Desferrioxamine

Registered South African indications:

• Treatment for chronic iron overload
  - Desferrioxamine is of value in increasing urinary excretion of iron in conditions associated with excessive iron storage in the tissues such as haemochromatosis in patients in whom concomitant disorders (e.g. severe anaemia, cardiac disease, hypoproteinaemia) preclude phlebotomy; haemosiderosis, and in iron overload following repeated transfusions e.g. thalassaemia
• Treatment of acute iron poisoning
• Treatment of chronic aluminium overload in patients with terminal renal failure (under maintenance dialysis) with
  - Aluminium-related bone disease and/or
  - Dialysis encephalopathy and/or
  - Aluminium-related anaemia
• Diagnosis of iron-storage disease or aluminium overload

Registered South African contraindications

• Known hypersensitivity to the active substance, except where successful desensitisation makes treatment possible
  - Three adult cases and one paediatric case of successful desensitisation has been described in the literature 
• Pregnancy
• Breastfeeding

South African recommendations

Caution in the following patient groups

• Severe renal impairment
• Hepatic impairment
• Elderly

Rapid intravenous infusion

• Rapid intravenous infusion may lead to hypotension and shock e.g. flushing, circulatory collapse and urticaria

Visual and hearing impairment

• High doses of deferoxamine, especially in patients with low ferritin plasma levels, may lead to disturbances of vision and hearing
• Patients with renal failure on maintenance dialysis with low ferritin levels may be particularly prone to adverse reactions
• Visual symptoms have been reported after single doses of deferoxamine
• The risk of side effects is reduced when low-dose therapy is employed
• If visual or auditory disturbances occur, deferoxamine should be discontinued immediately
• Changes induced by deferoxamine are usually reversible if identified early
• Treatment may be resumed later at a reduced dose with close monitoring of audiovisual function
• Special ophthalmological and audiological testing are recommended before starting treatment and every 3 months thereafter
• The risk of audiometric abnormalities in thalassemia patients may be reduced if the ratio of the mean daily dose (mg/kg) divided by the serum ferritin (micrograms/L) is kept below 0.025

Renal impairment

• In iron-overloaded patients with normal renal function, approximately half of the metal complex is excreted via the kidneys
• Caution is indicated in patients with severe renal failure
• The iron and aluminium complexes of deferoxamine are dialysable; elimination is increased by dialysis in patients with renal failure
• Isolated cases of acute renal failure have been reported; monitoring for changes in renal function (e.g. increased serum creatinine) should be considered

Paediatrics: growth retardation

• High doses of deferoxamine in patients with low serum ferritin, or commencement of treatment in young patients (< 3 years), have been associated with growth retardation
• Growth retardation from excessive deferoxamine must be distinguished from growth retardation caused by iron overload
• Growth retardation is rare if the dose is kept below 40mg/kg
• Reduction of the dose may result in return of growth velocity, though predicted adult height may not be attained
• Paediatric patients should be monitored for body weight and longitudinal growth every 3 months

Acute respiratory distress

• Acute respiratory distress syndrome has been described following excessively high i.v. doses of deferoxamine in patients with acute iron intoxication and thalassaemic patients
• Recommended daily doses should not be exceeded

Infections

• Deferoxamine may increase susceptibility to infections, such as Yersinia enterocolitica and Yersinia pseudotuberculosis
• If a patient develops fever with acute enteritis, abdominal pain, or pharyngitis, treatment should be temporarily discontinued
• Bacteriological tests should be performed and antibiotic therapy started immediately
• Rare cases of mucormycosis, some fatal, have been reported in patients receiving deferoxamine for aluminium or iron overload
• If signs of mucormycosis occur, deferoxamine should be discontinued and mycological tests carried out immediately

Urine discolouration

• Excretion of the iron complex may cause reddish-brown discoloration of the urine

Precautions related to use and handling

• Deferoxamine should not be given in doses higher than recommended
• The medicine should not be given at concentrations higher than 95 mg/mL for subcutaneous use to avoid local reactions
• Only clear solutions should be used; opaque or cloudy solutions must be discarded
• For subcutaneous infusion, the needle should not be inserted too close to the dermis

