DESFERRIOXAMINE MESILATE 2G POWDER FOR INJECTION, DESFERRIOXAMINE MESILATE 500 MG POWDER FOR INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Desferrioxamine Mesilate 500mg and 2g Powder for Injection.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Desferrioxamine mesilate 500mg or 2g per vial.

Following reconstitution, each ml of solution contains 100mg desferrioxamine mesilate.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for solution for injection or infusion.

White to cream powder or lyophilised plug.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Iron overload – acute iron poisoning; primary and secondary haemochromatosis including thalassaemia and transfusional haemosiderosis; in patients in whom concomitant disorders (e.g. severe anaemia, hypoproteinaemia, renal or cardiac failure) preclude phlebotomy; and for the diagnosis of iron storage disease and sideroblastic anaemia, auto-immune haemolytic anaemia and other chronic 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; and for diagnosis of aluminium overload.

4.2 Posology and method of administration

Desferrioxamine mesilate may be administered intramuscularly, intravenously, or subcutaneously. When administered subcutaneously the needle should not be inserted too close to the dermis.

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 or 2 g: by dissolving the contents of one 2 g vial in 20 ml of water for injection. When administered subcutaneously the needle should not be inserted too close to the dermis. The 10% Desferrioxamine mesilate 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 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.

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.

Parenteral Desferrioxamine mesilate 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 radioopacities (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 symptomatic 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 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. 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 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.

Theoretically 100 mg Desferrioxamine mesilate 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:

Desferrioxamine mesilate therapy should be commenced after the first 10– 20 blood transfusions, or when there is evidence from clinical monitoring that chronic iron overload is present (e.g. serum ferritin >1000 nanogram/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 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 nanogram/mL should require about 25 mg/kg/day, and those with levels between 2000 and 3000 nanogram/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 nanogram/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.

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 mesilate 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. 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 mesilate 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 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 drug that can be administered by IV 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 mesilate may lead to flushing, hypotension and circulatory 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 a sudden infusion of residual Desferrioxamine mesilate which may be present in the dead space of the line, as this may lead to flushing, hypotension and circulatory collapse (see section 4.4 Special warnings and precautions for use).

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). 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.

Desferrioxamine mesilate 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 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 nangogram/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 nanogram/mL: Desferrioxamine mesilate 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 nanogram/ml: Desferrioxamine mesilate 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 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 50nanogram/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. However, Desferrioxamine mesilate 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 Desferrioxamine mesilate infusion test is recommended in patients with serum aluminium levels > 60nanogram/mL associated with serum ferritin levels >100 nanogram/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 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 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 100 mg Desferrioxamine mesilate 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.

4.3 Contraindications

Hypersensitivity to desferrioxamine mesilate unless the patient can be desensitised.

4.4 Special warnings and precautions for use

Desferrioxamine mesilate should be used with caution in patients with renal impairment since the metal complexes are excreted mainly via the kidneys. In these patients, dialysis will increase the elimination of chelated iron and aluminium. Monitoring of patients for changes in renal function (e.g. increased serum creatinine) should be considered.

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

Treatment of aluminium overload may result in decreased serum calcium and aggravation of hyperparathyro­idism.

Treatment with desferrioxamine mesilate by the intravenous route should only be administered in the form of slow infusions. Rapid intravenous infusion may lead to hypotension and shock (e.g. flushing, tachycardia, circulatory collapse and urticaria). If an intramuscular injection is accidentally given intravenously, this may lead to circulatory collapse.

Desferrioxamine mesilate should not be administered subcutaneously in concentrations and/or doses higher than those recommended as otherwise local irritation at the site of administration may occur more frequently.

Patients suffering from iron overload are particularly susceptible to infection. There have been reports of desferrioxamine mesilate promoting some infections such as Yersinia enterocolitica and Y. Pseudotuberculosis. If patients develop fever with pharyngitis, diffuse abdominal pain or enteritis/ente­rocolitis, desferrioxamine mesilate therapy should be stopped, and appropriate treatment with antibiotics should be instituted. Desferrioxamine mesilate therapy may be resumed once the infection has cleared.

In patients undergoing haemodialysis while receiving desferrioxamine mesilate, there have been rare reports of severe fungal infection (i.e. cases of mucormycosis), some with fatal outcome. If any characteristic signs or symptoms occur desferrioxamine mesilate treatment should be discontinued, mycological tests carried out and appropriate treatment immediately instituted. Mucormycosis has been reported to occur in dialysis patients not receiving desferrioxamine mesilate, thus no causal link with the use of the medicinal product has been established.

