Deferasirox oral
- Drugs List
- Therapeutic Indications
- Dosage
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Oral formulations of deferasirox.
Drugs List
Therapeutic Indications
Uses
Treatment of chronic iron overload due to blood transfusions
Treatment of iron overload in non-transfusion dependent thalassaemias
Treatment of chronic iron overload due to frequent blood transfusions (greater than or equal to 7ml/kg/month of packed red blood cells) in patients with beta thalassaemia major aged 6 years and older.
Treatment of chronic iron overload due to blood transfusions when deferoxamine therapy is contraindicated or inadequate in the following patient groups:
In patients with beta thalassaemia major with iron overload due to frequent blood transfusions (greater or equal to 7ml/kg/month of packed red blood cells) aged 2 to 5 years old.
In patients with beta thalassaemia major with iron overload due to infrequent blood transfusions (less than 7ml/kg/month of packed red blood cells) aged 2 years and older.
In patients with other anaemias aged 2 years and older.
Treatment of chronic iron overload requiring chelation therapy when deferoxamine therapy is contraindicated or inadequate in patients with non-transfusion-dependent thalassaemia syndromes aged 10 years and older.
Dosage
Doses must be calculated based on the bodyweight of the patient (mg/kg) and rounded to the nearest whole tablet size.
Adults
Transfusional Iron Overload
Treatment should be started after the infusion of approximately 20 units (100ml/kg) of packed red blood cells or when there is evidence of chronic iron overload (e.g. serum ferritin greater than 1000 microgram/litre).
Starting dose
14mg/kg bodyweight to be taken once daily.
A daily dose of 21mg/kg may be considered for patients requiring reduction of elevated body iron levels and who receive more than 14ml/kg/month of packed red blood cells (approximately greater than 4 units/month for an adult).
A daily dose of 7mg/kg may be considered for patients who do not require reduction of body iron levels and who receive less than 7ml/kg/month of packed red blood cells (approximately less than 2 units/month for an adult). The patient's response must be monitored and the dose may be increased if sufficient efficacy is not achieved.
For patients well managed on deferoxamine, a starting dose of deferasirox that is one third the deferoxamine dose could be considered. For example, a patient receiving 40mg/kg/day of deferoxamine for 5 days per week (or equivalent) may be transferred to a starting dose of deferasirox of 14mg/kg/day. When this calculation results in a dose of less than 14mg/kg/day of deferasirox, the patient's response must be monitored and the dose may be increased if sufficient efficacy is not achieved.
Dose adjustment
Serum ferritin should be monitored every month and the dose of deferasirox adjusted every 3 to 6 months based on serum ferritin levels.
Dose adjustments should be made in steps of 3.5 to 7mg/kg depending on patient response and therapeutic goals (maintenance or reduction of iron burden).
In patients not adequately controlled with doses of 21mg/kg, doses of up to 28mg/kg may be considered.
If only very poor haemosiderosis control is achieved at doses up to 21mg/kg, a further increase (to a maximum of 28mg/kg) may not achieve satisfactory control. Treatment at such doses should not be maintained and alternative options should be considered whenever possible.
In patients treated with doses greater than 21mg/kg, and in patients whose serum ferritin level has reached the target, dose reductions in steps of 3.5 to 7mg/kg should be considered when control has been achieved to maintain serum ferritin levels within the target range and to minimise the risk of overchelation.
If serum ferritin falls consistently below 500 microgram/litre (in transfusional iron overload) or below 300 microgram/litre in non-transfusion-dependent thalassaemia syndromes, an interruption of treatment should be considered.
Doses above 28mg/kg/day are not recommended due to limited experience with doses of this level.
Non-Transfusion-Dependent Thalassaemia
Treatment should be started when the patient's liver iron concentration (LIC) is greater or equal to 5mg Fe/g dry weight, or if serum ferritin is consistently higher than 800 microgram/litre.
Starting Dose
7mg/kg bodyweight to be taken once daily.