Cardiac impairment with high doses of vitamin C

• In patients with severe chronic iron overload, impairment of cardiac function has been reported with concomitant high-dose vitamin C (over 500 mg daily)
• Vitamin C supplements should not be given to patients with cardiac failure
• Start vitamin C treatment only after an initial month of regular deferoxamine therapy
• Give vitamin C only if the patient is receiving deferoxamine regularly
• Do not exceed a daily dose of 200 mg of vitamin C in divided doses
• Monitoring of cardiac function is advisable during combined therapy

Patients treated for chronic aluminum overload

• In patients with aluminium-related encephalopathy, high doses of deferoxamine may exacerbate neurological dysfunction (seizures)
• Deferoxamine may precipitate the onset of dialysis dementia
• Pretreatment with clonazepam has been reported to prevent neurological deterioration
• Treatment of aluminium overload may result in hypocalcaemia and aggravation of hyperparathyroidism

Effects on ability to drive and use machines

• Patients experiencing dizziness or other central nervous disturbances, or impairment of vision or hearing, should refrain from driving a vehicle or operating machinery

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Treatment for chronic iron overload
- Desferrioxamine is of value in increasing urinary excretion of iron in conditions associated with excessive iron storage in the tissues such as haemochromatosis in patients in whom concomitant disorders (e.g. severe anaemia, cardiac disease, hypoproteinaemia) preclude phlebotomy; haemosiderosis, and in iron overload following repeated transfusions e.g. thalassaemia

Average daily dose

• IV/SC: 20-60mg/kg, dly

Serum ferritin level < 2000ng/ml

• IV/SC: 25 mg/kg/day

Serum ferritin level between 2000-3000ng/ml

• IV/SC: 35mg/kg/day

Higher serum ferritin

• IV/SC: 55mg/kg/day; It is not advisable to regularly exceed an average daily dose of 50mg/kg/day except when very intensive chelation is needed in patients who have completed growth

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The main aim of chelation therapy in iron overload in well-controlled patients is to maintain an iron balance and to prevent haemosiderosis, while in overloaded patients a negative iron balance is desirable in order to reduce increased iron stores and prevent the toxic effects of iron

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Desferrioxamine therapy should be started after the first 10 to 20 blood transfusions or when there is evidence from clinical monitoring that chronic iron overload is present (e.g. serum ferritin >1000ng/ml)

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The dosage and mode of administration may be individually determined and adapted during the course of therapy based on the severity of the patient's iron overload. Lowest effective dosage should be used
To assess the response to chelation therapy, 24-hour urinary iron excretion may initially be monitored daily and the response to increasing doses of desferrioxamine established. Once appropriate dosage has been established, urinary iron excretion rates may be assessed at intervals of a few weeks. Alternatively, the mean daily dose may be adjusted based on ferritin level in order to keep the therapeutic index below 0.025 (i.e. the mean daily dose (mg/kg) of desferrioxamine divided by the serum ferritin level (micrograms/l) should be 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

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If ferritin levels fall below 1000ng/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. The doses specified here are the average daily doses. Since most patients use desferrioxamine less than 7 days a week, the actual dose per infusion usually differs from the average daily dose; e.g. if an average daily dose of 40mg/kg/day is required and the patient wears the pump 5 nights a week, each infusion should contain 56mg/kg

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Prolonged regular chelation with desferrioxamine has been shown to improve life expectancy in patients with thalassaemia major

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Slow subcutaneous administration: Slow subcutaneous infusion using a portable, light-weight infusion pump over a period of 8 to 12 hours is regarded as effective and especially convenient for ambulant patients, but may also be given over a 24-hour period. Desferrioxamine should normally be used with the pump 5 to 7 times a week. (Desferrioxamine is not formulated to support subcutaneous bolus injection)

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See additional prescribing points for intravenous infusion during blood transfusion

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Treatment of acute iron poisoning

Desferrioxamine is an adjunct to standard measures generally used in the treatment of acute iron poisoning

• IV: 15mg/kg/hr, as a continuous infusion; Reduce as soon as circumstances permit, usually after 4-6hrs so that the total intravenous dose does not exceed the recommended 80mg/kg in any 24hr period

