DBL DESFERRIOXAMINE MESYLATE FOR INJECTION BP 500 mg/vial

PFIZER PRIVATE LIMITED

PFIZER PRIVATE LIMITED

Therapeutic

Prescription Only

INJECTION, POWDER, FOR SOLUTION

**4.2 Dose and method of administration** Desferrioxamine mesilate may be administered intramuscularly, or via intravenous or subcutaneous infusion. When administered subcutaneously the needle should not be inserted too close to the dermis. The presence of iron overload, preferably quantified, should be established before initiating therapy with desferrioxamine mesilate. **Chronic iron overload** In young patients with chronic iron overload the main aim of chelation therapy is to attain an iron balance and to prevent haemosiderosis. In older patients with chronic iron overload, the main aim of chelation therapy is a negative iron balance in order to slowly reduce the increased iron stores and to prevent the toxic effects of iron. _**Dosage**_ The dosage schedule for children should be individually titrated according to the extent of iron overload. In children, the earliest age at which therapy with desferrioxamine mesilate should be undertaken is 2 to 3 years. The minimum effective dose is not known, so an initial trial of chelation therapy should be performed. To assess the response to chelation therapy, 24 hour urinary iron excretion should be monitored daily initially and the response to increasing doses of desferrioxamine mesilate established, starting with 0.5 g daily and increasing the dose until urine iron excretion reaches a plateau. The lowest effective dose resulting in a negative iron balance should be used. In most patients daily doses of 20 to 40 mg/kg body weight are adequate. Higher doses should be administered only if the benefit for the patient outweighs the risk of unwanted effects associated with repeated high daily doses. Maximum doses of 80 mg/kg/day should not be exceeded. If ferritin values fall below 1,000 nanogram/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. Whichever route of administration is chosen, the maintenance dose selected will depend on the individual patient’s iron excretion rate. 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** – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). _**Monitoring therapy**_ Once the maintenance dosage has been established, urinary iron excretion rates should be assessed at intervals of a few weeks. The expected rate of excretion of iron is 10 to 20 mg/day. The patient’s total iron stores can be estimated by accurate recording of the amount of iron received through transfusions, supplemented by serum ferritin determination. Iron balance can be calculated based on the amount of iron excreted in the urine; negative iron balance is considered to be achieved when the total amount of iron excreted in the urine, plus a further 50% (approximate mean iron excretion in the stools), exceeds the total iron received from blood transfusions. Chelation therapy is considered satisfactory when serum ferritin levels are close to normal values (<300 microgram/L). _**Infusion**_ Intravenous infusions are usually more effective than subcutaneous infusions, but slow subcutaneous administration by means of a portable, lightweight infusion pump over a period of 8 to 12 hours is regarded as effective and convenient for ambulant patients. In some patients it is possible to achieve a further increase in iron excretion by infusing the same daily dose over a 24 hour period. Desferrioxamine mesilate is not formulated to support subcutaneous bolus injection. Patients and nurses should be warned against accelerating the intravenous infusions, 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** – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). Heavily iron loaded patients should receive infusions five to seven times a week as protection against iron toxicity. However, if the iron load is low, infusions may be given three to five times a week. _**Intramuscular**_ Desferrioxamine mesilate may be injected intramuscularly, though this method is less effective than subcutaneous infusion. The maximum locally tolerated dose by intramuscular injection lies in the range 0.5 to 1.5 g. The volume of solution should be not less than 3 mL for each gram of desferrioxamine mesilate (i.e., reconstitute each 500 mg vial of DBL Desferrioxamine Mesylate for Injection BP with not less than 1.5 mL of Water for Injections). _Note_. Ascorbic acid (approximately 200 mg daily) may be given as an adjuvant after about six months of regular chelation therapy with desferrioxamine mesilate. Ascorbic acid in doses of 150 to 250 mg daily enhances urinary iron excretion, but very high doses have been suspected of giving rise to cardiac complications or ocular toxicity (see section 4.5 **Interactions with other medicines and other forms of interactions** – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). **Acute iron poisoning** Desferrioxamine mesilate is an adjunct to standard measures generally used in treating acute iron poisoning. These may include gastric lavage, induction of emesis, control of shock and correction of acidosis. _**Iron levels**_ Plasma or serum iron should be measured three to four hours post-ingestion in the case of any iron preparation. Levels taken after four hours may underestimate toxicity because the subject iron may have either been distributed into tissues or be bound to ferritin. In the case of slow release or enteric coated tablets, levels should be repeated at six to eight hours as absorption may be erratic. As a lesser priority iron binding capacity may usually be