Dose Adjustment
After every 3 to 6 months of treatment a dose increase in increments of 3.5 to 7mg/kg should be considered if the patient's LIC is higher or equal to 7mg Fe/g dry weight, or if serum ferritin is consistently higher than 2,000 microgram/litre and not showing a downward trend, and the patient is tolerating the medicinal product well. Doses above 14mg/kg are not recommended.
In patients where LIC was not assessed and serum ferritin is lower or equal than 2,000 micrograms/litre, dosing should not exceed 7mg/kg.
For patients in whom the dose was increased to more than 7mg/kg, a dose reduction to 7mg/kg or less is recommended when LIC is lower than 7mg Fe/g dry weight or serum ferritin is lower or equal to 2,000 microgram/litre.
Once a satisfactory body iron level has been achieved (LIC lower than 3mg Fe/g dry weight or serum ferritin lower than 300 microgram/litre), treatment should be stopped.
Elderly
(See Dosage; Adult)
In clinical trials, elderly patients experienced a higher frequency of adverse reactions than younger patients (in particular diarrhoea) and should be monitored closely for adverse events that may require a dose adjustment.
Children
Transfusional Iron Overload
Children aged 2 to 18 years
(See Dosage; Adult)
Changes in weight over time must be considered when calculating the dose required.
Bioavailability in children aged 2 to 5 years is lower than in adults therefore children with transfusional iron overload may require higher doses than those administered to adults. However, the initial dose should be the same as for adults followed by individual titration.
Non-Transfusion-Dependent Thalassaemia
Children aged 10 to 18 years
In children with non-transfusion-dependent thalassaemia syndromes, dosing should not exceed 7mg/kg. Closer monitoring of LIC and monthly assessments of serum ferritin is essential in these patients to avoid over-chelation. LIC should be monitored every three months when serum ferritin is lower or equal to 800 microgram/litre.
Patients with Renal Impairment
For adult patients, if serum creatinine increases more than 33% above the pre-treatment average and creatinine clearance falls below 90ml/minute on two consecutive occasions and cannot be attributed to another cause, dosage may be reduced by 7mg/kg/day.
For paediatric patients, if serum creatinine increases above the age-appropriate upper limit of normal and/or estimated creatinine clearance falls below the lower limit of normal range (below 90ml/minute) on two consecutive occasions and cannot be attributed to another cause, dosage may be reduced by 7mg/kg/day.
If despite a dose adjustment, serum creatinine continues to remain more than 33% above the average pre-treatment levels and/or calculated creatinine clearance falls below the lower limit of normal range, treatment should be interrupted. Treatment may be reinitiated depending on the circumstances of the individual patient.
If renal function tests reveal abnormalities, a dose reduction or interruption of treatment may be considered.
Creatinine clearance less than 60ml/minute: Contraindicated.
Patients with Hepatic Impairment
Reduce dose considerably in patients with moderate hepatic impairment followed by a progressive increase in dose up to a limit of 50%.
Treatment with deferasirox should be interrupted if there is a persistent and progressive rise in serum transaminase levels that cannot be attributed to another cause. When the cause of the abnormal test is determined or when the tests return to normal levels, treatment may be reinitiated with caution and at a lower dose. A gradual increase in dose may be considered as required.
