Desferal® 0.5 g

/ Novartis

Treatment for chronic iron overload: The main aim of chelation therapy in iron overload in well-controlled patients is to maintain an iron balance and to prevent hemosiderosis, while in overloaded patients a negative iron balance is desirable in order to reduce increased iron stores and prevent the toxic effects of iron.
Children and adults: Desferal therapy should be started after the first 10 to 20 blood transfusions or when there is evidence from clinical monitoring that chronic iron overload is present (e.g. serum ferritin >1,000 ng/mL). Growth retardation may result from iron overload or excessive Desferal doses. If chelation is begun in patients under 3 years of age, growth must be monitored carefully and the mean daily dose should not exceed 40 mg/kg. The dosage and mode of administration may be individually determined and adapted during the course of therapy based on the severity of the patient’s iron burden. The lowest effective dosage should be used. To assess the response to chelation therapy, 24-hour urinary iron excretion may initially be monitored daily and the response to increasing doses of Desferal established. Once the appropriate dosage has been established, urinary iron excretion rates may 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 Desferal divided by the serum ferritin level (micrograms/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. The average daily dose of Desferal is usually between 20 and 60 mg/kg. In general patients with serum ferritin level below 2,000 ng/mL require about 25 mg/kg/day. Patients with serum ferritin level between 2,000 and 3,000 ng/mL require about 35 mg/kg/day. Patients with higher serum ferritin may require up to 55 mg/kg/day. It is not advisable 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 levels fall below 1,000 ng/mL, the risk of Desferal toxicity increases; it is important to monitor these patients particularly carefully and perhaps to consider lowering the total weekly dose. The doses specified here are the average daily doses. Since most patients use Desferal less than 7 days a week, the actual dose per infusion usually differs from the average daily dose; e.g. if an average daily dose of 40 mg/kg/day is required and the patient wears the pump 5 nights a week, each infusion should contain 56 mg/kg. Regular chelation with Desferal has been shown to improve life expectancy in patients with thalassemia.
Slow subcutaneous infusion: Slow subcutaneous infusion using a portable, light-weight infusion pump over a period of 8 to 12 hours is regarded as effective and especially convenient for ambulant patients, but may also be given over a 24hour period. Desferal should normally be used with the pump 5 to 7 times a week. Desferal is not formulated to support subcutaneous bolus injection.
Geriatrics: Clinical studies of Desferal did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently compared to younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
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 Desferal 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 the venous site of injection. The patient’s pump should be used to administer Desferal as usual. Because of the limited amount of drug that can be administered by IV infusion during blood transfusion, the clinical benefit of this mode of administration is limited. Patients and nurses should be warned against accelerating the infusion, as an intravenous bolus of Desferal may lead to acute collapse.
Continuous intravenous infusion: Implanted intravenous systems can be used when intensive chelation is carried out. Continuous intravenous infusion is indicated in patients who are incapable of continuing subcutaneous infusions and in those who have cardiac problems secondary to iron overload. The dose of Desferal depends on the extent of the patient’s iron overload. The 24-hour urinary iron excretion should be measured regularly where intensive chelation (i.v.) is required, and the dose adjusted accordingly. Care should be taken when flushing the line in order to avoid a sudden infusion of residual Desferal which may be present in the dead space of the line, as this may lead to circulatory collapse.
Intramuscular administration: Since subcutaneous infusions are more effective, intramuscular injections are given only when subcutaneous infusions are not feasible.
Whichever route of administration is chosen, the individual maintenance dose to be selected will depend on the patient’s iron excretion rate.
Concomitant use of vitamin C: Patients with iron overload usually develop vitamin C deficiencies, probably because iron oxidizes the vitamin. As an adjuvant to chelation therapy, vitamin C in doses up to 200 mg daily may be given in divided doses, starting after an initial month of regular treatment with Desferal. Vitamin C increases the availability of iron for chelation. In general, 50 mg suffices for children under 10 years of age and 100 mg for older children. Larger doses of vitamin C fail to produce any additional increase in the excretion of the iron complex.
