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Therapeutic Indications
Dosage
Administration
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Monograph

Dosage

Adults
Elderly
Children
Patients with Renal Impairment
Additional Dosage Information

Treatment for chronic iron overload

The main aim of therapy in well-controlled patients is to achieve an iron balance and prevent haemosiderosis, whilst in overloaded patients a negative iron balance is desirable in order to slowly deplete the increased iron stores and to prevent the toxic effects of iron.

Desferrioxamine therapy should be initiated after the first 10-20 blood transfusions or when the ferritin levels reach 1000 nanogram/ml (indication of transferrin saturation). Dosage and route of administration should be individually adapted according to the degree of iron overload.

The lowest effective dose should be used. The average daily dose will probably lie between 20-60 mg/kg/day. Patients with serum ferritin levels of less than 2000 nanogram/ml should require about 25mg/kg per day, and those with levels between 2000 and 3000 nanogram/ml about 35mg/kg per day. Higher doses should only be employed if the benefit for the patient outweighs the risk of unwanted effects.

Patients with higher serum ferritin may require up to 55mg/kg per day. It is inadvisable regularly to exceed an average daily dose of 50mg/kg per day except when very intensive chelation is needed in patients who have completed growth. If ferritin values fall below 1000 nanogram/ml, the risk of desferrioxamine toxicity increases. It is important to monitor these patients particularly carefully and perhaps to consider lowering the total weekly dose.

To assess the chelation therapy, 24 hour urinary iron excretion should initially be monitored daily. Starting with a dose of 500mg daily the dose should be raised until a plateau of iron excretion is reached. Once the appropriate dose has been established, urinary iron excretion rates can be assessed at intervals of a few weeks.

Alternatively, the mean daily dose may be adjusted according to the ferritin value to keep the therapeutic index less than 0.025 (i.e. mean daily dose (mg/kg) of desferrioxamine divided by the serum ferritin level (microgram/L) below 0.025). The therapeutic index is a valuable tool in protecting the patient from excess chelation but it is not a substitute for careful clinical monitoring.

Treatment for acute iron poisoning

Consider treatment with parenteral desferrioxamine in any of the following situations;

i) all patients who are symptomatic and exhibit more than transient minor symptoms (e.g. more than one episode of emesis or passage of one soft stool).

ii) patients with lethargy, significant abdominal pain, hypovolaemia, or acidosis.

iii) patients with positive abdominal radiograph results demonstrating multiple radio-opacities (the majority of these patients will go on to develop symptomatic iron poisoning).

iv) any patient who is symptomatic and with a serum iron level greater than 300 to 350 micrograms/dL regardless of the total iron binding capacity (TIBC). It has also been suggested that a conservative approach without desferrioxamine or challenge should be considered when serum iron levels are in the 300 to 500 micrograms/dL range in asymptomatic patients, as well as those with self limiting, non-bloody emesis or diarrhoea without other symptoms.

Desferrioxamine is an adjunct to standard measures generally used in treating acute iron poisoning. It is important to initiate treatment as soon as possible.

The dosage and route of administration should be adapted to the severity of the poisoning.

Continuous intravenous administration (preferred route): Recommended rate of infusion is 15mg/kg per hour and should be reduced as soon as the situation permits, usually after 4 to 6 hours so that the total intravenous dose does not exceed a recommended 80mg/kg in any 24-hour period.

Intramuscular route (if intravenous route not available): A dose of 2g for an adult administered as a single dose.

Desferrioxamine mesilate therapy should be continued until the following criteria are satisfied:
-Patient is free of signs and symptoms of systemic iron poisoning (e.g. no acidosis or worsening hepatotoxicity).
-Corrected serum iron level (less than 100 micrograms/dL).
-Repeat abdominal radiograph test demonstrates the disappearance of multiple radio-opacities in patients in whom these were initially apparent.
-Vin-rose coloured urine has returned to normal.

The effectiveness of treatment is dependent on an adequate urine output in order that the iron complex (ferrioxamine) is excreted from the body. Therefore, if oliguria or anuria develop, peritoneal dialysis or haemodialysis may become necessary to remove ferrioxamine.

It should be noted that the serum iron level may rise sharply when the iron is released from the tissues. Theoretically, 100mg of desferrioxamine can chelate 8.5mg of ferric iron.

Diagnosis of iron storage disease and certain anaemias

The test for iron overload is based on the principle that normal subjects do not excrete more than a fraction of a milligram of iron in their urine daily, and that a standard intramuscular injection of 500mg of desferrioxamine will not increase this above 1mg (18 micro mol). In iron storage diseases, however, the increase may be well over 1.5mg (27 micro mol). It should be borne in mind that the test only yields reliable results when renal function is normal.