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Desferrioxamine treatment is indicated in any of the following situations

- All symptomatic patients exhibiting more than transient minor symptoms (e.g. more than one episode of emesis or passage of one soft stool)
- Patients with evidence of lethargy, significant abdominal pain, hypovolaemia, or acidosis
- Patients with positive abdominal radiograph results demonstrating multiple radiopacities (the great majority of these patients will go on to develop symptomatic iron poisoning)
- Any symptomatic patient with a serum iron level greater than 300 to 350µg/dL regardless of total iron binding capacity (TIBC). It has also been suggested that a conservative approach without desferrioxamine therapy or challenge should be considered when serum iron levels are in the 300 to 500µg/dL range in asymptomatic patients, as well as in those with self-limited, non-bloody emesis or diarrhoea without other symptoms

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See additional prescribing points for appropriate requirements for cessation of treatment

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Treatment of chronic aluminium overload in patients with terminal renal failure (under maintenance dialysis) with
- Aluminium-related bone disease and/or
- Dialysis encephalopathy and/or
- Aluminium-related anaemia

• IV: 5mg/kg, once weekly; Post-desferrioxamine test serum aluminium levels up to 300ng/ml: Slow IV infusion during the last 60 min. of a dialysis session; Post-desferrioxamine test serum aluminium level above 300ng/ml: Admin. by slow IV infusion 5hrs prior to the dialysis session; After completion of the first 3-month course of treatment, followed by a 4-week wash-out period, an infusion test should be performed. If two successive infusion tests performed at 1-month intervals yield serum aluminium levels less than 50ng/ml above baseline, further treatment is not recommended

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The iron and aluminium complexes are dialysable. Their elimination will be increased by dialysis in patients with renal failure. Patients with evidence of symptoms or organ dysfunction due to aluminium overload should receive desferrioxamine treatment. Even in asymptomatic patients, desferrioxamine treatment should be considered if serum aluminium levels are consistently above 60ng/mL and are associated with a positive desferrioxamine infusion test. This is particularly the case if bone biopsy findings present evidence of aluminium

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In patients on continuous ambulatory peritoneal dialysis (CAPD) or continuous cyclic peritoneal dialysis (CCPD)

• IV/IM/SC/Intraperitoneal: 5mg/kg, once weekly prior to the final exchange of the day; The intraperitoneal route is recommended in these patients, but desferrioxamine can also be given i.m., by slow infusion i.v. or s.c

Diagnosis of iron-storage disease or aluminium overload

Desferrioxamine test in patients with normal renal function

• IM: 500mg as a single dose; Collect urine for a period of 6hrs and its iron content determined; An excretion of 1 to 1.5mg of iron (18 to 27µmol) during this 6hr period is suggestive of an iron overload; Values of more than 1.5mg (27µmol) may be regarded as pathological. This test yields reliable results only in cases where renal function is normal

Desferrioxamine infusion test for aluminium overload in end-stage renal failure patients

• IV: 5mg/kg, during the last 60 min. of the haemodialysis session; At the start of the next haemodialysis session (i.e. 44hrs after the aforementioned desferrioxamine infusion), the second blood sample is taken to determine the serum aluminium level once more; The desferrioxamine test is considered positive if the increase in serum aluminium above the baseline level exceeds 150ng/ml. A negative test, however, does not absolutely exclude the diagnosis of aluminium overload

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Method of administration

Slow subcutaneous administration: Slow subcutaneous infusion using a portable, light-weight infusion pump over a period of 8 to 12 hours is regarded as effective and especially convenient for ambulant patients, but may also be given over a 24-hour period. Desferrioxamine should normally be used with the pump 5 to 7 times a week. Desferrioxamine is not formulated to support subcutaneous bolus injection

Continuous intravenous infusion: Implanted intravenous systems can be used when intensive chelation is carried out. Continuous intravenous infusion is indicated in patients who are incapable of continuing subcutaneous infusions and in those who have cardiac problems secondary to iron overload. The dose of desferrioxamine depends on the extent of the patient's iron overload. The 24-hour urinary iron excretion should be measured regularly where intensive chelation (i.v.) is required, and the dose adjusted accordingly. Care should be taken when flushing the line in order to avoid a sudden infusion of residual 
desferrioxamine which may be present in the dead space of the line, as this may lead to circulatory collapse