Treatment for acute iron poisoning: Desferal is an adjunct to standard measures generally used in the treatment of acute iron poisoning. Desferal treatment is indicated 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, hypovolemia, or acidosis,
– patients with positive abdominal radiograph results demonstrating multiple radiopacities (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 micrograms/dL regardless of total iron binding capacity (TIBC). It has also been suggested that a conservative approach without Desferal therapy or challenge should be considered when serum iron levels are in the 300 to 500 micrograms/dL range in asymptomatic patients, as well as in those with self-limited, non-bloody emesis or diarrhea without other symptoms. Continuous intravenous administration of Desferal is the preferred route. The recommended infusion rate is 15 mg/kg per hour and should be reduced as soon as circumstances permit, usually after 4 to 6 hours, so that the total intravenous dose does not exceed the recommended 80 mg/kg in any 24-h period. The following suggested criteria are believed to represent appropriate requirements for cessation of Desferal. Chelation therapy should be continued until all of the following criteria are satisfied:
– The patient must be free of signs or symptoms of systemic iron poisoning (e.g. no acidosis, no worsening hepatotoxicity).
– Ideally, a corrected serum iron level should be normal or low (i.e. below 100 micrograms/dL). Given that laboratories cannot measure serum iron concentrations accurately in the presence of Desferal, it is acceptable to discontinue Desferal when all other criteria are met if measured serum iron level is not elevated.
– Repeat abdominal radiograph test should be obtained in patients who initially demonstrated multiple radiopacities to ensure they have disappeared before Desferal is discontinued because they serve as a marker for continued iron absorption,
– If the patient initially developed vin-rosé colored urine with Desferal therapy, it seems reasonable that urine color should return to normal before halting Desferal (absence of vin-rosé urine is not sufficient by itself to warrant discontinuation of Desferal). The effectiveness of treatment is dependent on an adequate output of urine in order to ensure that the iron complex ferrioxamine is excreted from the body. If oliguria or anuria develop, peritoneal dialysis, hemodialysis, or hemofiltration may become necessary.
Treatment for chronic aluminium overload in patients with end-stage renal failure: The iron and aluminium complexes of Desferal are dialyzable. Their elimination will be increased by dialysis in patients with renal failure. Patients with evidence of symptoms or organ dysfunction due to aluminium overload should receive Desferal treatment. Even in asymptomatic patients, Desferal treatment should be considered if serum aluminium levels are consistently above 60 ng/mL and are associated with a positive Desferal infusion test. This is particularly the case if bone biopsy findings present evidence of aluminium-related bone disease. Desferal should be administered with a once-weekly 5 mg/kg dose. For patients with post-DFO test serum aluminium levels up to 300 ng/mL Desferal should be given as a slow i.v. infusion during the last 60 minutes of a dialysis session. For patients with a post-DFO test serum aluminium level above 300 ng/mL Desferal should be administered by slow i.v. infusion 5 hours prior to the dialysis session. After completion of the first 3-month course of Desferal treatment, followed by a 4-week wash-out period, a Desferal infusion test should be performed. If two successive Desferal infusion tests performed at 1-month intervals yield serum aluminium levels less than 50 ng/mL above baseline, further Desferal treatment is not recommended. In patients on continuous ambulatory peritoneal dialysis (CAPD) or continuous cyclic peritoneal dialysis (CCPD) Desferal should be given once weekly at a 5 mg/kg dose prior to the final exchange of the day. The intraperitoneal route is recommended in these patients, but Desferal can also be given i.m., by slow infusion i.v. or s.c.
Desferal test: This test is based on the principle that in normal subjects Desferal does not raise iron excretion above a certain limit.
Desferal test for iron overload in patients with normal kidney function: 0.5 g Desferal should be injected intramuscularly. The urine should then be collected for a period of 6 hours and its iron content determined. An excretion of 1 to 1.5 mg of iron (18 to 27 micromol) during this 6-hour period is suggestive of an iron overload; values of more than 1.5 mg (27 micromol) can be regarded as pathological. The test yields reliable results only in cases where renal function is normal.
For full details see prescribing information.

