Desferrioxamine Mesilate 2g Powder for Solution for Injection or Infusion

Each vial contains desferrioxamine mesilate 2g. For the full list of excipients, see section 6.1

A sterile, lyophilised powder available in vials containing 2g of desferrioxamine mesilate.

Treatment for chronic iron overload, e.g.

• transfusional haemosiderosis in patients receiving regular transfusions e.g. thalassaemia major.

• primary and secondary haemochromatosis in patients in whom concomitant disorders (e.g. severe anaemia, hypoproteinaemia, renal or cardiac failure) preclude phlebotomy.

Treatment for acute iron poisoning.

For the diagnosis of iron storage disease and certain 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.

Method of Administration

Desferrioxamine Mesilate may be administered parenterally (intramuscularly, intravenously, or subcutaneously).

For parenteral administration:

The medicinal product should preferably be employed in the form of a 10% solution, e.g. 2g: by dissolving the contents of one 2g vial in 20mL 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 (Sodium Chloride 0.9% Infusion, Dextrose 5% Infusion, combination of Sodium Chloride 0.9% 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.

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 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. 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.

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.

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 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 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 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.

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.

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. 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 medicinal product 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 medicinal product 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 (IV) 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).

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). 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.

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. However, Desferrioxamine Mesilate can also be given i.m., by slow infusion i.v. or s.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.

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 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 desferrioxamine can bind 4.1 mg Al³⁺.

Use in the elderly

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

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

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. Isolated cases of acute renal failure have been reported (see also section

4.8 Undesirable effects). Monitoring patients for changes in renal function (e.g. increased serum creatinine) should be considered.

Neurological impairment

Used alone desferrioxamine 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. Pretreatment with clonazepam has been shown to afford protection against such impairment. Also, treatment of aluminium overload may result in decreased serum calcium and aggravation of hyperparathyroidism.

Rapid intravenous infusion

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).

Instructions for use and handling

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

Infections

Patients suffering from iron overload are particularly susceptible to infection. There have been reports of desferrioxamine 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, receiving desferrioxamine for aluminium and/or iron overload there have been rare reports of mucormycosis (a severe fungal infection), some with fatal outcome. If any characteristic signs or symptoms occur desferrioxamine 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, thus no causal link with the use of the medicinal product has been established.

Visual and hearing impairment

Disturbances of vision and hearing have been reported during prolonged desferrioxamine therapy. In particular, this has occurred in patients on higher than recommended therapy 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 therapy with Desferrioxamine Mesilate and at 3-monthly intervals during treatment particularly if ferritin levels are low. By keeping the ratio of the mean daily dose (mg/kg of Desferrioxamine Mesilate) divided by the serum ferritin (micro g/L) below 0.025 the risk of audiometric abnormalities may be reduced in thalassaemia patients. A detailed ophthalmological assessment is recommended (visual field measurements, fundoscopy, and 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 are usually 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.

Paediatric population: growth retardation

The use of inappropriately high doses of desferrioxamine 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 pretreatment 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 must be distinguished from growth retardation from iron overload. Growth retardation from desferrioxamine 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

Acute respiratory distress syndrome has been described following treatment with excessively high i.v. doses of desferrioxamine in patients with acute iron intoxication, and also in thalassaemic patients (see section 4.8 Undesirable effects). The recommended daily doses should therefore not be exceeded.

It should be noted that desferrioxamine will affect aluminium levels and may necessitate some dosage adjustment of erythropoietin if co-prescribed.

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; 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 regularly and should not be administered within the first month of desferrioxamine therapy. In patients with severe chronic iron-storage disease undergoing combined treatment with desferrioxamine 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.

Gallium⁶⁷ imaging results may be distorted because of the rapid urinary excretion of desferrioxamine - bound radiolabel. Discontinuation of desferrioxamine 48 hours prior to scintigraphy is advised.

Pregnancy

There is a limited amount of data on the use of desferrioxamine in pregnant patients. Studies in animals (rabbits) have shown reproductive toxicity/teratogenicity (see section 5.3 Preclinical safety data). The risk to the foetus/mother is unknown.

