Desferrioxamine Mesilate 500 Mg Powder For Solution For Injection Or Infusion
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Desferrioxamine Mesilate 500 mg Powder for Solution for Injection or Infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains deferoxamine mesilate 500 mg.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
A sterile, lyophilised powder available in vials containing 500mg of deferoxamine mesilate.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
• 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.
4.2 Posology and method of administration
Deferoxamine mesilate may be administered intramuscularly, intravenously, or subcutaneously. When administered subcutaneously the needle should not be inserted too close to the dermis.
The drug should preferably be employed in the form of a 10% solution, by dissolving the contents of a 500 mg vial in 5ml of water for injection.
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).
Treatment of acute iron poisoning
Adults and children:
Desferrioxamine Mesilate is 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 asymptomatic patients, as well as in those with self-limited, non-bloody emesis or diarrhoea without other symptoms.
The dosage and route of administration should be adapted to the severity of the poisoning.
Dosage:
The continuous intravenous administration of 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 patients with iron overload not complicated by toxic effects is to achieve an iron balance and prevent haemosiderosis, whilst in patients with severe iron overload a negative iron balance is desirable in order to slowly 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 serum ferritin levels reach 1000 ng/mL, indicating saturation of the transferrin. The dose and mode of administration should be individually adapted according to the degree of iron overload.
Growth retardation may result from iron overload or excessive 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).
Dose:
The lowest effective dose should be used. The average daily dose will probably lie between 20 and 60 mg/kg/day. Patients with serum ferritin levels of < 2000 ng/mL should require about 25 mg/kg/day,
and those with levels between 2000 and 3000 ng/mL about 35 mg/kg/day. Higher doses should only be employed if the benefit for the patient outweighs the risk of unwanted effects.
Patients with higher serum ferritin may require up to 55 mg/kg/day. It is inadvisable regularly to exceed an average daily dose of 50 mg/kg/day except when very intensive chelation is needed in patients who have completed growth. If ferritin values fall below 1000 ng/mL, the risk of 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 according to the ferritin value to keep the therapeutic index less than 0.025 (i.e. mean daily dose (mg/kg) of Desferrioxamine Mesilate divided by the serum ferritin level (mcg/L) below 0.025).
Mode of administration:
Slow subcutaneous infusion 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 5-7 times a week depending on the degree of iron overload.
Desferrioxamine Mesilate is not formulated to be administered as a subcutaneous bolus.
Since the subcutaneous infusions are more effective, intramuscular injections are given only when subcutaneous infusions are not feasible.
Desferrioxamine Mesilate can be administered by intravenous infusion during blood transfusion.
Due to the small quantity of deferoxamine that can be administered by intravenous infusion during blood transfusion, the clinical benefit is limited.
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 the venous site of injection. The patient's pump should be used to administer Desferrioxamine Mesilate as usual. Patients and nurses should be warned against accelerating the infusion, as an intravenous bolus of Desferrioxamine Mesilate may lead to flushing, hypotension and acute collapse (see section 4.4).
Continuous intravenous infusion is recommended for patients incapable of continuing subcutaneous infusions and in those who have cardiac problems secondary to iron overload. 24 hour urinary iron excretion should be measured regularly where intensive chelation (i.v.) is required, and the dose adjusted accordingly. Implanted intravenous systems can be used when intensive chelation is carried out.
Care should be taken when flushing the line to avoid the sudden infusion of residual Desferrioxamine Mesilate which may be present in the dead space of the line, as this may lead to flushing; hypotension and acute collapse (see section 4.4).
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 frmol). In iron storage diseases, however, the increase may be well over 1.5 mg (27 frmol). 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 frmol) of iron during this 6-hour period is suggestive of iron overload; values greater than 1.5 mg (27 frmol) 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 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-deferoxamine test serum aluminium levels up to 300 ng/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- deferoxamine test serum aluminium value above 300 ng/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 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.
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 Mesilate can bind 4.1 mg Al3+.
Use in the elderly
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 treatment with other medicines.
4.3 Contraindications
Hypersensitivity to deferoxamine mesilate unless the patients 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 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. Also, 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, collapse and urticaria).
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.
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 receiving Desferrioxamine Mesilate 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 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 drug 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 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 Mesilate. 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 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.