Therapeutic: Treatment of chronic iron overload, e.g.
– transfusional hemosiderosis, especially in thalassemia major, sideroblastic anemia, autoimmune haemolytic anemia, and other chronic anemias.
– idiopathic (primary) hemochromatosis in patients in whom concomitant disorders (e.g. severe anemia, cardiac disease, hypoproteinemia) preclude phlebotomy.
– iron overload associated with porphyria cutanea tarda. Treatment for acute iron poisoning.
Treatment for chronic aluminium overload in patients with terminal renal failure (under maintenance dialysis) with
– aluminum-related bone disease,
– and/or dialysis encephalopathy
– and/or aluminum-related anemia.
Diagnostic: Diagnostic test for iron overload.

Hypersensitivity to the active substance, except where successful desensitization makes treatment possible. Pregnancy, lactation.

Rapid intravenous infusion: Rapid intravenous infusion may lead to hypotension and shock (e.g., flushing, tachycardia, circulatory collapse and urticaria).
Visual and hearing impairment: High doses of Desferal, especially in patients with low ferritin plasma levels, may lead to disturbances of vision and hearing. Patients with renal failure who are on maintenance dialysis and have low ferritin levels may be particularly prone to adverse reactions, visual symptoms having been reported after single doses of Desferal. The risk of side effects is reduced when low-dose therapy is employed. If visual or auditory disturbances occur, Desferal should be discontinued immediately. The changes induced by Desferal are usually reversible if identified early. Treatment with Desferal may be resumed later at a reduced dose, with close monitoring of audiovisual function. Specialist ophthalmological and audiological testing are recommended before the start of Desferal treatment, and at regular intervals thereafter (every 3 months), particularly if ferritin levels are low. The risk of audiometric abnormalities may be reduced in thalassemia patients if the ratio of the mean daily dose (mg/kg) of Desferal divided by the serum ferritin (micrograms/L) is kept below 0.025.
Renal impairment: Approximately half of the metal complex is excreted via the kidneys in iron-overloaded patients with normal renal function. Accordingly, caution is indicated in patients with severe renal failure. The iron and aluminum complexes of deferoxamine are dialyzable; their elimination will be increased by dialysis in patients with renal failure. Isolated cases of acute renal failure have been reported. Monitoring patients for changes in renal function (e.g. increased serum creatinine) should be considered.
Pediatrics: growth retardation: Patients with low serum ferritin levels on high doses of Desferal, or patients at young age (< 3 years at commencement of treatment) have been associated with growth retardation. Growth retardation if associated with excessive doses of Desferal must be distinguished from growth retardation resulting from iron overload. Growth retardation from Desferal 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, the predicted adult height will not be attained.
Pediatric patients receiving Desferal should be monitored for body weight and longitudinal growth every 3 months.
Acute respiratory distress: syndrome Acute respiratory distress syndrome has been described following treatment with excessively high i.v. doses of Desferal in patients with acute iron intoxication, and also in thalassaemic patients. The recommended daily doses should therefore not be exceeded.
Infections: In patients with iron overload it has been reported that Desferal increases susceptibility to infections, e.g. with Yersinia enterocolitica and Yersinia pseudotuberculosis. If a patient under treatment with Desferal develops fever accompanied by acute enteritis/enterocolitis, diffuse abdominal pain, or pharyngitis, treatment should be temporarily discontinued, bacteriological tests performed, and suitable antibiotic therapy started at once. Treatment with Desferal can be resumed after the infection has resolved. Rare cases of mucormycosis, some with a fatal outcome, have been reported in patients receiving Desferal for aluminum and/or iron overload. If any of the suspected signs or symptoms occur, Desferal should be discontinued, mycological tests carried out and appropriate treatment instituted immediately. Mucormycosis may also occur in patients who are not receiving Desferal, indicating that other factors (such as dialysis, diabetes mellitus, disturbance of acid-base balance, hamatological malignancies, immunosuppressive drugs, or a compromised immune system) may play a role in the development of this infection.
Cardiac impairment: with high doses of vitamin C In patients with severe chronic iron overload, impairment of cardiac function has been reported following concomitant treatment with Desferal and high doses of vitamin C (more than 0.5 g daily). Cardiac dysfunction was reversible when vitamin C was discontinued. The following precautions should be taken when Desferal and vitamin C are used concomitantly:
– Vitamin C supplements should not be given to patients with cardiac failure.
– Start treatment with vitamin C only after an initial month of regular treatment with Desferal. • Give vitamin C only if the patient is receiving Desferal regularly, ideally soon after setting up the pump.
– Do not exceed a daily dose of 200 mg of vitamin C, given in divided doses.
– Monitoring of cardiac function is advisable during such combined therapy.
Patients treated for chronic aluminum overload: In patients with aluminum-related encephalopathy, high doses of Desferal may exacerbate neurological dysfunction (convulsion), probably owing to an acute increase in circulating aluminum. Desferal may precipitate the onset of dialysis dementia. Pre-treatment with clonazepam has been reported to prevent this neurological deterioration. Also, treatment of aluminum overload may result in hypocalcemia and aggravation of hyperparathyroidism.
Instructions for use and handling: Desferal should not be given in doses higher than recommended. The drug should not be given at concentrations higher than 95 mg/mL when given subcutaneously as this increases the risk of local reactions by the subcutaneous route. Where intramuscular use is the only option it may be necessary to use higher concentrations to facilitate the injection. At the recommended concentration of 95 mg/mL, the reconstituted solution is clear, and colorless to slightly yellowish. Only clear solutions should be used. Opaque or cloudy solutions should be discarded. Due care must be taken with the injection technique. For subcutaneous infusion, the needle should not be inserted too close to the dermis. Patients experiencing dizziness or other central nervous disturbances, or impairment of vision or hearing, should refrain from driving a vehicle or operating machines.
Urine discoloration: Excretion of the iron complex may cause a reddish-brown discoloration of the urine.