Intramuscular administration: Since subcutaneous infusions are more effective, intramuscular injections are given only when subcutaneous infusions are not feasible. Whichever route of administration is chosen, the individual maintenance dose to be selected will depend on the patient's iron excretion rate

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Treatment for chronic iron overload
- Desferrioxamine is of value in increasing urinary excretion of iron in conditions associated with excessive iron storage in the tissues such as haemochromatosis in patients in whom concomitant disorders (e.g. severe anaemia, cardiac disease, hypoproteinaemia) preclude phlebotomy; haemosiderosis, and in iron overload following repeated transfusions e.g. thalassaemia

• See adult dosage

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Desferrioxamine therapy should be started after the first 10 to 20 blood transfusions or when there is evidence from clinical monitoring that chronic iron overload is present (e.g. serum ferritin >1000 ng/ml). Growth retardation may result from iron overload or excessive desferrioxamine doses. If chelation is begun in patients under 3 years of age, growth must be monitored carefully and the mean daily dose should not exceed 40mg/kg

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Treatment of acute iron poisoning

Desferrioxamine is an adjunct to standard measures generally used in the treatment of acute iron poisoning

• See adult dosage

Treatment of chronic aluminium overload in patients with terminal renal failure (under maintenance dialysis) with
- Aluminium-related bone disease and/or
- Dialysis encephalopathy and/or
- Aluminium-related anaemia

• See adult dosage

Diagnosis of iron-storage disease or aluminium overload

• See adult dosage

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Paediatrics: growth retardation

High doses of deferoxamine in patients with low serum ferritin, or commencement of treatment in young patients (< 3 years), have been associated with growth retardation
Growth retardation from excessive deferoxamine must be distinguished from growth retardation caused by iron overload
Growth retardation is rare if the dose is kept below 40mg/kg
Reduction of the dose may result in return of growth velocity, though predicted adult height may not be attained
Paediatric patients should be monitored for body weight and longitudinal growth every 3 months

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See Additional Prescribing Points

Pregnancy

South African recommendations

• Contraindicated
• There is a limited amount of data on the use of desferrioxamine in pregnant patients. Studies in animals (rabbits) have shown reproductive toxicity/teratogenicity. The risk to the foetus/mother is unknown
• Safety in human pregnancy has not been established

Breastfeeding

South African recommendations

• Contraindicated
• Desferrioxamine passes into the breast milk and its use is best avoided in lactating women. Because many medicines are excreted in human milk, and because of the potential for serious adverse reactions in breastfed newborns/infants, a decision should be made whether to abstain from breastfeeding or to abstain from using the medicine, taking into account the importance of the medicine to the mother

Fertility

South African recommendations

• No information available

South African recommendations

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended
  The iron and aluminium complexes of desferrioxamine are dialysable; their elimination will be increased by dialysis in patients with renal failure
  Monitoring patients for changes in renal function (e.g. increased serum creatinine) should be considered

South African recommendations

• Caution; no information available

South African recommendations

• Caution; no dose adjustment recommended
  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 medicine therapy

Central Nervous System Disorders

• Neurological disturbances
  - Dizziness
  - Precipitation or exacerbation of aluminium-related dialysis encephalopathy
  - Peripheral neuropathy
  - Paraesthesia
• Seizures
• Headache

Cardiovascular Disorders

• Hypotension
• Tachycardia
• Shock
  - Flushing
  - Tachycardia
  - Circulatory collapse
  - Urticaria

Respiratory Disorders

• Acute respiratory distress syndrome
• Lung infiltration
• Asthma

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Abdominal pain
• Yersinia infections

Genitourinary Disorders

• Acute renal failure
• Renal tubular disorder
• Increased creatinine
• Reddish-brown discoloration of the urine

Endocrine and Metabolic Disorders

• Hypocalcemia
• Aggravation of hyperparathyroidism

Musculoskeletal Disorders

• Growth retardation
• Bone disorder
  - Metaphyseal dysplasia
• Muscle spasms
• Arthralgia
• Myalgia

