DESFERRIOXAMINE MESILATE

Method of Administration Desferrioxamine Mesilate may be administered parenterally (intramuscularly, intravenously, or subcutaneously). g. 500 mg: by dissolving the contents of one 500 mg vial in 5mL of water for injection. When administered subcutaneously the needle should not be inserted too close to the dermis.

9% and Dextrose 5% Infusion solutions, Ringer’s Lactate), although these should not be used as solvent for the dry substance. Dissolved Desferrioxamine Mesilate can 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 Desferrioxamine Mesilate solutions should be used. Opaque, cloudy or discoloured solutions should be discarded. Heparin is pharmaceutically incompatible with Desferrioxamine Mesilate solutions.

Posology 1) Treatment of acute iron poisoning Adults and children:

Desferrioxamine Mesilate may be administered parenterally. Desferrioxamine Mesilate is an adjunct to standard measures generally used in treating acute iron poisoning. It is important to initiate treatment as soon as possible. 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 radio-opacities (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 350 micro g/dL regardless of the total iron binding capacity (TIBC).

It has also been suggested that a conservative approach without Desferrioxamine Mesilate therapy or challenge should be considered when serum iron levels are in the 300 to 500 micro g/dL range in asymptomatic patients, as well as in those with self-limited, non-bloody emesis or diarrhoea without other symptoms.

The dosage and route of administration should be adapted to the severity of the poisoning. Dose and method of administration The continuous intravenous administration of Desferrioxamine Mesilate is the preferred route and the recommended rate for infusion is 15 mg/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 80 mg/kg in any 24 hour period.

However, if the option to infuse intravenously is not available and if the intramuscular route is used the normal dosage is 2 g for an adult and 1g for a child, administered as a single intramuscular dose. The decision to discontinue Desferrioxamine Mesilate therapy must be a clinical decision; however, the following suggested criteria are believed to represent appropriate requirements for the cessation of Desferrioxamine Mesilate.

g. no acidosis, no worsening hepatoxicity), • ideally, a corrected serum iron level should be normal or low (when iron level falls below 100 micro g/dL). Given that laboratories cannot measure serum iron concentrations accurately in the presence of Desferrioxamine Mesilate, it is acceptable to discontinue Desferrioxamine Mesilate when all other criteria are met if the measured serum iron concentration is not elevated.

• Repeat abdominal radiograph test should be obtained in patients who initially demonstrated multiple radio-opacities to ensure they have disappeared before Desferrioxamine Mesilate is discontinued because they serve as a marker for continued iron absorption, • If the patient initially developed vin-rose coloured urine with Desferrioxamine Mesilate therapy, it seems reasonable that urine colour should return to normal before halting Desferrioxamine Mesilate (absence of vin-rose urine is not sufficient by itself to indicate discontinuation of Desferrioxamine Mesilate).

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. 5 mg of ferric iron. 2) Chronic Iron Overload The main aim of therapy in well-controlled patients is to maintain an iron balance and prevent haemosiderosis, whilst in overloaded patients a negative iron balance is desirable in order to deplete the increased iron stores and to prevent the toxic effects of iron.

g. serum ferritin >1000 ng/mL). The dose and mode of administration should be individually adapted according to the degree of iron overload. Growth retardation may result from iron overload or excessive Desferrioxamine Mesilate 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 (see section

). Hepatic impairment No studies have been performed in patients with hepatic impairment. g. in patients who comply poorly with and/or do not tolerate subcutaneous infusions. The Desferrioxamine Mesilate 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 to venous site of injection.

The patient's pump should be used to administer Desferrioxamine Mesilate as usual. Because of the limited amount of medicinal product that can be administered by IV infusion during blood transfusion, the clinical benefit of this mode of administration is limited.

4 Special warnings and precautions for use). 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. 4 Special warnings and precautions for use). 3) Diagnosis of iron storage disease and certain anaemias The Desferrioxamine Mesilate 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 500 mg of Desferrioxamine Mesilate will not increase this above 1 mg of iron (18 micro mol).

5 mg (27 micro mol). It should be borne in mind that the test only yields reliable results when renal function is normal. Desferrioxamine Mesilate is administered as 500 mg intramuscular injection. Urine is then collected for a period of 6 hours and its iron content determined.

5 mg (27 micro mol) can be regarded as pathological. 4) Treatment for aluminium overload in patients with end stage renal failure Patients should receive Desferrioxamine Mesilate if: - they have symptoms or evidence of organ impairment due to aluminium overload - they are asymptomatic but their serum aluminium levels are consistently above 60 ng/mL and associated with a positive Desferrioxamine Mesilate test (see below), particularly if a bone biopsy provides evidence of aluminium related bone disease.

The iron and aluminium complexes of Desferrioxamine Mesilate are dialysable. In patients with renal failure their elimination will be increased by dialysis. Adults and children Patients on maintenance haemodialysis or haemofiltration: 5 mg/kg once a week.