Disturbances of vision and hearing have been reported during prolonged desferrioxamine mesilate therapy. In particular this has occurred in patients on higher than recommended doses, or in patients with low serum ferritin levels. Patients with renal failure who are receiving maintenance dialysis and have low ferritin levels may be particularly prone to adverse reactions, visual symptoms having been reported after single doses of desferrioxamine. Therefore, ophthalmological and audiological tests should be carried out both prior to the institution of long-term therapy with desferrioxamine mesilate and at 3-monthly intervals during treatment. By keeping the ratio of the mean daily dose (mg/kg of desferrioxamine) divided by the serum ferritin (micrograms/litre) below 0.025 the risk of audiometric abnormalities may be reduced in thalassaemia patients. A detailed ophthalmological assessment is recommended (visual field measurements, funduscopy, colour vision testing using pseudoisochromatic plates and the Farnsworth D-15 colour test, slit lamp investigation, visual evoked potential studies).

If disturbances of vision or hearing do occur, treatment with desferrioxamine mesilate should be stopped. Such disturbances may be reversible. If desferrioxamine mesilate therapy is re-instituted later at a lower dosage, close monitoring of ophthalmologi­cal/auditory function should be carried out with due regard to the riskbenefit ratio.

The use of inappropriately high doses of desferrioxamine mesilate in patients with low ferritin levels or young children (<3 years at commencement of treatment) has also been associated with growth retardation; dose reduction has been found to restore the growth rate to pre-treatment levels in some cases. Three monthly checks on body weight and height are recommended in children.

Growth retardation, if associated with excessive doses of desferrioxamine mesilate, must be distinguished from growth retardation from iron overload. Growth retardation from desferrioxamine mesilate use is rare if the dose is kept below 40 mg/kg; if growth retardation has been associated with doses above this value, then reduction of the dose may result in return in growth velocity, however, predicted adult height is not attained.

Acute respiratory distress syndrome has been described following treatment with excessively high IV doses of desferrioxamine in patients with acute iron intoxication, and also in thalassaemic patients The recommended daily doses should therefore not be exceeded.

4.5 Interaction with other medicinal products and other forms of interaction

Oral administration of vitamin C (up to a maximum of 200 mg daily, given in divided doses) may serve to enhance excretion of the iron complex in response to desferrioxamine mesilate; larger doses of vitamin C fail to produce an additional effect. Monitoring of cardiac function is indicated during such combined therapy. Vitamin C should be given only if the patient is receiving desferrioxamine mesilate regularly, and should not be administered within the first month of desferrioxamine mesilate therapy. In patients with severe chronic iron-storage disease undergoing combined treatment with desferrioxamine mesilate and high doses of vitamin C (more than 500 mg daily) impairment of cardiac function has been encountered; this proved reversible when the vitamin C was withdrawn. Vitamin C supplements should not therefore be given to patients with cardiac failure.

Desferrioxamine mesilate should not be used in combination with prochlorperazine (a phenothiazine derivative) since prolonged unconsciousness may result. Caution is advised when desferrioxamine mesilate is used in combination with any phenothiazine.

Gallium imaging results may be distorted because of the rapid urinary excretion of desferrioxamine-bound radiolabel. Discontinuation of desferrioxamine mesilate 48 hours prior to scintigraphy is advised.

There is evidence that aluminium intoxication causes reduced erythropoiesis. In dialysed patients with aluminium and/or iron overload treated with desferrioxamine mesilate and erythropoietin some dosage adjustment of the latter may be necessary. Regular monitoring of iron stores should also be carried out.

4.6 Fertility, pregnancy and lactation

Pregnancy

Desferrioxamine mesilate has caused teratogenic effects in animals when given during pregnancy (see also section 5.3), particularly in the first trimester.

Malformations have not occurred in children born to patients reported to have received desferrioxamine during pregnancy.

Lactation

It is not known whether desferrioxamine mesilate is excreted into the breast milk.

Desferrioxamine mesilate should not be given to pregnant or lactating women unless in the judgement of the physician, the expected benefits to the mother outweigh the potential risk to the child. This particularly applies to the first trimester.

4.7 Effects on ability to drive and use machines

Desferrioxamine mesilate has a major influence on the ability to drive and use machines in patients experiencing CNS effects such as dizziness or impaired vision/hearing. Patients should be warned against driving or operating machinery.

