Desferal

DESFERAL is an iron-chelating agent indicated:

• As an adjunct to standard measures for the treatment of acute iron intoxication. (
  1.1     Acute Iron Intoxication

  DESFERAL is indicated as an adjunct to standard measures for the treatment of acute iron intoxication.
  )
  
• For the treatment of transfusional iron overload in patients with chronic anemia. (
  1.2     Chronic Iron Overload

  DESFERAL is indicated for the treatment of transfusional iron overload in patients with chronic anemia.
  )
  

Desferal is not indicated for the treatment of primary hemochromatosis (since phlebotomy is the method of choice for removing excess iron in this disorder).

The dosage (based on body weight in mg/kg/day), rates of administration, and mode of administration for both adults and pediatric patients are individually determined and adapted during the course of therapy based on the severity of the patient's iron overload. The minimum daily dose of Desferal is 20 mg/kg/day for both adults and pediatric patients. The maximum daily dose is 40 mg/kg/day for pediatric patients and 60 mg/kg/day for adults.

For injection: 500 mg of deferoxamine mesylate (corresponding to 426.82 mg of deferoxamine as free base) as a white to almost white lyophilized powder in a single-dose vial for reconstitution.

• Lactation: Advise not to breastfeed (
  8.2     Lactation

  There are no data on the presence of deferoxamine or its metabolite in either human or animal milk, the effects on the breastfed child, or the effects on milk production. It is not known whether deferoxamine is excreted in human milk. Because of the potential for serious adverse reactions in the breastfed child, advise patients not to breastfeed during treatment with Desferal, and for one week after the last dose.
  )
  
• Geriatric Use: Increased risk of ocular disorders (
  8.5     Geriatric Use

  Clinical Studies of Desferal did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from the younger subjects. Postmarketing reports suggest a possible trend for an increased risk of eye disorders in the geriatric population, specifically the occurrence of color blindness, maculopathy, and scotoma. However, it is unclear if these eye disorders were dose related. Although the number of reports was very small, certain elderly patients may be predisposed to eye disorders when taking Desferal. Postmarketing reports also suggest that there may be an increased risk of deafness and hearing loss in the geriatric population

  [see Adverse Reactions (6)]

  . In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
  )
  

• Hypersensitivity Reactions: More common with rapid intravenous infusion. Administer intramuscularly or by slow subcutaneous or intravenous infusion. (
  5.1     Hypersensitivity Reactions

  Hypersensitivity reactions, including anaphylaxis, have occurred in Desferal-treated patients. Reactions have included flushing of the skin, urticaria, hypotension, and shock. These reactions typically occur when Desferal was administered by rapid intravenous injection. Therefore, administer Desferal intramuscularly or by slow subcutaneous or intravenous infusion.
  )
  
• Auditory and Ocular Toxicity: Have been reported when administered over prolonged periods of time, at high doses, or in patients with low ferritin levels. (
  5.2     Auditory and Ocular Toxicity

  Ocular and auditory toxicities have been reported in Desferal-treated patients. The ocular toxicities observed have included blurring of vision; cataracts after prolonged administration in chronic iron overload; decreased visual acuity, including visual loss, visual defects, scotoma; impaired peripheral, color, and night vision; optic neuritis, cataracts, corneal opacities, and retinal pigmentary abnormalities. The auditory toxicities reported have been tinnitus and hearing loss, including high frequency sensorineural hearing loss. Risk factors for both ocular and auditory disturbances include prolonged treatment duration, higher doses, or low ferritin levels. In most cases, both ocular and auditory disturbances were reversible upon immediate cessation of treatment

  [see Adverse Reactions (6)]

  .

  Visual acuity tests, slit-lamp examinations, funduscopy, and audiometry are recommended periodically in patients treated for prolonged periods of time. Toxicity is more likely to be reversed if symptoms or test abnormalities are detected early.
  )
  
• Renal Toxicity: Cases of acute renal failure, renal tubular disorders and increase in serum creatinine have occurred. Monitor patients for changes in renal function. (
  5.3     Renal Toxicity

  Renal toxicity, including increases in serum creatinine (possibly dose-related), acute renal failure and renal tubular disorders has occurred in Desferal-treated patients. Desferal is contraindicated in patients with severe renal disease

  [see Contraindications (4)]

  . Monitor serum creatinine to assess for changes in renal function.
  )
  
• Respiratory Toxicity: Acute respiratory distress syndrome has occurred. Risk increased with high intravenous doses. Recommended daily dose should not be exceeded. (
  5.4     Respiratory Toxicity

  Acute respiratory distress syndrome has occurred in Desferal-treated patients following treatment with excessively high intravenous doses of Desferal in patients with acute iron intoxication or thalassemia. The recommended daily doses should therefore not be exceeded.
  )
  
• Growth Suppression: Has occurred in pediatric patients treated with high doses and concomitant low ferritin levels. Dose reduction may partially resume growth velocity to pre-treatment rates. (
  5.5     Growth Suppression

  High doses of Desferal and concomitant low ferritin levels have also been associated with growth suppression in pediatric patients. After reduction of Desferal dose, growth velocity may partially resume to pre-treatment rates. Monitor growth (weight and height) in pediatric patients treated with Desferal every 3 months.
  )
  
• Serious Infections: Cases of mucormycosis and Yersinia infections, some fatal, have occurred. Discontinue Desferal and initiate appropriate treatment immediately. (
  5.6     Serious Infections

  Yersinia Infections

  Desferal may increase the risk of

  Yersinia enterocolitica

  and

  Yersinia pseudotuberculosis

  infections. Avoid starting Desferal treatment in patients with active Yersinia infections. Should Yersinia infection develop, interrupt Desferal treatment until the infection is resolved.