Desferrioxamine is administered as 500mg intramuscular injection. Urine is then collected for a period of 6 hours and its iron content determined.

Excretion of 1 - 1.5mg (18-27 micro mol) of iron during this 6-hour period is suggestive of iron overload. Values greater than 1.5mg (27 micro mol) can be regarded as pathological.

Treatment of aluminium overload in patients with end-stage renal failure

Patients should receive desferrioxamine if:
1) They have symptoms or evidence of organ impairment due to aluminium overload.
2) They are asymptomatic but their serum aluminium levels are consistently above 60 nanogram/ml and associated with a positive desferrioxamine test, particularly if a bone biopsy provides evidence of aluminium related bone disease.

The iron and aluminium complexes of desferrioxamine are dialysable. In patients with renal failure their elimination will be increased by dialysis.

Patients on maintenance haemodialysis or haemofiltration:
5mg/kg once a week. Patients with post-desferrioxamine test serum aluminium levels up to 300 nanogram/ml should be given desferrioxamine as a slow intravenous infusion during the last 60 minutes of a dialysis session (to reduce loss of free drug in the dialysate). For patients with a post-desferrioxamine test serum aluminium value above 300 nanogram/ml, desferrioxamine should be administered by slow intravenous infusion 5 hours prior to the dialysis session.

Four weeks after the completion of a 3 month course of desferrioxamine treatment, a desferrioxamine infusion test should be performed, followed by a second test 1 month later. Serum aluminium increases above baseline of less than 50 (some authorities state 75) nanogram/ml measured in two successive infusion tests indicate that further desferrioxamine treatment is not necessary.

Patients on CAPD or CCPD:
5mg/kg once a week prior to the final exchange of the day. It is recommended that the intraperitoneal route be used in these patients. However, desferrioxamine can also be given intramuscularly, by slow intravenous infusion or subcutaneous infusion.

Diagnosis of aluminium overload in patients with end-stage renal failure

A desferrioxamine infusion test is recommended in patients with serum levels greater than 60 nanogram/ml associated with serum ferritin levels greater than 100 nanogram/ml.

Serum aluminium values should be determined from the blood samples taken:
-immediately before a haemodialysis session (baseline). 5mg/kg should then be administered as a slow intravenous infusion during the last hour of the dialysis.
-at the start of the next haemodialysis session.

An increase in serum aluminium above the baseline of more than 150 nanogram/ml is suggestive of aluminium overload. It should be noted that a negative test does not completely exclude the possibility of aluminium overload.

Theoretically, 100mg desferrioxamine can bind 4.1mg of aluminium (trivalent) ion.

Desferrioxamine has limited efficacy in children under 3 years of age.

Treatment for chronic iron overload

No dosage adjustment is necessary - see Adult dosage

Growth retardation may result from iron overload or excessive desferrioxamine doses. If chelation is started before 3 years of age growth must be monitored carefully and the mean daily dose should not exceed 40mg/kg.

Treatment for acute iron poisoning

Desferrioxamine is an adjunct to standard measures generally used in treating acute iron poisoning. It is important to initiate treatment as soon as possible.

The dosage and route of administration should be adapted to the severity of the poisoning.

Slow intravenous infusion (preferred route): Recommended rate of infusion is 15mg/kg per hour and should be reduced as soon as the situation permits, usually after 4 to 6 hours so that the total intravenous dose does not exceed a recommended 80mg/kg in any 24-hour period.

Intramuscular route (if intravenous route not available): A dose of 1g for child administered as a single dose.
Desferrioxamine mesilate therapy should be continued until the following criteria are satisfied:
-Patient is free of signs and symptoms of systemic iron poisoning
-Corrected serum iron level (less than 100micrograms/dL)
-Multiple radio-opacities have disappeared, where these were initially apparent.
-Vin-rose coloured urine has returned to normal

The effectiveness of treatment is dependent on an adequate urine output in order that the iron complex (ferrioxamine) is excreted from the body. Therefore, if oliguria or anuria develop, peritoneal dialysis or haemodialysis may become necessary to remove ferrioxamine.

It should be noted that the serum iron level may rise sharply when the iron is released from the tissues. Theoretically, 100mg of desferrioxamine can chelate 8.5mg of ferric iron.

Diagnosis of iron storage disease and certain anaemias

See Adult dosage

Treatment for aluminium overload in patients with end-stage renal failure

See Adult dosage

Diagnosis of aluminium overload in patients with end-stage renal failure

See Adult dosage

Administration

Route of desferrioxamine mesilate administration is dependant on the patient's medical condition and the dosage being given.