4.8 Undesirable effects

The following adverse events have been reported:

Frequency estimate: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000) including isolated reports, not known (cannot be estimated from the available data).

Blood and the lymphatic system disorders: Rare: blood dyscrasias (e.g. thrombocytopenia), aplastic anaemia.

Not known: leucopenia.

Infections and infestation: Rare: mucormycosis (some fatal). Very rare: gastroenteritis yersinia infections.

Immune system disorders: Rare: anaphylactic/a­naphylactoid reactions with or without shock, angioedema including laryngeal oedema.

Endocrine disorders: Rare: growth retardation.

Nervous system disorders: Common: headache. Rare: neurological disturbances, dizziness, convulsions (mainly reported in dialysed patients with aluminium overload), exacerbation of neurological impairment in aluminium-related encephalopathy. Isolated cases: precipitation of dialysis dementia, peripheral sensory neuropathy, paraesthesia.

Eye disorders: Rare: blurred vision, decreased visual acuity, loss of vision, impairment of colour vision, night blindness, visual field defects, scotoma, retinopathy (pigmentary degeneration of the retina), optic neuritis, cataracts, corneal opacities, chromatopsia.

Ear and labyrinth disorders: Uncommon: tinnitus; hearing loss (including high frequency sensorineural hearing loss), deafness neurosensory.

Vascular disorders: Rare: hypotension if precautions for administration are not followed (see Section 4.2 Posology and method of administration).

Respiratory, thoracic and mediastinal disorders: Uncommon: asthma. Very rare: adult respiratory distress syndrome (with dyspnoea, cyanosis and interstitial pulmonary infiltrates); following excessively high intravenous doses of desferrioxamine mesilate, lung infiltration.

Gastrointestinal disorders: Rare: nausea, vomiting, diarrhoea, abdominal cramps.

Hepato-biliary disorders: Rare: impaired hepatic function.

Skin and subcutaneous tissue disorders: Rare: generalised rash, pruritus, urticaria.

Musculoskeletal, connective tissue and bone disorders: Very common: arthralgia/myalgia. Common: growth retardation and bone changes (e.g. metaphyseal dysplasia) are common in chelated patients given doses of 60 mg/kg especially those who begin iron chelation in the first three years of life. If doses are kept to 40 mg/kg or below, the risk is considerably reduced. Rare: Leg cramps and bone pain have also been reported in isolated cases.

Renal and urinary disorders: Very Rare: impaired renal function. Not known: acute renal failure, renal tubular disorder.

General disorders and administration site conditions: Very common: infiltration and eschar/crust. Common: pain, swelling, induration, erythema, burning, pruritus, wheals, rash at the injection/infusion site. Occasionally accompanied by fever, chills and malaise. Uncommon: vesicles and local oedema at the injection site.

Investigations: Not known: blood creatinine increased.

Some of the adverse events mentioned above must be considered as signs and symptoms of the underlying disease. Excretion of iron complex during treatment with desferrioxamine mesilate causes reddish-brown discolouration of the urine.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

Desferrioxamine mesilate is usually administered parenterally and acute poisoning is unlikely to occur

Signs and symptoms: Tachycardia, hypotension and gastrointestinal symptoms have occasionally occurred in patients who received an overdose of desferrioxamine mesilate. Accidental administration of desferrioxamine mesilate by the intravenous route may be associated with acute but transient loss of vision, aphasia, agitation, headache, nausea, bradycardia, acute renal failure and hypotension.

Acute respiratory distress syndrome has been described following treatment with excessively high IV doses of deferoxamine in patients with acute iron intoxication, and also in thalassemic patients.

Treatment: There is no specific antidote to desferrioxamine mesilate but signs and symptoms may be eliminated by reducing the dosage and desferrioxamine mesilate is dialysable.

Appropriate supportive therapy should be instituted.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Iron chelating agents, ATC Code: V03A C01

Desferrioxamine mesilate is a chelating agent for trivalent iron and aluminium ions; the resulting chelates (ferrioxamine and aluminoxamine) are stable and non-toxic. Neither chelate undergoes significant intestinal absorption, and any formed systemically as a result of parenteral administration is rapidly excreted via the kidneys without deleterious effects. Desferrioxamine mesilate 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 mesilate promotes the excretion of iron and aluminium in urine and faeces thus reducing pathological iron or aluminium deposits in the organs and tissues.