  Mucormycosis

  Cases of mucormycosis, some with a fatal outcome, have occurred in Desferal-treated patients. Signs or symptoms are specific to the site of infection. If mucormycosis is suspected, discontinue Desferal, conduct mycological testing, and treat immediately.
  )
  
• Cardiac Dysfunction with Concomitant Use of Vitamin C: Avoid coadministration in patients with cardiac failure. Delay Vitamin C for one month after start of Desferal. Avoid exceeding 200 mg daily in adults. Monitor cardiac function with combined treatment. (
  5.7     Cardiac Dysfunction With Concomitant Use of Vitamin C

  Cardiac dysfunction has occurred in Desferal-treated patients with severe chronic iron overload following concomitant treatment with high doses of vitamin C (more than 500 mg daily in adults). The cardiac dysfunction was reversible when vitamin C was discontinued. The following precautions should be taken when vitamin C and Desferal are to be used concomitantly:

  • Vitamin C supplements should not be given to patients with cardiac failure.
  • Start supplemental vitamin C only after an initial month of regular treatment with Desferal.
  • Give vitamin C only if the patient is receiving Desferal regularly, ideally soon after setting up the infusion pump.
  • Do not exceed a daily vitamin C dose of 200 mg in adults, given in divided doses. In general, 50 mg daily suffices for pediatric patients under 10 years old and 100 mg for older pediatric patients.
  • Clinical monitoring of cardiac function is advisable during such combined therapy.
  )
  
• Risks of Desferal Treatment in Patients with Aluminum Overload: Risks include neurological dysfunction (including seizures), dialysis dementia, and aggravation of hyperparathyroidism. (
  5.8     Risks of Desferal Treatment in Patients With Aluminum Overload

  Desferal may cause neurological dysfunction (including seizures) in patients with aluminum-related encephalopathy and receiving dialysis, possibly due to an acute increase in circulating aluminum

  [see Adverse Reactions (6)]

  .

  Desferal may precipitate the onset of dialysis dementia.

  Treatment with Desferal in the presence of aluminum overload may result in decreased serum calcium and aggravation of hyperparathyroidism.
  )
  
• Effects on Ability to Drive and Use Machines: May cause dizziness. (
  5.9     Effects on Ability to Drive and Use Machines

  Desferal may cause dizziness, which may impair the ability to drive a car or operate machinery. Patients should not drive or operate machinery until they know how Desferal will affect their ability to engage in these activities.
  )
  
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use effective contraception. (
  5.10     Embryo-Fetal Toxicity

  Based on findings in animals, Desferal can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of deferoxamine to pregnant mice and rabbits during the period of organogenesis caused adverse developmental outcomes including decreased fetal body weights and malformations at maternal doses less than those in patients at maximum recommended human dose (MRHD). Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with Desferal and for one month after the last dose

  [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)]

  .
  ,
  8.1     Pregnancy

  Risk Summary

  There are no available data on Desferal use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriages or adverse maternal or fetal outcomes.

  In animal reproduction studies subcutaneous administration of deferoxamine to pregnant animals (mice or rabbits) during organogenesis at doses approximately ≥ 0.2 (mice) and ≥ 0.7 (rabbits) times the maximum recommended human dose resulted in maternal toxicity and adverse developmental outcomes (

  see Data

  ). Advise pregnant women of the potential risk to a fetus. Consider the benefits and risks of Desferal for the mother and possible risks to the fetus when prescribing Desferal to a pregnant woman.

  The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

  Data

  Animal Data

  In an embryo-fetal developmental study in mice, pregnant animals administered subcutaneous doses of deferoxamine at 180, and 540 mg/kg/day from gestation day 7 to gestation day 12 resulted in a dose dependent delay and irregularities of fetal skeletal maturation at doses ≥ 0.2 times the MRHD. At the highest dose of 540 mg/kg, in 1/23 fetuses had a unilateral lesion to the eye lens (approximately 0.5 times the MRHD).

  In the embryo-fetal developmental studies in rabbits, pregnant animals administered subcutaneous doses of deferoxamine either 200 mg/kg or 200, 300, and 540 mg/kg from gestation day 6 to gestation day 14 resulted in maternal toxicity and embryo-fetal developmental effects at 0.7 times the MRHD). Maternal toxicity included reduced fetal body weights and embryo-fetal effects included malformations of spina bifida, and increased incidence of abnormally ossified ribs and vertebrae.

  No maternal toxicity or embryo-fetal effects were observed in rats at deferoxamine doses tested (up to 0.9 times the MRHD).
  ,
  8.3     Females and Males of Reproductive Potential

  Based on animal data, Desferal can cause malformations at doses less than the human dose

  [see Use in Specific Populations (8.1)]

  .

  Contraception

  Females

  Desferal can cause embryo-fetal harm when administered to pregnant women

  [see Use in Specific Populations (8.1)]

  . Advise female patients of reproductive potential to use effective contraception during treatment with Desferal and for one month after the last dose.
  )