When administered subcutaneously the needle should not be inserted too close to the dermis.

For parenteral administration desferrioxamine should be employed in the form of a 10% solution by dissolving the contents of one 500mg vial in 5ml water for injections or the contents of one 2g vial in 20ml of water for injections.

Treatment for chronic iron overload

Slow subcutaneous infusion by means of a portable, light-weight infusion pump over a period of 8-12 hours is effective and particularly convenient for ambulant patients. It may be possible to achieve a further increase in iron excretion by infusing the same daily dose over a 24 hour period. Patients should be treated 5-7 times a week depending on the degree of iron overload. Desferrioxamine mesilate is not formulated to support subcutaneous bolus injections.

Since the subcutaneous infusions are more effective, intramuscular injections are given only when subcutaneous infusions are not feasible.

The availability of an intravenous line during blood transfusions makes it possible to administer an intravenous infusion. The desferrioxamine solution should not be put directly into the blood bag but may be added to the blood line by means of a Y adapter located near to the venous site of injection. The patient's pump should be used to administer desferrioxamine as usual. Patients and nurses should be warned against accelerating the infusion, as an intravenous bolus of desferrioxamine may lead to flushing, hypotension and acute collapse.

Continuous intravenous infusion is recommended for patients incapable of continuing subcutaneous infusions and in those who have cardiac problems secondary to iron overload. 24-hour urinary iron excretion should be measured regularly where intensive chelation (IV) is required, and the dose adjusted accordingly. Implanted intravenous systems can be used when intensive chelation is carried out.

Care should be taken when flushing the line to avoid the sudden infusion of residual desferrioxamine which may be present in the dead space of the line, as this may lead to flushing, hypotension and acute collapse.

Treatment for acute iron poisoning

Desferrioxamine may be administered by intravenous infusion (preferable) or by intramuscular injection .

Diagnosis of iron storage disease and certain anaemias

Desferrioxamine mesilate should be administered via an intramuscular injection in these patients.

Treatment for aluminium overload in patients with end-stage renal failure

Patients on maintenance haemodialysis or haemofiltration:
Desferrioxamine mesilate should be administered via a slow intravenous infusion in these patients. The infusion should be 5 hours prior to the dialysis session.

Patients on CAPD or CCPD:
The intraperitoneal route is recommended in these patients (dissolved desferrioxamine may be added to dialysis fluid), however, desferrioxamine may also be given as intramuscular, intravenous or subcutaneous slow infusion.

Diagnosis of aluminium overload in patients with end-stage renal failure

Desferrioxamine mesilate should be administered via a slow intravenous infusion in these patients.

Handling

The product should be used immediately after reconstitution (commencement of treatment within 3 hours). If not used immediately, in-use storage times and conditions prior to administration are the responsibility of the user.
When reconstitution is carried out under validated aseptic conditions the reconstituted solution may be stored for a maximum of 24 hours at room temperature (25 degrees C or below) before administration. Unused solution should be discarded.

Reconstitution

The drug should preferably be employed in the form of a 10% solution, by dissolving the contents of one 500mg vial in 5ml of water for injections or dissolving the contents of one 2g vial in 20ml of water for injections.

The 10% desferrioxamine solution can be further diluted with routinely used infusion solutions, such as saline, glucose or glucose-saline infusion solutions, although these should not be used as solvent for the dry substance.

Dissolved desferrioxamine may also be added to dialysis fluid and given intraperitoneally to patients on continuous ambulatory peritoneal dialysis (CAPD) or continuous cyclic peritoneal dialysis (CCPD).

Only clear pale yellow solutions should be used. Opaque, cloudy or discoloured solutions should be discarded.

Compatibilities

The 10% desferrioxamine solution can be further diluted with routinely used infusion solutions, such as saline, glucose, or glucose-saline infusion solutions, although these should not be used as solvent for the dry substance.

Similarly the desferrioxamine solution can be added to peritoneal dialysis solutions.

Incompatibilities

Heparin is pharmaceutically incompatible with desferrioxamine solutions.

Precautions and Warnings

Use with caution in renal impairment, as the metal complexes are excreted via the kidney. In these patients, dialysis can increase the elimination of chelated iron and aluminium.

Desferrioxamine mesilate given via the intravenous route should always be administered as a slow infusion. If dose given too quickly hypotension and shock (flushing, tachycardia, collapse and urticaria) may occur.

Subcutaneous injection - desferrioxamine mesilate given in doses and/or concentrations greater than recommended is more likely to cause local irritation at the site of administration.

Used alone desferrioxamine may exacerbate neurological impairment in patients with aluminium related encephalopathy. This deterioration manifests as seizures and is probably related to an increase in brain aluminium secondary to elevated circulating levels. Pre-treatment with clonazepam has been shown to afford protection against such impairment.