Contraindications
Children under 2 years
Breastfeeding
Renal impairment - creatinine clearance below 60ml/minute
Severe hepatic impairment
Precautions and Warnings
Children aged 2 to 5 years
Diarrhoea
Patients over 65 years
Platelet count below 50 x 10 to the power of 9 / L
Predisposition to acidosis
Vomiting
Moderate hepatic impairment
Pregnancy
Renal impairment - creatinine clearance 60-90ml/minute
Reduce dose if creatinine clearance <90ml/min on 2 consecutive occasions
Reduce dose in patients with moderate hepatic impairment
Advise patient dizziness may affect ability to drive or operate machinery
Treatment to be initiated and supervised by a specialist
Different formulations are not bioequivalent
Assess renal function in duplicate before initiating therapy
Monitor auditory function before then annually during long term therapy
Monitor for proteinuria before and monthly during treatment
Monitor ophthalmic function before then annually during long-term therapy
Discontinue if signs of gastro-intestinal bleeding occur
Monitor ammonia levels if hyperammonaemia suspected
Monitor cardiac function during prolonged treatment
Monitor for development of acidosis
Monitor growth and development in children on prolonged therapy
Monitor liver function before, every 2wks during 1st month & monthly after
Monitor patients receiving concurrent anticoagulants
Monitor serum creatinine after a dose change or formulation switch
Monitor serum creatinine weekly (induction) / monthly (maintenance)
Monitor serum ferritin levels monthly
Advise patients to report signs or symptoms of gastro-intestinal ulcer
Consider discontinuing treatment if serum transaminase levels rise
Consider dose reduction or withdrawal if metabolic acidosis occurs
Discontinue if signs of gastro-intestinal ulceration occur
Monitor for signs of mental confusion or loss of consciousness
Consider dose interruption if patient develops severe cytopenias
Discontinue and do not restart if severe cutaneous adverse reactions occur
Discontinue permanently if severe hypersensitivity reactions occur
Interrupt or reduce dose if significant gastrointestinal disturbances occur
Non-transfusion:Consider interruption if ferritin below 300micrograms/litre
Transfusion: Consider interruption if ferritin below 500micrograms/litre
Not licensed for all indications in all age groups
Advise patient to avoid aluminium containing antacids
Female: Effect of hormonal contraceptive may be reduced
Female: Ensure adequate contraception during treatment
Advise patient to seek medical advice if taking NSAIDs
Advise patients to report skin rash
Rashes may occur during therapy and are likely to resolve spontaneously. If the interruption of therapy is necessary, treatment may be reintroduced at a lower dose after the rash has resolved. A gradual increase in dose may be considered as required. In cases of severe rash, the reintroduction of deferasirox could be combined with a short period of oral steroid administration.
In patients with short life expectancy, especially when co-morbidities could increase the risk of adverse events, the benefit of deferasirox might be limited, and may be inferior to risks. Consequently, treatment with deferasirox is not recommended in these patients.
Body weight, height and sexual development should be monitored prior to therapy and annually in paediatric patients.
Concomitant administration of deferasirox may increase the risk of gastrointestinal toxicity with substances known to have ulcerogenic potential such as NSAIDs, corticosteroids or oral bisphosphonates and may also increase the risk of gastrointestinal haemorrhage with concomitant administration with anticoagulants and in patients with platelet counts below 50,000 per cubic millimetres.
Auditory and ocular disturbances have been reported. Auditory and opthalmic testing (including fundoscopy) is recommended before the start of treatment and at regular intervals thereafter (every 12 months). Consider dose reduction or interrupt treatment if auditory or ocular disturbances occur during treatment.
Avoid over chelation by monitoring serum ferritin monthly.
During treatment with high doses and when serum ferritin levels are close to the target range consider dose reduction and closer monitoring of serum ferritin and renal and hepatic function.
Renal Function
Dose dependent increases in serum creatinine were observed in clinical trials, although cause has not been established.
Patients receiving high doses of deferasirox and/or low rates of transfusion (below 7ml/kg/month of packed red blood cells or below 2 units/month in adults) or patients receiving concomitant medicinal products that depress renal function deserve particular attention.
An increased risk of renal adverse events with deferasirox doses above 21mg/kg cannot be excluded.
Serum creatinine, creatinine clearance, and/or plasma cystatin C levels should be monitored prior to therapy, weekly in the first month after initiation of therapy or after dose changes and then once monthly. Patients with pre-existing renal conditions and patients who are receiving medicinal products that depress renal function may be more at risk of complications. Care should be taken to maintain adequate hydration in patients who develop diarrhoea or vomiting.