Desferrioxamine Mesilate should be used during pregnancy only if the expected benefits to the mother outweigh the potential risk to the foetus.

Breastfeeding

It is not known whether desferrioxamine is excreted into the breast milk. Because many medicinal products are excreted in human milk, and because of the potential for serious adverse drug reactions in breast-fed newborns/infants, a decision should be made whether to abstain from breast-feeding or to abstain from using the medicinal product, taking into account the importance of the medicinal product to the mother.

Fertility

In women of child-bearing potential, in each case the benefits for the mother must be weighed against the risks for the child.

Patients experiencing CNS effects such as dizziness or impaired vision or hearing should be warned against driving or operating machinery.

Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: very common (≥1/10); common (≥1/100 to < 1/10); uncommon (≥1/1,000 to

≤1/100); rare (≥1/10,000 to ≤1,000); very rare (≤1/10,000); including isolated reports ; not known (frequency cannot be estimated from the available data).

Some signs and symptoms reported as adverse effects may also be manifestations of the underlying disease (iron and/or aluminium overload).

Table 1

Special remarks

At the injection site pain, swelling, infiltration, erythema, pruritus and eschar/crust are very common; vesicles, localised oedema and burning are uncommon reactions. The local manifestations may be accompanied by systemic reactions like arthralgia/myalgia (very common), headache (common), urticaria (common), nausea (common), pyrexia (common), vomiting (uncommon), or abdominal pain (uncommon) or asthma (uncommon).

Excretion of the iron complex may cause reddish-brown discoloration of the urine. Convulsion has been mainly reported in dialysed patients with aluminium overload. Patients treated for chronic aluminium overload

Desferrioxamine Mesilate chelation therapy aluminium overload may result in hypocalcemia and aggravation of hyperparathyroidism (see section 4.4 Special warnings and precautions for use).

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 Yellow Card Scheme, www.mhra.gov.uk/yellowcard.

Desferrioxamine Mesilate 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 desferrioxamine. Accidental administration of desferrioxamine 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 desferrioxamine 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 desferrioxamine but signs and symptoms may be eliminated by reducing the dosage and desferrioxamine is dialysable. Appropriate supportive therapy should be instituted.

Pharmacotherapeutic group: Chelating agent, ATC code: V03AC01

Desferrioxamine is a chelating agent for trivalent iron and aluminium ions; the resulting chelates (ferrioxamine and aluminoxamine) are stable and non-toxic. Neither chelate undergoes intestinal absorption, and any formed systemically as a result of parenteral administration is rapidly excreted via the kidneys without deleterious effects. 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.

Absorption

Desferrioxamine is rapidly absorbed after intramuscular bolus injection or slow subcutaneous infusion, but is only poorly absorbed from the gastrointestinal tract in the presence of intact mucosa.

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

Distribution

In healthy volunteers peak plasma concentrations of desferrioxamine (15.5 micro mol/L (87 micro g/mL)) were measured 30 minutes after an intramuscular injection of 10 mg/kg desferrioxamine. One hour after injection the peak concentration of ferrioxamine was 3.7 micro mol/L (2.3 micro g/mL).

Less than 10% of desferrioxamine is bound to serum proteins in vitro.

Biotransformation

Four metabolites of desferrioxamine were isolated from the 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.

Elimination

Both desferrioxamine and ferrioxamine a biphasic elimination after intramuscular injection in healthy volunteers; for desferrioxamine the apparent distribution half-life is 1 hour, and for ferrioxamine 2.4 hours. The apparent terminal half-life is 6 hours for both. Within six hours of injection, 22% of the dose appears in the urine as desferrioxamine and 1% as ferrioxamine.

Characteristics in patients

In patients with haemochromatosis peak plasma levels of 7.0 micro mol/L (3.9 micro g/mL) were measured for desferrioxamine, and 15.7 micro mol/L (9.6 micro g/mL) for ferrioxamine, 1 hour after an intramuscular injection of 10 mg/kg desferrioxamine. 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 infused i.v. within 1 hour, the plasma concentration at the end of the infusion was 152 micro mol/L (85.2 micro 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 approximately 7.0 micro mol/L (4.3 micro g/mL) with concomitant aluminoxamine levels of 2-3 micro mol/litre (1.2-1.8 micro g/mL). After the infusion was discontinued, the plasma concentrations 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 approximately 7 micro mol/L (4 micro g/mL). Following dialysis the plasma concentration of aluminoxamine fell to 2.2 micro mol/L (1.3 micro g/mL), indicating that the aluminoxamine complex is dialysable.

