

  • Rarely, life-threatening mucormycosis can occur with deferoxamine treatment. This warrants the withdrawal of treatment.

• Ocular effects

  • High doses of chronic therapy can cause ocular problems such as blurred vision, eye strain, visual loss, and corneal opacities.
  • Patients with low levels of ferritin and older age are at greater risk of developing ocular diseases.
  • For prolonged treatment, periodic ophthalmic examinations are necessary.

• Effects on the renal system:

  • Dialyzable Deferoxamine can be obtained easily
  • Iron chelated with deferoxamine is water-soluble and excreted renally.
  • Deranged renal function, acute renal failure and renal tubular problems can all be caused by dexaminamine therapy.

• Urine discoloration:

  • Patients should be aware that urine can have a pinkish, reddish or orange discoloration (often called vin rose discoloration).

• Aluminum toxicity

  • Patients with aluminum toxicities can develop hypocalcemia or aggravate hyperparathyroidism after receiving deferoxamine.
  • Some patients may experience neurological symptoms, such as a seizure due to aluminum-related dementia.

• Hemochromatosis:

  • Primary hemochromatosis is not treated with Deferoxamine. The best treatment is phlebotomy.

Deferoxamine: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Risk Factor D (Consider therapy modification)
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.
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.
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.
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.
Prochlorperazine	Deferoxamine may enhance the adverse/toxic effect of Prochlorperazine. Specifically, prolonged loss of consciousness has been reported.

Monitoring parameters:

• Serum iron, ferritin, and total iron-binding capacity
• CBC with differential
• Liver function tests
• Renal function tests
• Growth and body weight in children (every 3 months).
• Ophthalmologic exam (visual acuity tests, fundoscopy, slit-lamp exam)
• Audiometry with long-term treatment
• Deferoxamine forms a water-soluble compound (ferrixoamine) with iron that imparts discoloration of the urine, often described as vin rosé (dark pink) discoloration.
• However, 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, the test is considered positive if the serum aluminum increases ≥50 mcg/L.

How to administer Desferal (Deferoxamine)?

Intravenous Administration:

• The rapid intravascular infusion can lead to hypotension, urticaria, flushing of the skin, and shock.
• Adverse effects can be avoided with limiting infusion rate to 15 mg/kg/hour.

Acute iron toxicity:

• The intravenous 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.
• Deferoxamine can be given on the same day of blood transfusion, either before or following transfusion in patients with poor compliance.

It should not be given concurrently with transfusion.

• Patients having severe cardiac iron deposition requires intravenous longer infusion times (24 hours).

Diagnosis or treatment of aluminum-induced toxicity with CKD: The dose should be given over 1 hour, during the last hour of dialysis.

SubQ Administration:

• Therapy over 8 to 12 hours using a portable infusion pump is generally recommended in case of chronic iron overload, however, longer infusion times (24 hours) may also be used.
• Induration or erythema can be managed with topical anesthetic or glucocorticoid creams.

Intramuscular Administration:

• Patients without any severe symptoms of acute iron toxicity can be treated using the IM route as per the manufacturer, but the IV route is preferred.
• IM route may also be used in the treatment of chronic iron toxicity.

Mechanism of action of Desferal (Deferoxamine):

• Deferoxamine binds to trivalent ions (ferric ions), in the vascular area, forming ferrioxamine.
• This is then excreted by the kidneys in the urine.
• As ferrioxamine is excreted, it may cause a pinkish-to-red-or orange-colored urine.
• 100 mg of deferoxamine will bond about 8.5 mg free circulating iron (85 mg per 1000 mg dose).
• However, it cannot remove iron from hemoglobin or transferrin.
• By binding to cytoplasmic iron, you can reduce the free iron-induced damage to mitochondrial cell membranes or enzyme systems.

Absorption: IM, SubQ:

• Well absorbed.

Distribution:

• Distributed throughout body fluids.

Protein binding:

• <10%.

Metabolism is via plasma enzymes:

• It binds with iron to form ferrioxamine (iron complex).

Half-life elimination:

• 14 hours;
• plasma: 20 to 30 minutes.

Excretion:

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

International Brands of Deferoxamine:

• Desferal
• PMS-Deferoxamine
• Desferin
• Talifer

Deferoxamine Brand Names in Pakistan:

deferoxamine Injection 500 mg
Desferal	Novartis Pharma (Pak) Ltd

deferoxamine Tablets 125 mg
Osveral	Nextar Pharma (Pvt) Ltd.

deferoxamine Tablets 250 mg
Osveral	Nextar Pharma (Pvt) Ltd.

deferoxamine Tablets 500 mg]
Osveral	Nextar Pharma (Pvt) Ltd.