Cases of acute renal failure have been reported following post-marketing use of deferasirox. In some post-marketing cases, renal function deterioration has led to renal failure requiring temporary or permanent dialysis.
Additional renal function tests may also be monitored as necessary. These tests may include proteinuria, monitoring glycosuria (in non-diabetics), serum potassium, phosphate, magnesium or urate, phosphaturia and aminoaciduria. If these tests reveal abnormalities, dose reduction or interruption of treatment may be considered.
If after dose reduction or therapy interruption, the serum creatinine remains significantly high and there is a persistent abnormality in another test of renal function (e.g. proteinuria, Fanconi's Syndrome), the patient should be referred to a renal specialist for further investigation and possible kidney biopsy.
In patients who develop unexplained changes in mental status, consider hyperammonaemic encephalopathy and measure ammonia levels.
Maintain adequate hydration in patients who experience volume-depleting events (such as diarrhoea or vomiting), particularly in children with acute illness.
It is recommended that serum transaminases, biliruben and alkaline phosphatase be checked before the initiation of treatment, every 2 weeks during the first month and monthly thereafter in all patients.
Pregnancy and Lactation
Pregnancy
Use deferasirox with caution during pregnancy.
The manufacturer states that deferasirox should be avoided during pregnancy unless clearly necessary.
At the time of writing there is limited published information regarding the use of deferasirox during pregnancy. The manufacturer states animal studies have shown some reproductive toxicity, however Briggs (2015) states reproductive studies in rats and rabbits have shown no evidence of impaired fertility or foetal harm. Transfer across the human placenta is unknown, however, due to its long elimination half-life and the drug�s molecular weight, embryo-foetal exposure is likely. The potential risk is unknown.
Lactation
Deferasirox is contraindicated during breastfeeding.
The manufacturer states breastfeeding is not recommended while taking deferasirox.
At the time of writing, there is limited published information regarding the use of deferasirox during breastfeeding. Animal studies demonstrated the rapid and extensive excretion of deferasirox into maternal milk but no effect on the offspring was observed. It is unknown if deferasirox is excreted in human milk. There is a theoretical risk of excretion due to the molecular weight and the long elimination half-life. A risk to neonates cannot be excluded.
Side Effects
Abdominal distension
Abdominal pain
Acute pancreatitis
Acute renal failure
Alopecia
Altered consciousness
Anaphylaxis
Angioedema
Anxiety
Cataracts
Cholelithiasis
Constipation
Deafness
Decrease in creatinine clearance
Diarrhoea
Dizziness
Drug rash with eosinophilia and systemic symptoms (DRESS)
Duodenal ulcer
Dyspepsia
Erythema multiforme
Exacerbation of anaemia
Fanconi syndrome
Fatigue
Gallstones
Gastric ulceration
Gastritis
Gastro-intestinal perforation
Gastrointestinal bleeding
Glycosuria
Headache
Hepatic failure
Hepatitis
Hepatobiliary disorders
Hyperammonaemic encephalopathy
Hypersensitivity reactions
Increase of liver transaminases
Interstitial nephritis
Laryngeal discomfort
Lens opacities
Maculopathy
Metabolic acidosis
Nausea
Nephrolithiasis
Neutropenia
Oedema
Oesophagitis
Optic neuritis
Pancytopenia
Proteinuria
Pruritus
Pyrexia
Rash
Renal tubular necrosis
Serum creatinine increased
Skin pigmentation changes
Sleep disturbances
Stevens-Johnson syndrome
Thrombocytopenia
Toxic epidermal necrolysis
Urticaria
Vasculitis
Vomiting
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last full review date: February 2020
Reference Sources
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.
Summary of Product Characteristics: Exjade film-coated tablets. Novartis Pharmaceuticals UK Ltd. Revised July 2020.
NICE Evidence Services Available at: www.nice.org.uk Last accessed: 10 January 2020
Medscape UK | Univadis prescription drug monographs & interactions are based on FDB Multilex Content
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