In patients with thalassaemia continuous intravenous infusion of 50mg/kg/24h of desferrioxamine resulted in plasma steady state levels of desferrioxamine of 7.4 micro mol/L. Elimination of desferrioxamine from plasma was biphasic with a mean distribution half-life of 0.28 hours and an apparent terminal half-life of 3.0 hours. The total plasma clearance was 0.5 L/h/kg and the volume of

distribution at steady state was estimated at 1.35 L/kg. Exposure to the main iron binding metabolite was around 54% of that of desferrioxamine in terms of AUC. The apparent monoexponential elimination half-life of the metabolite was 1.3 hours.

Clinical studies

Desferrioxamine was used as a comparator in a randomized, one-year clinical trial investigating the use of another iron chelator (deferasirox) in patients with beta-thalassemia and transfusional hemosiderosis. A total of 290 patients were treated with subcutaneous desferrioxamine at starting doses of 20 to 60 mg/kg for 5 days per week. The study showed a dose-dependent effect of desferrioxamine on serum ferritin levels, liver iron concentration and iron excretion rate.

Desferrioxamine was also used as a comparator in a second open-label, randomized, one-year trial investigating the use of deferasirox in patients with sickle cell disease and transfusional hemosiderosis. A total of 63 patients were treated with subcutaneous desferrioxamine at starting doses of 20 to 60 mg/kg at least 5 days per week. At the end of the study, the mean change in liver iron concentration (LIC) was -0.7 mg Fe/g dry weight.

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the Summary of Product Characteristics..

Sodium hydroxide (for pH adjustment)

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

4 years.

Vial: Store below 25°C.

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 25°C 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.

Glass (Ph. Eur., type I) vials containing a white to practically white lyophilisate, closed with rubber (Ph. Eur., type I) stoppers.

Pack Size: Bt x 1 vial x 2 g Bt x 5 vials x 2 g

Bt x 10 vials x 2 g

Bt x 50 vials x 2 g

Single use only, whereby any unused solution should be discarded.

The use of freshly prepared solutions is recommended. Τhese maintain potency for at least 24 hours at 25°C.

The reconstituted solution should be clear. Do not use if particles are present.

Desferrioxamine Mesilate injection should preferably be employed in the form of a 10% aqueous solution, by dissolving the contents of a 2g vial in 20mL of Water for injections.

Intramuscular administration: The volume of solvent should be not less than 3 mL for each gram of desferrioxamine mesilate (i.e. reconstitute each 500 mg vial of Desferrioxamine Mesilate injection with not less than 1.5 mL of Water for injections).

Intravenous administration: Administration by the intravenous route should be in the form of slow infusion. The 10% desferrioxamine mesilate solution can be diluted with routinely employed infusion solutions (Sodium Chloride 0.9% Infusion, Dextrose 5% Infusion, combination of Sodium Chloride 0.9% and Dextrose 5% infusion solutions, Ringer's Lactate), although these should not be used as solvent for the dry substance. The rate of infusion should not exceed 15 mg/kg/hr for the first 1 g of desferrioxamine mesilate. Subsequent IV dosing must be at a slower rate, not exceeding 125 mg/hr.

Subcutaneous Administration: Desferrioxamine Mesilate injection should be administered over 8-24 hours, utilizing a small portable pump capable of providing continuous mini-infusion.

Intraperitoneal administration: The 10% desferrioxamine mesilate solution can also be added to dialysis fluid and given intraperitoneally to patients on continuous ambulatory peritoneal dialysis (CAPD) or continuous cyclic peritoneal dialysis (CCPD).

Noridem Enterprises Ltd. Evagorou & Makariou Mitsi Building 3

Office 115, 1065 Nicosia

Cyprus

PL 24598/0021

14 March 2012 / 08 March 2016

12/04/2017