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 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 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 i.v. doses of Desferrioxamine Mesilate in patients with acute iron intoxication, and also in thalassaemic patients (see section 4.8). The recommended daily doses should therefore not be exceeded.
It should be noted that deferoxamine will affect aluminium levels and may necessitate some dosage adjustment of erythropoietin if co-prescribed.
In patients with severe chronic iron overload, impairment of cardiac function has been reported following concomitant treatment with Desferrioxamine Mesilate and high doses of vitamin C (more than 500 mg daily in adults). The cardiac dysfunction was reversible when vitamin C was discontinued. The following precautions should be taken when vitamin C and Desferrioxamine Mesilate are to be used concomitantly:
• Vitamin C supplements should not be given to patients with cardiac failure.
• Start supplemental vitamin C only after an initial month of regular treatment with Desferrioxamine Mesilate.
• Give vitamin C only if the patient is receiving Desferrioxamine Mesilate regularly, ideally soon after setting up the infusion pump.
• Do not exceed a daily vitamin C dose of 200 mg in adults, given in divided doses.
Clinical monitoring of cardiac function is advisable during such combined therapy.
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.
Gallium imaging results may be distorted because of the rapid urinary excretion of Desferrioxamine Mesilate -bound radiolabel. Discontinuation of Desferrioxamine Mesilate 48 hours prior to scintigraphy is advised.
4.6 Fertility, Pregnancy and lactation
Pregnancy
Deferoxamine mesilate has caused teratogenic effects in animals when given during pregnancy. (see also section 5.3.)
Lactation
It is not known whether deferoxamine mesilate is excreted into the breast milk.
Deferoxamine 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.
Fertility
There are no data from the use of deferoxamine mesilate on fertility
4.7 Effects on ability to drive and use machines
Patients experiencing CNS effects such as dizziness or impaired vision or hearing should be warned against driving or operating machinery.
4.8 Undesirable effects
Frequency estimate: very common (^ 1/10), common (^ 1/100 to < 1/10), uncommon (^ 1/1,000 to ^ 1/100), rare (^ 1/10,000 to ^ 1,000), very rare 1/10,000) including isolated reports.
Some signs and symptoms reported as adverse effects may also be manifestations of the underlying disease (iron and/or aluminium overload).
Special remarks
At the injection site pain, swelling, infiltration, erythema, pruritus and eschar/crust are very common; vesicles, local 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).
Immune system disorders
Very rare: anaphylactic shock, anaphylactic reactions, angioneurotic oedema.
Eye disorders
Rare: loss of vision, scotoma, retinal degeneration, optic neuritis, cataracts (visual acuity decreased), blurred vision, night blindness, visual field defects, chromatopsia (impairment of colour vision), corneal opacities, (see section 4.4). Eye disorders are rare, except if high doses are given.
Ear and labyrinth disorders
Uncommon: deafness neurosensory, tinnitus (see section 4.4). Keeping within dose guidelines helps minimise risk of hearing side effects.
Skin and subcutaneous tissue disorders
Very rare: rash generalised.
Musculoskeletal and connective tissue disorders
Common: growth retardation and bone disorder (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 (see section 4.4).
Respiratory, thoracic and mediastinal disorders
Very rare: acute respiratory distress lung infiltration (see section 4.4).
Nervous system disorders
Very rare: neurological disturbances, dizziness, precipitation or exacerbation of aluminium-related dialysis encephalopathy, neuropathy peripheral, paraesthesia (see section 4.4).
Gastrointestinal disorders
Very rare: diarrhoea.
Renal and urinary disorders
Very rare: renal impairment (see section 4.4).
Vascular disorders
Rare: hypotension, tachycardia and shock if precautions for administration are not followed (see section 4.2 and section 4.4).
Blood and lymphatic system disorders
Very rare: blood disorders (e.g. thrombocytopenia).
Infections and infestations
Rare: Mucormycosis infections have been reported (see section 4.4).
Very rare: Gastroenteritis yersinia infections have been reported (see section 4.4).
Patients treated for aluminium overload
In patients treated for aluminium overload, the therapy with Desferrioxamine Mesilate may result in decreased serum calcium and aggravation of hyperparathyroidism (see section 4.4).
