DESFERAL Sterile, lyophilised powder Ref.[2723] Active ingredients: Deferoxamine

Desferal may be administered parenterally.

For parenteral administration

The drug should preferably be employed in the form of a 10% solution, e.g. 500 mg: by dissolving the contents of one 500mg vial in 5ml of water for injection. When administered subcutaneously the needle should not be inserted too close to the dermis. The 10% Desferal solution can be diluted with routinely employed infusion solutions (saline, glucose, dextrose or dextrose-saline), although these should not be used as solvent for the dry substance. Dissolved Desferal 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 Desferal solutions should be used. Opaque, cloudy or discoloured solutions should be discarded. Heparin is pharmaceutically incompatible with Desferal solutions.

Treatment of acute iron poisoning

Adults and children

Desferal may be administered parenterally. Desferal is an adjunct to standard measures generally used in treating acute iron poisoning. It is important to initiate treatment as soon as possible.

Parenteral Desferal treatment should be considered 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 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 Desferal 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.

Dosage

The continuous intravenous administration of Desferal 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 Desferal therapy must be a clinical decision; however, the following suggested criteria are believed to represent appropriate requirements for the cessation of Desferal. Chelation therapy should be continued until all of the following criteria are satisfied:

• The patient must be free of signs and symptoms of systemic iron poisoning (e.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 Desferal, it is acceptable to discontinue Desferal 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 Desferal is discontinued because they serve as a marker for continued iron absorption,
• If the patient initially developed vin-rose coloured urine with Desferal therapy, it seems reasonable that urine colour should return to normal before halting Desferal ( absence of vin-rose urine is not sufficient by itself to indicate discontinuation of Desferal).

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 100 mg Desferal can chelate 8.5 mg of ferric iron.

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.

Adults and children

Desferal therapy should be commenced after the first 10-20 blood transfusions, or when serum ferritin levels reach 1000 ng/mL, indicating saturation of the transferrin. 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 Desferal 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 4.4 Special warnings and precautions for use).

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 regularly to 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 Desferal 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.

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 Desferal divided by the serum ferritin level (micro g/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.

Mode 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. Desferal should normally be used with the pump 5-7 times a week. Desferal 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 Desferal did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently compared to younger subjects. In general, 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 drug therapy' (see sections 4.4 Special warnings and precautions for use and 4.8 Undesirable effects).

Hepatic impairment

No studies have been performed in patients with hepatic impairment.

Intravenous infusion during blood transfusion

The availability of an intravenous line during blood transfusions makes it possible to administer an intravenous infusion, e.g. in patients who comply poorly with and/or do not tolerate subcutaneous infusions.

The Desferal 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 the venous site of injection. The patient’s pump should be used to administer Desferal as usual. Patients and nurses should be warned against accelerating the infusion, as an intravenous bolus of Desferal may lead to flushing, hypotension and acute collapse (see section 4.4 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 (i.v.) 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 Desferal which may be present in the dead space of the line, as this may lead to flushing; hypotension and acute collapse (see section 4.4 Special warnings and precautions for use).

Diagnosis of iron storage disease and certain anaemias

The Desferal 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 Desferal will not increase this above 1 mg (18 micro mol). In iron storage diseases, however, the increase may be well over 1.5 mg (27 micro mol). It should be borne in mind that the test only yields reliable results when renal function is normal.

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

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

Treatment for aluminium overload in patients with end stage renal failure

Patients should receive Desferal 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 Desferal test (see below), particularly if a bone biopsy provides evidence of aluminium related bone disease.

The iron and aluminium complexes of Desferal 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: Desferal should be given as a slow i.v. infusion during the last 60 minutes of a dialysis session (to reduce loss of free drug in the dialysate). Patients with a post-desferrioxamine test serum aluminium value above 300 ng/ml: Desferal should be administered by slow i.v. infusion 5 hours prior to the dialysis session.

Four weeks after the completion of a three month course of Desferal treatment a Desferal 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 Desferal 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. However, Desferal can also be given i.m., by slow infusion i.v. or s.c.

Diagnosis of aluminium overload in patients with end stage renal failure

A Desferal 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.

At the start of the next haemodialysis session (i.e. 44 hours after the aforementioned Desferal 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.

Theoretically 100 mg Desferal can bind 4.1 mg Al⁺⁺⁺.

Use in the elderly

No special dosage regime is necessary but concurrent renal insufficiency should be taken into account.

Desferal is usually administered parenterally and acute poisoning is unlikely to occur.

Signs and symptoms

Tachycardia, hypotension and gastro-intestinal symptoms have occasionally occurred in patients who received an overdose of Desferal. Accidental administration of Desferal by the i.v. route may be associated with acute but transient loss of vision, aphasia, agitation, headache, nausea, bradycardia, hypotension and acute renal failure (see section 4.8 Undesirable effects).

Acute respiratory distress syndrome has been described following treatment with excessively high i.v. doses of Desferal in patients with acute iron intoxication, and also in thalassemic patients (see also section 4.4 Special warnings and precautions for use).

Treatment

There is no specific antidote to Desferal but signs and symptoms may be eliminated by reducing the dosage and Desferal is dialysable. Appropriate supportive therapy should be instituted.

36 months.

Vial: Do not store above 25°C.

Reconstituted solution: Single use only.

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

Each vial contains a white to practically white lyophilisate supplied in a clear glass vial in a pack size of 10 (500 mg).

None stated.