5.2 Pharmacokinetic properties

Desferrioxamine mesilate is rapidly absorbed following intramuscular or subcutaneous administration. In healthy volunteers peak plasma concentrations of desferri oxamine (15.5^mol/l / 8.7^g/ml) and ferri oxamine (3.7^mol/l / 2.3^g/ml) were observed at 30 minutes and 1 hour respectively, following an injection (10mg/kg) of desferrioxamine mesilate. It is only poorly absorbed from the gastrointestinal tract in the presence of intact mucosa.

Serum protein binding of desferrioxamine is less than 10 % in vitro.

Four metabolites of desferrioxamine mesilate were isolated and identified from urine of patients with iron overload. The following biotransformation reactions were found to occur with desferrioxamine: transamination and oxidation yielding an acid metabolite, beta-oxidation also yielding an acid metabolite, decarboxylation and N-hydroxylation yielding neutral metabolites.

In healthy subjects elimination is biphasic, first phase half-lives for desferrioxamine and ferrioxamine are 1 hour and 2.4 hours, respectively. In the second phase both compounds have a half-life of 6 hours. Of the injected dose 22% appears in the urine as desferrioxamine and 1% as ferrioxamine, after 6 hours.

In patients with haemochromatosis peak plasma levels of 7.0^mol/l (3.9^g/ml) were measured for desferrioxamine, and 15.7^mol/l (9.6^g/ml) for ferrioxamine, 1 hour after intramuscular injection of 10mg/kg desferrioxamine mesilate. These patients eliminated desferrioxamine and ferrioxamine with half-lives of 5.6 and 4.6 hours, respectively. Six hours after the injection 17% of the dose was excreted in the urine as desferrioxamine and 12% as ferrioxamine.

In patients dialysed for renal failure who received 40mg/kg desferrioxamine mesilate infused intravenously within 1 hour, the plasma concentration at the end of the infusion was 152^mol/l (85.2^g/ml) when the infusion was given between dialysis sessions. Plasma concentrations of desferrioxamine were between 13% and 27% lower when the infusion was administered during dialysis. Concentrations of ferrioxamine were in all cases approx. 7.0^mol/l (4.3^g/ml) with concomitant aluminoxamine levels of 2–3Limol/litre (1.2–1.8^g/ml). After the infusion was discontinued, the plasma concentration of desferrioxamine decreased rapidly with a half-life of 20 minutes. A smaller fraction of the dose was eliminated with a longer half-life of 14 hours. Plasma concentrations of aluminoxamine continued to increase for up to 48 hours post-infusion and reached values of approx. 7L mol/l (4L g/ml). Following dialysis the plasma concentration of aluminoxamine fell to 2.2L mol/l (1.3L g/ml), indicating that the aluminoxamine complex is dialysable.

During peritoneal dialysis desferrioxamine is absorbed if administered in the dialysis fluid.

5.3 Preclinical safety data

In rabbits desferrioxamine mesilate caused skeletal malformations. However, these teratogenic effects in the fetuses were observed at doses which were toxic to the mother animal. In mice and rats desferrioxamine mesilate appears to be free of teratogenic activity.

Long-term carcinogenicity studies have not been performed.

Evidence of mutagenicity has been observed in mouse lymphoma cells.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

None

6.2 Incompatibilities

Heparin is pharmaceutically incompatible with desferrioxamine mesilate solutions.

6.3 Shelf life

30 months

In use: Following dilution in water for injections, chemical and physical in-use stability has been demonstrated for up to 48 hours at 20°C. From a microbiological point of view, however, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and dilution should take place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Do not store above 25°C.

After opening: use immediately.

After dilution: do not refrigerate or freeze.

6.5 Nature and contents of container

Type I glass vials with bromobutyl rubber stoppers containing 500mg or 2g of powder.

500mg vial: Cartons of 10 vials.

2g vial: Cartons of 1 vial.

6.6 Special precautions for disposal

For parenteral administration: The medicinal product should preferably be employed in the form of a 10% solution, e.g. by dissolving the contents of one 500mg vial in 5 ml of Water for Injections. The 10% desferrioxamine mesilate solution can be diluted with routinely employed infusion solutions (sodium chloride 9mg/ml (0.9%), glucose 50mg/ml (5%), or sodium chloride 1.8mg/ml (0.18%) and glucose 40mg/ml (4%)), 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.

Unused portions of opened vials must not be stored and should be discarded immediately.

Hospira UK Limited, Horizon, Honey Lane, Hurley, Maidenhead, SL6 6RJ, United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 04515/0103

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

20/02/2009