Iron-Chelating Therapy

Regular blood transfusion results in the gradual accumulation of iron, initially in the liver, and then throughout the body including the heart and endocrine organs. If iron is allowed to accumulate it causes tissue damage, with hepatic, endocrine and cardiac failure, the latter resulting in death if untreated. Cardiac iron overlaod is rare in children with sickle cell disease, but an important complication in thalassaemia. Iron chelators remove iron and prevent this tissue damage. Any child who is receiving regular blood transfusion over a six month period or more should be considered for iron chelation.

Indications for Starting Iron Chelation

  • The need for iron chelation should be discussed from an early stage when it is clear that a child is going to need long-term regular transfusion. This should be included in any discussions with the parents concerning the risks and benefits of transfusion.
  • Iron chelation should be started when:

  • 10 or more blood transfusions have been given
  • The serum ferritin is consistently more than 1000์g/l
  • The child has been receiving regular transfusions for more than one year
  • It is planned to continue the transfusions for at least a further 12 months
  • Ideally chelation should not be started before the age of 2 years

Initiating Treatment Iron Chelation Treatment

1. Desferrioxamine is the first choice iron chelator and should be started initially unless

  • The family/child are very strongly against or refuse to use desferrioxamine as opposed to oral iron chelation; this may be influenced by social circumstances, previous family experiences and any parental disability
  • In practice, most children and parents are strongly in favour or oral iron chelation

2. If the child and parents decide that they could not use subcutaneous chelation, deferasirox should be started at a dose of about 20mg/kg. 3. Deferiprone is not offered as a first choice iron chelator. Screen Shot 2556-02-13 at 9.02

Comparison of Currently Available Iron Chelators

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Characteristics Deferoxamine Deferiprone Deferasirox Dos range 20-60 mg/kg/d 50-100 mg/kg/d 20-30 mg/kg/d Administration Subcutaneous or instravenous 8-10 hr/day
5-7 day/week
Oral
Once Daily
Oral
Three times daily Indication
Transfusional iron overload Transfusional iron overload in patients with thalassemia major.
when deferoxamine therapy is contraindicated or inadequate.
Transfusional iron overload Pregnancy Category C Category D Category C Pediatric use Safety and effectiveness in pediatric patients under the age 3 years have not been established. Safety and efficacy not established Safety and effectiveness in pediatric patients under the age 2 years have not been established.

 

Phamacokinetics
Characteristics Deferoxamine Deferiprone Deferasirox Absorption Well absorbed by intramuscular and subcutaneous routes - Well absorbed
- Time to peak = 1-2 hrs
Tmax 1.5-4 hours. Distribution The serum protein binding rate is less than 10%. - Distribution: 1.6 L/kg (in thalassemia patients)
- Protein binding: <10%
- Highly protein bound almost to serum Albumin
- Vd = 14.37±2.69 L in Adult Metabolism
The metabolism reactions to occur were transamination and oxidation yielding ana acid metabolite. - Primarily by UGT 1A6; major metabolite (3-O-glucuronide) lacks iron-binding capacity - main metabolic pathway is Glucuronidation with biliary excretion. Extretion Through the kidneys by glomerular filtration and tubular secreation.  Half life elimination: 1.9 hours
- 75-90% excreates in Urine
- 84% excreates in the feces
- t1/2 = 8-16 hours

Initiating Treatment Iron Chelation Treatment

1. Iron chelation should be discussed regularly with children and parents when they attend for blood transfusion. 2. After about 10 transfusions the clinical nurse specialist will give the information leaflets on desferrioxamine and deferasirox to parents and discuss the advantages and disadvantages. 3. Desferrioxamine is the first choice iron chelator and should be started initially unless
  • The family/child are very strongly against or refuse to use desferrioxamine as opposed to oral iron chelation; this may be influenced by social circumstances, previous family experiences and any parental disability
  • In practice, most children and parents are strongly in favour or oral iron chelation

4. If the child and parents decide that they could not use subcutaneous chelation,deferasirox should be started at a dose of about 20mg/kg. 5. Deferiprone is not offered as a first choice iron chelator.

Management of Chelation Side-Effects

If a child is thought to be allergic to an iron chelator, it should be stopped and an alternative used.

  • Referral to the paediatric allergy team may be helpful at a later stage to establish the degree and nature of any sensitivity

A. Desferrioxamine

The main problem is pain and inflammation at the site of the infusion
  • Children and parents should be taught to rotate the site of infusion
  • Other factors which may help include changing the type of needle used, altering the volume/concentration of the desferrioxamine
  • Any infection should be treated appropriately with systemic antibiotics

B. Deferasirox

The main side-effects are gastronintestinal disturbances and mild skin rashes .
  • Altering the time of day when it is taken, typically from the morning to the evening
  • Eating natural yoghurt or lactase supplements a few hours before deferasirox
  • Taking the drug in divided doses

Mild rashes may fade whilst continuing the drug at the same dose If severe rashes occur, the deferasirox should be stopped and reintroduced at a low dose once the rash has faded

Management of Chelation Toxicity

A. Desferrioxamine

The main problem is pain and inflammation at the site of the infusion
  • Main toxicities include retinopathy, hearing loss and growth restriction, particularly of the spine
  • If these are detected the dose of desferrioxamine should be reviewed and reduced, depending on the urgency of iron chelation

B. Deferasirox

The main side-effects are gastronintestinal disturbances and mild skin rashes .
  • If serum creatinine more than doubles, the dose of deferasirox should be reduced, and gradually increased once the renal function has returned to normal.
  • If ALT increases above the upper limit of normal, or doubles if elevated before starting deferasirox, reduce dose of drug and monitor. The dose can be gradually increased once ALT returns to base-line levels.
  • If reintroduction causes the creatinine or ALT to increase significantly again, the patient should be switched to desferrioxamine.

C. Deferiprone

The main side-effects are gastronintestinal disturbances and mild skin rashes .
  • Neutropenia is the main toxicity and weekly full blood counts should be performed.
  • If neutropenia (<1×109/l) occurs deferiprone should be stopped and alternative chelation used.

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