Desferrioxamine Mesilate 500 mg and 2 g Powder for Injection.

Desferrioxamine mesilate 500 mg or 2 g per vial.

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

For a full list of excipients, see section 6.1.

Powder for solution for injection or infusion.

White to cream powder or lyophilised plug.

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.

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

Desferrioxamine mesilate has limited efficacy in children under three years of age.

Treatment of acute iron poisoning: Adults, adolescents and children: desferrioxamine mesilate may be administered parenterally (intramuscularly, intravenously, or subcutaneously). It is important to initiate treatment as soon as possible.

Patients with -

?.- serum iron levels > 500 µg/dl (89.5 µmol/l), or

?.- serum iron levels> 350 µg/dl (62.6 µmol/l) with evidence of free iron, or

?.- with signs and symptoms of acute iron poisoning, should be given desferrioxamine mesilate, either intramuscularly or intravenously to eliminate iron that has already been absorbed. The dosage and route of administration should be adapted to the severity of the poisoning.

Dose: The normal dose is 2 g for an adult and adolescent, and 1 g for a child, administered as a single dose by intramuscular injection.

If the patient is hypotensive or in shock, the intravenous route of administration is recommended. Initially the maximum rate of intravenous administration should be 15 mg/kg/hr. It should be reduced after 4-6 hours so that the total dose does not exceed 80 mg/kg/24 hours. However, in the absence of adverse reactions, much larger doses may be tolerated.

Therapy should be continued until serum iron levels are less than the total iron binding capacity.

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.

100 mg desferrioxamine mesilate can chelate 8.5 mg of ferric iron.

Primary and secondary haemochromatosis including thalassaemia, in patients in whom concomitant disorders (e.g. severe anaemia, hypoproteinaemia) preclude phlebotomy: The main aim of therapy in younger patients is to achieve an iron balance and prevent haemosiderosis, whilst in the older patient a negative iron balance is desirable in order to slowly deplete the increased iron stores and to prevent the toxic effects of iron.

Adults, adolescents and children: Desferrioxamine mesilate therapy should be commenced after the first 10-15 blood transfusions, or when serum ferritin levels reach 1,000 ng/ml. The dose and route of administration should be individually adapted according to the degree of iron overload.

Dose: The lowest effective dose should be used. The average daily dose will lie between 20 and 60 mg/kg. Patients with serum ferritin levels of < 2,000 ng/ml should require about 25 mg/kg/day, and those with levels between 2,000 and 3,000 ng/ml about 35 mg/kg/day. Higher doses should only be employed if the benefit for the patient outweighs the risk of adverse events.

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 can be assessed at intervals of a few weeks.

Mode of administration: Slow subcutaneous infusions 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 4-7 times a week depending on the degree of iron overload.

As intramuscular injections are less effective, they should be given only when subcutaneous infusions are not appropriate.

Desferrioxamine mesilate can be administered by intravenous infusion during blood transfusion.

Continuous intravenous infusion is recommended for patients incapable of continuing subcutaneous infusions and in those who have cardiac problems secondary to iron overload. Implanted intravenous systems can be used when intensive chelation is carried out at home.

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 (18 µmol). In iron storage diseases, however, the increase may be well over 1.5 mg (27 µmol). It should be borne in mind that the test only yields reliable results when renal function is normal.

Desferrioxamine mesilate is administered as a 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 µmol) of iron during this 6-hour period is suggestive of iron overload; values greater than 1.5 mg (27 µmol) can be regarded as pathological.

Use in the elderly: No special dosage regime is necessary but concurrent renal insufficiency should be taken into account.

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 are dialyzable. Their excretion can be increased by dialysis in patients with renal failure.

Adults, adolescents and children: Patients on maintenance haemodialysis or haemofiltration: 5 mg/kg once a week administered during the last hour of a dialysis as a slow intravenous infusion (to reduce loss of free active substance in the dialysate).

Four weeks after the completion of a 3-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 above baseline of less than 75 ng/ml measured in 2 successive infusion tests indicate that further desferrioxamine mesilate treatment is not necessary.