Skin and Subcutaneous Tissue Disorders

• Generalised rash
• Injection site reactions
  - Swelling
  - Infiltration
  - Erythema
  - Pruritus
  - Eschar/crust
  - Vesicles
  - Local oedema
  - Burning
• Urticaria

Immune, Blood and Lymphatic System Disorders

• Blood disorders
• Thrombocytopenia
• Leukopenia
• Anaphylactic shock
• Anaphylactic reactions
• Angioneurotic oedema
• Mucormycosis infections
• Gastroenteritisyersinia infections
• Fever

Sensory Disorders

• Loss of vision
• Scotoma
• Retinal degeneration
• Optic neuritis
• Cataracts
• Blurred vision
• Night blindness
• Visual field defects
• Chromatopsia
• Corneal opacities
• Neurosensory deafness
• Tinnitus

• Vitamin C
• Prochlorperazine
• Gallium⁶⁷ imaging

• Serum iron
• Ferritin
• CBC with differential
• Total iron-binding capacity
• Renal function
• Hepatic function
• Ophthalmological function

Specific cases may require

• Auditory function
• Cardiac monitoring

Additional observations

• Weight and height (children)

Intravenous infusion during blood transfusion

• The availability of an intravenous line during blood transfusions makes it possible to administer an intravenous infusion, e.g. for patients who comply poorly with and/or do not tolerate subcutaneous infusions. 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" adaptor located near the venous site of injection
• The patient's pump should be used to administer desferrioxamine as usual. Because of the limited amount of medicine that can be administered by i.v. infusion during blood transfusion, the clinical benefit of this mode of administration is limited. Patients and nurses should be warned against accelerating the infusion, as an intravenous bolus of desferrioxamine may lead to circulatory collapse

Concomitant use of vitamin C

• Patients with iron overload usually develop vitamin C deficiencies, probably because iron oxidises the vitamin. As an adjuvant to chelation therapy, vitamin C in doses up to 200 mg daily may be given in divided doses, starting after an initial month of regular treatment with desferrioxamine. Vitamin C increases the availability of iron for chelation. In general, 50mg suffices for children under 10 years of age and 100mg for older children. Larger doses of vitamin C fail to produce any additional increase in the excretion of the iron complex

Appropriate requirements for cessation of treatment

The following suggested criteria are believed to represent appropriate requirements for cessation of desferrioxamine

• Chelation therapy should be continued until all of the following criteria are satisfied
  • The patient must be free of signs or symptoms of systemic iron poisoning (e.g., no acidosis, no worsening hepatotoxicity)
  • Ideally, a corrected serum iron level should be normal or low (i.e. below 100 µg/dL)
• Given that laboratories cannot measure serum iron concentrations accurately in the presence of desferrioxamine, it is acceptable to discontinue desferrioxamine when all other criteria are met if measured serum iron level is not elevated
  • Repeat abdominal radiograph test should be obtained in patients who initially demonstrated multiple radiopacities to ensure they have disappeared before desferrioxamine is discontinued because they serve as a marker for continued iron absorption
• If the patient initially developed vin-rose coloured urine with desferrioxamine therapy, the urine colour should return to normal before halting desferrioxamine (absence of vin-rose urine is not sufficient by itself to warrant discontinuation of desferrioxamine). The effectiveness of treatment is dependent on an adequate output of urine in order to ensure that the iron complex ferrioxamine is excreted from the body. If oliguria or anuria develops, peritoneal dialysis, haemodialysis, or haemofiltration may become necessary

Desferrioxamine is a chelating agent for trivalent iron and aluminium ions; the resulting chelates, ferrioxamine and aluminoxamine, are stable and non-toxic. Desferrioxamine takes up iron either free or bound to ferritin and haemosiderin. Similarly it mobilises and chelates tissue bound aluminium. It does not remove iron from haemin containing substances including haemoglobin and transferrin. Since both ferrioxamine and aluminoxamine are completely excreted, Desferrioxamine promotes the excretion of iron and aluminium in urine and faeces, thus reducing pathological iron or aluminium deposits in the organs and tissues. 

Injection (per vial) 500mg 

• Desferal (Novartis) originator