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

Absorption

Desferrioxamine 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 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 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.