4.9 Overdose
Desferrioxamine Mesilate is usually administered parenterally and acute poisoning is unlikely to occur.
Acute respiratory distress syndrome has been reported following treatment with excessively high intravenous doses of Desferrioxamine Mesilate in patients with acute iron poisoning and in patients with thalassemia.
Signs and symptoms
Tachycardia, hypotension and gastro-intestinal symptoms have occasionally occurred in patients who received an overdose of Desferrioxamine Mesilate. Accidental administration of Desferrioxamine Mesilate 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.
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
Chelating agent (ATC code: V03AC01)
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 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
Absorption
Desferrioxamine Mesilate is rapidly absorbed after intramuscular bolus injection or slow subcutaneous infusion, but only poorly absorbed from the gastrointestinal tract in the presence of intact mucosa.
During peritoneal dialysis deferoxamine is absorbed if administered in the dialysis fluid.
Distribution
In healthy volunteers peak plasma concentrations of deferoxamine (15.5 micro mol/L (87 micro g/mL)) were measured 30 minutes after an intramuscular injection of 10 mg/kg deferoxamine. One hour after injection the peak concentration of ferrioxamine was 3.7 micro mol/L (2.3 micro g/mL).
Less than 10% of deferoxamine is bound to serum proteins in vitro. Biotransformation
Four metabolites of deferoxamine were isolated from urine of patients with iron overload. The following biotransformation reactions were found to occur with deferoxamine: transamination and oxidation yielding an acid metabolite, beta-oxidation also yielding an acid metabolite, decarboxylation and N-hydroxylation yielding neutral metabolites.
Elimination
Both deferoxamine and ferrioxamine a biphasic elimination after intramuscular injection in healthy volunteers; for deferoxamine 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 deferoxamine and 1% as ferrioxamine.
In patients with haemochromatosis peak plasma levels of 7.0 pmol/L (3.9 mcg/mL) were measured for deferoxamine, and 15.7 pmol/L (9.6 mcg/mL) for ferrioxamine, 1 hour after an intramuscular injection of 10 mg/kg deferoxamine. These patients eliminated deferoxamine 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 deferoxamine and 12% as ferrioxamine.
In patients dialysed for renal failure who received 40 mg/kg deferoxamine infused i.v. within 1 hour, the plasma concentration at the end of the infusion was 152 gmol/L (85.2 mcg/mL) when the infusion was given between dialysis sessions. Plasma concentrations of deferoxamine were between 13% and 27% lower when the infusion was administered during dialysis. Concentrations of ferrioxamine were in all cases approximately 7.0 gmol/L (4.3 mcg/mL) with concomitant aluminoxamine levels of 2-3 pmol/litre (1.2-1.8 mcg/mL). After the infusion was discontinued, the plasma concentrations of deferoxamine 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 postinfusion and reached values of approximately 7 gmol/L (4 mcg/mL). Following dialysis the plasma concentration of aluminoxamine fell to 2.2 gmol/L (1.3 mcg/mL), indicating that the aluminoxamine complex is dialysable.
In patients with thalassaemia continuous intravenous infusion of 50mg/kg/24h of deferoxamine resulted in plasma steady state levels of deferoxamine of 7.4 pmol/L. Elimination of deferoxamine
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 deferoxamine in terms of AUC. The apparent monoexponential elimination half-life of the metabolite was 1.3 hours.
5.3 Preclinical safety data
In rabbits deferoxamine 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 deferoxamine 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
None
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life
48 months
6.4 Special precautions for storage
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.
6.5 Nature and contents of container
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 10 vials x 500 mg
6.6 Special precautions for disposal and other handling
Single use only, whereby any unused solution should be discarded.
The use of freshly prepared solutions is recommended. These 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 500 mg vial in 5ml of Water for injections.
Intramuscular administration: The volume of solvent should be not less than 3 mL for each gram of deferoxamine 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% deferoxamine 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 deferoxamine 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% deferoxamine 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).
7 MARKETING AUTHORISATION HOLDER
Noridem Enterprises Ltd. Evagorou & Makariou Mitsi Building 3 Suit. 115, 1065 Nicosia Cyprus
8 MARKETING AUTHORISATION NUMBER(S)
PL 24598/0020
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
14/03/2012
10 DATE OF REVISION OF THE TEXT
26/09/2012