During treatment of aluminium overload serum calcium may decrease and hyperparathyroidism may be exacerbated.

Pregnancy - see Pregnancy section.
Breastfeeding - see Lactation section.

Monitoring of cardiac function is indicated during combined therapy with desferrioxamine and vitamin C. Do not give vitamin C supplements to patients with cardiac failure.

It is recommended that height and weight is monitored at 3-monthly intervals in children.
Inappropriately high doses in patients with low serum ferritin levels and young children (under 3 years) has been associated with growth retardation. In some cases, dose reduction may restore the normal growth rate. Growth retardation is rare if doses are kept below 40mg/kg.
Growth retardation associated with desferrioxamine must be distinguished from growth retardation due to iron overload.

Monitor audiometric/ophthalmic function before and at 3-monthly intervals during long-term use.
Visual and hearing disturbances have been reported during prolonged therapy, especially when recommended doses are exceeded and in patients with low serum ferritin levels. Dialysed patients with renal failure and low serum ferritin levels may have an increased risk of developing adverse effects and visual symptoms (including after the first dose). Discontinue treatment if disturbances of vision or hearing occur. Such disturbances are usually reversible. If therapy is re-instituted at a lower dosage, close monitoring of ophthalmological/auditory function should be carried out with due regard to the risk-benefit ratio.
A detailed ophthalmological examination is recommended including visual field measurements, fundoscopy, colour vision testing using pseudoisochromatic plates and the Farnsworth D-15 colour test, slit lamp investigation and visual evoked potential studies.
By keeping the mean daily dose (mg/kg of desferrioxamine) divided by the serum ferritin (micro g/L) ratio below 0.025 the risk of audiometric abnormalities may be reduced in thalassaemia patients.

Patients suffering from iron overload may be more susceptible to infections (e.g. Yersinia enterocolitica or Y. pseudotuberculosis )
Discontinue if patient develops fever with pharyngitis, diffuse abdominal pain or enteritis/enterocolitis and institute appropriate antibiotic therapy. Treatment with desferrioxamine may be resumed once the infection has cleared.

Patients receiving desferrioxamine for aluminium and/or iron overload have rarely reported the development of severe fungal infections (e.g. mucormycosis) and in some cases this infection proved fatal. Discontinue if signs or symptoms of fungal infection develop and institute appropriate treatment immediately.

Excessively high intravenous doses may lead to the development of Adult Respiratory Distress Syndrome (ARDS).

Desferrioxamine mesilate administration will reduce aluminium levels. As high aluminium levels reduce erythropoiesis, reduction in the aluminium level may require adjustment of erythropoietin if co-prescribed.

Patients experiencing CNS effects such as dizziness or impaired vision or hearing should be warned against driving or operating machinery.

Distortion of Gallium 67 imaging may occur due to the rapid excretion of desferrioxamine bound radiolabel. Therefore desferrioxamine should be discontinued 48 hours prior to scintigraphy.

Pregnancy and Lactation

Pregnancy

Use desferrioxamine mesilate with caution in pregnancy.

Studies in animals have shown reproductive toxicity/teratogenicity.

Briggs (2011) cites several published human pregnancy exposures and notes that although the number of cases is small, no toxic or teratogenic effects were reported.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Use desferrioxamine mesilate with caution in breastfeeding.

It is not known whether desferrioxamine mesilate is secreted in human breast milk. However, Hale (2010) states that its transfer to milk is unlikely and as its oral bioavailability is insignificant, adverse effects on the breastfed infant are unlikely.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Presentation

Powder for solution for injection containing 500mg desferrioxamine mesilate.
Powder for solution for injection containing 2g desferrioxamine mesilate.

Drugs List

DESFERAL 500mg injection

desferrioxamine 2g injection

desferrioxamine 500mg injection

Therapeutic Indications

Uses

Treatment for chronic iron overload for example in:
1) Transfusional haemosiderosis in patients receiving regular transfusions (e.g. thalassaemia major).
2) Primary or secondary haemochromatosis in patients in whom concurrent disorders (severe anaemia, hypoproteinaemia, renal or cardiac failure) preclude phlebotomy.

Treatment for acute iron poisoning

For the diagnosis of iron storage disease and certain anaemias

Aluminium overload in patients on maintenance dialysis for end stage renal failure where preventative measures (e.g. reverse osmosis) have failed and with proven aluminium-related bone disease and/or anaemia, dialysis encephalopathy.

Diagnosis of aluminium overload

Dosage

Dosage regime for desferrioxamine mesilate is dependant on the patient's condition and the route of administration.

Adults