Patients with post-desferrioxamine test serum aluminium levels up to 300 ng/mL:

Desferrioxamine Mesilate should be given as a slow IV infusion during the last 60 minutes of a dialysis session (to reduce loss of free active substance in the dialysate).

Patients with a post- desferrioxamine test serum aluminium value above 300 ng/mL:

Desferrioxamine Mesilate should be administered by slow IV infusion 5 hours prior to the dialysis session. Four weeks after the completion of a three month course of Desferrioxamine Mesilate treatment a Desferrioxamine Mesilate infusion test should be performed, followed by a second test 1 month later.

Serum aluminium increases of less than 50ng/mL above baseline measured in 2 successive infusion tests indicate that further Desferrioxamine Mesilate treatment is not necessary. Patients on CAPD or CCPD: 5 mg/kg once a week prior to the final exchange of the day.

It is recommended that the intraperitoneal route be used in these patients. v. c. 5) Diagnosis of aluminium overload in patients with end stage renal failure A Desferrioxamine Mesilate infusion test is recommended in patients with serum aluminium levels > 60ng/mL associated with serum ferritin levels >100 ng/mL.

Just before starting the haemodialysis session, a blood sample is taken to determine the baseline level serum aluminium level. During the last 60 minutes of the haemodialysis session a 5mg/kg dose is given as a slow intravenous infusion.

e. 44 hours after the aforementioned Desferrioxamine Mesilate infusion) the second blood sample is taken to determine the serum aluminium level once more. An increase in serum aluminium above baseline of more than 150 ng/mL is suggestive of aluminium overload.

It should be noted that a negative test does not completely exclude the possibility of aluminium overload. 1 mg Al3+. Use in the elderly No special dosage regime is necessary but concurrent renal insufficiency should be taken into account.

3 Contraindications Hypersensitivity to the active substance unless the patients can be desensitised. 4 Special warnings and precautions for use Renal impairment Desferrioxamine Mesilate should be used with caution in patients with renal impairment since the metal complexes are excreted via the kidneys.

In these patients, dialysis will increase the elimination of chelated iron and aluminium. 8 Undesirable effects). Monitoring patients for […]

). Dose The lowest effective dose should be used. The average daily dose will probably lie between 20 and 60 mg/kg/day. Patients with serum ferritin levels of < 2000 ng/mL should require about 25 mg/kg/day, and those with levels between 2000 and 3000 ng/mL about 35 mg/kg/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 55 mg/kg/day. It is inadvisable to regularly exceed an average daily dose of 50 mg/kg/day except when very intensive chelation is needed in patients who have completed growth.

If ferritin values fall below 1000 ng/mL, the risk of Desferrioxamine Mesilate 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 500 mg 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. e.

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. Method of administration Slow subcutaneous infusion using 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. Desferrioxamine Mesilate should normally be used with the pump 5-7 times a week. Desferrioxamine Mesilate is not formulated to support subcutaneous bolus injection.

Since the subcutaneous infusions are more effective, intramuscular injections are given only when subcutaneous infusions are not feasible. Elderly Clinical studies of desferrioxamine did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently compared to younger subjects.

8 Undesirable effects). Hepatic impairment No studies have been performed in patients with hepatic impairment. g. in patients who comply poorly with and/or do not tolerate subcutaneous infusions. The Desferrioxamine Mesilate 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 to venous site of injection.

The patient's pump should be used to administer Desferrioxamine Mesilate as usual. Because of the limited amount of medicinal product that can be administered by IV infusion during blood transfusion, the clinical benefit of this mode of administration is limited.

4 Special warnings and precautions for use). 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. 4 Special warnings and precautions for use). 3) Diagnosis of iron storage disease and certain anaemias The Desferrioxamine Mesilate 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 500 mg of Desferrioxamine Mesilate will not increase this above 1 mg of iron (18 micro mol).

5 mg (27 micro mol). It should be borne in mind that the test only yields reliable results when renal function is normal. Desferrioxamine Mesilate is administered as 500 mg intramuscular injection. Urine is then collected for a period of 6 hours and its iron content determined.

5 mg (27 micro mol) can be regarded as pathological. 4) Treatment for aluminium overload in patients with end stage renal failure Patients should receive Desferrioxamine Mesilate if: - they have symptoms or evidence of organ impairment due to aluminium overload - they are asymptomatic but their serum aluminium levels are consistently above 60 ng/mL and associated with a positive Desferrioxamine Mesilate test (see below), particularly if a bone biopsy provides evidence of aluminium related bone disease.

The iron and aluminium complexes of Desferrioxamine Mesilate are dialysable. In patients with renal failure their elimination will be increased by dialysis. Adults and children […]

Hypersensitivity to the active substance unless the patients can be desensitised.