Posology : מינונים

4.2 Posology and method of administration
Ifosfamide should only be administered when there are facilities for regular monitoring of clinical, biochemical and haematological parameters before, during and after administration and under the direction of a specialist oncology service by physicians experienced with this drug.
Dosage must be individualised. Doses and duration of treatment and/or treatment intervals depend on the therapeutic indication, the scheme of a combination therapy, the patient's general state of health and organ function, and the results of laboratory monitoring.
In combination with other agents of similar toxicity, a dose reduction or extension of the therapy-free intervals may be necessary.

Method of administration
A guide to the dosage regimens used for most indications is given below: a) 8-12 g/m2 equally fractionated as single daily doses over 3-5 days every 2-4 weeks.
b) 5-6 g/m2 (maximum 10 g) given as a 24 hour infusion every 3-4 weeks.
The frequency of dosage is determined by the degree of myelosuppression and the time taken to recover adequate bone marrow function. The usual number of courses given is 4, but up to 7 (6 by 24 hour infusion) courses have been given. Re-treatment has been given following relapse.
During or immediately after administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urothelial toxicity. See Section 4.4.
For prophylaxis of haemorrhagic cystitis, ifosfamide should be used in combination with mesna.

Use in Patients with Renal Impairment
In patients with renal impairment, particularly in those with severe renal impairment, decreased renal excretion may result in increased plasma levels of ifosfamide and its metabolites. This may result in increased toxicity (e.g., neurotoxicity, nephrotoxicity, haematotoxicity) and should be considered when determining the dosage in such patients.
See section 4.3.
Ifosfamide and its metabolites are dialyzable.

Use in Patients with Hepatic Impairment
Hepatic impairment, particularly if severe, may be associated with decreased activation of ifosfamide. This may alter the effectiveness of ifosfamide treatment. Low serum albumin and hepatic impairment are also considered risk factors for the development of CNS toxicity.
Hepatic impairment may increase the formation of a metabolite that is believed to cause or contribute to CNS toxicity and also contribute to nephrotoxicity. This should be considered when selecting the dose and interpreting response to the dose selected. See section 4.3.

Use in Paediatric Patients
In children, the dosage and administration should be determined by the tumour type, tumour stage, the general condition of the patient, any previous cytotoxic therapy, and whether chemotherapy or radiotherapy is to be administered concurrently. Clinical trials have involved doses of: a) 5 g/m2 over 24 hours b) 9 g/m2 equally fractionated as single daily doses over 5 days c) 9 g/m2 as a continuous infusion over 72 hours- repeated at three weekly intervals.

Use in Elderly Patients
In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (See Section 5.2).

Administration:
Ifosfamide is inert until activated by enzymes in the liver. However, safe handling is required and advice is included under Pharmaceutical Precautions.
Care must be taken to ensure that the ready-to-use ifosfamide solution does not exceed a concentration of 4%.
For intravenous infusion (about 30 - 120 min), IFO-cell® is diluted with 250 ml 0.9% sodium chloride solution or 5% glucose solution. For prolonged administration over one to two hours, dilution of IFO-cell® with 500 ml 0.9% sodium chloride solution or 5% glucose solution is recommended. For continuous 24 h infusion with high-dose ifosfamide, IFO-cell® is diluted with 3 litres of 0.9% sodium chloride solution or 5% glucose solution, e.g. 5 g/m2 BSA.

Care should be taken that extravasation does not take place, however, should it occur local tissue damage is unlikely and no specific measures need be taken. Repeated intravenous injections of large doses of Ifosfamide have resulted in local irritation.
Mesna should be used to prevent urothelial toxicity.
Where Ifosfamide is used as an I.V. bolus, increased dosages of mesna are recommended in children, patients whose urothelium may be damaged from previous therapies and those who are not adequately protected by the standard dose of mesna.
The patient should be well hydrated and maintained in fluid balance, replacement fluids being given as necessary to achieve this. The fluid intake of patients on the intermittent regimen should be at least 2 litres in 24 hours. As Ifosfamide may exert an antidiuretic effect, a diuretic may be necessary to ensure an adequate urinary output.
Urine should be sent for laboratory analysis before, and at the end of, each course of treatment, and the patient should be monitored for output and evidence of proteinuria and haematuria at regular intervals (4-hourly if possible) throughout the treatment period. The patient should be instructed to report any signs or symptoms of cystitis. Ifosfamide should be avoided in patients with cystitis from any cause until it has been treated.
Antiemetics given before, during and after therapy may reduce nausea and vomiting. Oral hygiene is important.
If leucocyte count is below 4,000/mm3 or the platelet count is below 100,000/mm3, treatment with Ifosfamide should be withheld until the blood count returns to normal.
There should be no signs or symptoms of urothelial toxicity or renal or hepatic impairment prior to the start of each course of Ifosfamide.