Patients on CAPD (Continuous ambulatory peritoneal dialysis) or CCPD (Continuous cyclic peritoneal dialysis): 5 mg/kg once a week prior to the final exchange of the day. Desferrioxamine mesilate may be administered intravenously (by slow infusion), intramuscularly, subcutaneously or intraperitoneally; the intraperitoneal route is recommended for these patients.

Diagnosis of aluminium overload in patients with end-stage renal failure: A desferrioxamine mesilate infusion test is recommended in patients with serum aluminium levels > 60 ng/ml associated with serum ferritin levels > 100 ng/ml.

Serum aluminium values should be determined from blood samples taken: -immediately before a haemodialysis session (baseline); 5 mg/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 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.

100 mg desferrioxamine mesilate can bind 4.1 mg Al⁺⁺⁺.

Hypersensitivity to desferrioxamine mesilate unless the patient can be desensitised.

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.

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 with desferrioxamine mesilate by the intravenous route should only be administered in the form of slow infusions. 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). 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. 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. 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 risk-benefit 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.

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.

Gallium⁶⁷ 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.

Desferrioxamine mesilate has caused teratogenic effects in animals when given during pregnancy (see also section 5.3).

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.

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.

The following adverse events have been reported:

Frequency estimate: Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000) including isolated reports.

Blood and the lymphatic system disorders: Rare: blood dyscrasias

(e.g. thrombocytopenia), aplastic anaemia.

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

Endocrine disorders: Rare: growth retardation.

Nervous system disorders: Rare: neurological disturbances, dizziness, convulsions, 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.

Ear and labyrinth disorders: Uncommon: Tinnitus; hearing loss (including high frequency sensorineural hearing loss).

Cardiac disorders: Rare: hypotension.

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

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

Hepato-biliary disorders: Rare: impaired hepatic function.

Musculoskeletal, connective tissue and bone disorders: 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.

General disorders and administration site conditions: Common: pain, swelling, induration, erythema, burning, pruritus, wheals, rash at the injection/infusion site, occasionally accompanied by fever, chills and malaise.

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

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.

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 and hypotension.

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.

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.

Desferrioxamine mesilate is rapidly absorbed following intramuscular or subcutaneous administration. In healthy volunteers peak plasma concentrations of desferrioxamine (15.5 µmol/l / 8.7 µg/ml) and ferrioxamine (3.7 µmol/l / 2.3 µg/ml) were observed at 30 minutes and 1 hour respectively, following an injection (10 mg/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 µmol/l (3.9 µg/ml) were measured for desferrioxamine, and 15.7 µmol/l (9.6 µg/ml) for ferrioxamine, 1 hour after intramuscular injection of 10 mg/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 40 mg/kg desferrioxamine mesilate infused intravenously within 1 hour, the plasma concentration at the end of the infusion was 152 µmol/l (85.2 µg/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 µmol/l (4.3 µg/ml) with concomitant aluminoxamine levels of 2-3 µmol/litre (1.2-1.8 µg/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. 7 µmol/l (4 µg/ml). Following dialysis the plasma concentration of aluminoxamine fell to 2.2 µmol/l

(1.3 µg/ml), indicating that the aluminoxamine complex is dialysable.

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

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.

None

Heparin is pharmaceutically incompatible with desferrioxamine mesilate solutions.

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 20ºC. 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.

Do not store above 25°C.

After opening: use immediately.

After dilution: do not refrigerate or freeze.

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

500 mg vial: Cartons of 10 vials.

2 g vial: Cartons of 1 vial.

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 500 mg vial in 5 ml of Water for Injections. The 10 % desferrioxamine mesilate solution can be diluted with routinely employed infusion solutions (sodium chloride 9 mg/ml (0.9 %), glucose 50 mg/ml (5 %), or sodium chloride 1.8 mg/ml (0.18 %) and glucose 40 mg/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

Queensway,

Royal Leamington Spa, Warwickshire

CV313RW

PL 04515/0103

9 January 2001

January 2008