measured. Blood for plasma/serum iron measurement should be taken before chelation therapy is commenced. The following quantities are recommended: plasma/serum iron >0.5 mL of blood in serum or heparinised tube (plasma from heparinised blood allows more rapid analysis); total iron binding >2 mL of blood in serum or heparinised tube. _**Iron level treatment**_ <62 micromol/L for general support only; 62 to 90 micromol/L for brief chelation therapy; 90 to 180 micromol/L for vigorous support and chelation; >189 micromol/L for vigorous support and chelation therapy, and possible exchange transfusion or haemodialysis. _**Indications for chelation therapy**_ Desferrioxamine mesilate should be used if serum iron >62 micromol/L or the patient has severe symptoms and serum iron is not yet available. The end point of desferrioxamine therapy is indicated by the disappearance of reddish-brown coloured urine. In patients in whom reddish-brown coloured urine does not develop, the end point for chelation therapy occurs when serum iron concentration falls to less than 54 micromol/L (300 microgram/100 mL). To eliminate iron that has already been absorbed, desferrioxamine mesilate should be given either intramuscularly or, preferably, intravenously. The dosage and route of administration should be adapted to the severity of the poisoning, preferably by reference to the serum iron concentrations and total iron binding capacity, which should be monitored regularly. Facilities for monitoring serum iron should be available round the clock. In addition, the total amount of iron ingested and remaining in the gastrointestinal tract should be taken into account. If the patient is normotensive, desferrioxamine mesilate may be given in a single intramuscular dose: 2 g for an adult and 1 g for a child. However, intravenous infusion is preferable since the rate of administration can be controlled and adapted to the patient’s condition. If the patient is hypotensive, the intravenous route is recommended. The maximum rate for intravenous administration is 15 mg/kg/hour and is reduced after four to six hours so that the total intravenous dose in general, does not exceed 80 mg/kg/24 hours. However, in an adult patient with severe iron poisoning, an infusion of desferrioxamine mesilate 37.1 g over 52 hours has been tolerated without apparent unwanted effects. Therapy should be continued until the serum iron concentrations are less than the total iron binding capacity. 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 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. **Desferrioxamine test** This test is based on the principle that in normal subjects desferrioxamine mesilate is incapable of raising iron excretion above a certain limit. _**Normal renal function**_ Desferrioxamine mesilate 500 mg should be injected intramuscularly. The urine should then be collected for a period of six hours and its iron content determined. An excretion of 1 to 1.5 mg (18 to 27 micromol) during this six hour period is suggestive of iron overload; values of more than 1.5 mg (27 micromol) can be regarded as definitely pathological. The test yields reliable results only in cases where renal function is normal. _**Renal failure**_ In patients with terminal renal failure receiving haemodialysis, serum iron values should be determined before and after the administration of desferrioxamine mesilate 500 mg intramuscularly or intravenously. A continuous increase in serum iron during the following hours is suggestive of overload. **Dosage adjustment** _**Treatment in patients with terminal renal failure**_ The iron complex is dialysable. In patients with renal failure, its elimination can be increased by dialysis. Administration of desferrioxamine mesilate may precipitate aluminium toxicity in patients on dialysis. In patients on maintenance haemodialysis or haemofiltration, desferrioxamine mesilate doses between 1 and 4 g per week have proven effective. **Method of administration** _**Preparation and administration of solution**_ For parenteral administration, DBL Desferrioxamine Mesylate for Injection BP should be reconstituted with Water for Injections (5 mL for the 500 mg vial and 20 mL for the 2 gram vial) to produce an approximate 10% solution (see below). However for intramuscular administration, each 500 mg vial of DBL Desferrioxamine Mesylate for Injection BP may be reconstituted with not less than 1.5 mL of Water for Injections. The drug should be completely dissolved to produce a clear solution before use. DBL Desferrioxamine Mesylate for Injection BP 500 mg vials reconstituted with 5 mL will yield desferrioxamine mesilate concentrations of 93.5 mg/mL (the displacement volume of DBL Desferrioxamine Mesylate for Injection BP is approximately 7% when reconstituted with 5 mL of Water for Injections BP). For intravenous infusion, further dilution may be performed with 0.9% Sodium Chloride Intravenous Infusion, 5% Glucose Intravenous Infusion or Ringer’s-Lactate Intravenous Infusion at a concentration of 1 to 8 mg/mL, although these should not be used as solvents for the dry substance. For subcutaneous administration, the reconstituted solution may be given undiluted. Dissolved desferrioxamine mesilate can also be added to the dialysis fluid and given intraperitoneally to patients on chronic ambulatory peritoneal dialysis or continuous cycling peritoneal dialysis. Desferrioxamine is sometimes used for home infusions. If home use is to be instituted, it is important that patients and families be fully instructed on the safe and appropriate technique of administration.