Very common: Arthralgia, myalgia, Injection site reaction including pain, swelling, infiltration, erythema, pruritus, eschar, crust.
Common: Headache, Nausea, Urticaria, Growth retardation and bone disorder (e.g. metaphyseal dysplasia) in higher doses and young children, Pyrexia.
For full details see prescribing information.

Concurrent treatment with Desferal and prochlorperazine, a phenothiazine derivative, may lead to temporary impairment of consciousness. In patients with severe chronic iron-storage disease undergoing combined treatment with Desferal and high doses of vitamin C (more than 0.5 g daily), impairment of cardiac function has been encountered; this proved reversible when the vitamin C was withdrawn. Gallium-67-imaging results may be distorted because of the rapid urinary excretion of Desferal-bound gallium-67. Discontinuation of Desferal 48 hours prior to scintigraphy is advisable.

Pregnancy: There is a limited amount of data on the use of deferoxamine in pregnant patients. The risk to the fetus/mother is unknown.
Deferoxamine should be used during pregnancy only if the expected benefit outweighs the potential risk to the fetus.
Breast-feeding: It is not known whether deferoxamine passes into the breast milk. Because many drugs 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.

Signs and symptoms: Inadvertent administration of an overdose or inadvertent intravenous bolus administration/ rapid intravenous infusion may be associated with hypotension, tachycardia and gastrointestinal disturbances;acute but transient loss of vision, aphasia, agitation, headache, nausea, bradycardia, as well as acute renal failure  have been reported.Acute respiratory distress syndrome has been described following treatment with excessively high i.v. doses of Desferal in patients with acute iron into xication, and also in thalassemic patients.
Treatment: There is no specific antidote. Desferal should be discontinued and appropriate symptomatic measures undertaken. Desferal is dialysable.

Incompatibilities: Heparin injectable solution. Physiological saline (0.9 %) should not be used as a solvent for the dry substance; but, after reconstitution of the Desferal solution with water for injection, it can be employed for further dilution.
Storage: Do not store above 25°C. One vial is for single use only. The product should be used immediately after reconstitution (commencement of treatment within 3 hours). When reconstitution is carried out under validated aseptic conditions the product may be stored for a maximum period of 24 hours at room temperature before administration.