IFOSFAMIDE INJECTION Powder for concentrate for solution for infusion Ref.[9061] Active ingredients: Ifosfamide

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:

• 8-12 g/m² equally fractionated as single daily doses over 3-5 days every 2-4 weeks.
• 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:

• 5 g/m² over 24 hours
• 9 g/m² equally fractionated as single daily doses over 5 days
• 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. The dry contents of a vial should be dissolved in Water for Injections as follows:

1 g vial: add 12.5 ml of Water for Injections

The resultant solution of 8% of ifosfamide should not be injected directly into the vein. The solution may be:

1. diluted to less than a 4% solution and injected directly into the vein, with the patient supine.
2. infused in 5% dextrose-saline or normal saline over 30-120 mins.
3. injected directly into a fast-running infusion,
4. made up in 3 × 1 litres of dextrose-saline or normal saline and infused over 24 hours. Each litre should be given over eight hours, and should be freshly made up immediately before infusion.

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.

Serious consequences of overdosage include manifestations of dose-dependent toxicities such as CNS toxicity, nephrotoxicity, myelosuppression, and mucositis. See Section 4.4.

Patients who received an overdose should be closely monitored for the development of toxicities.

No specific antidote for ifosfamide is known.

Overdosage should be managed with supportive measures, including appropriate, state-of-the-art treatment for any concurrent infection, myelosuppression, or other toxicity, should it occur.

Ifosfamide as well as ifosfamide metabolites are dialyzable. Consider haemodialysis in cases of severe overdose presenting early, particularly in patients with renal impairment.

Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with overdose.

Shelf life: Five years.

The reconstituted solution should be used immediately. The product does not contain a preservative, therefore microbial stability cannot be guaranteed. When prepared under strict aseptic conditions, ifosfamide is, as a 4% solution, however, chemically stable for 7 days at room temperature with Water for Injections, 0.9% saline, dextrose/saline and dextrose solutions. Ifosfamide and mesna when prepared under strict aseptic conditions at the recommended dilutions are chemically stable with:

• 0.9% saline and dextrose/saline solution for one week at room temp.
• Water for Injections for one week under refrigeration.
• 5% dextrose solution for 24 hours at room temperature, and
• 0.9% saline solution for 28 days at room temperature.

Do not store above 25°C.

Keep container in outer carton.

Type I or Type III clear glass injection vial with bromobutyl rubber closure and beading cap. Vials are packed singly in a cardboard box.

Vials are packed with or without a protective plastic overwrap. Protective plastic overwrap does not come into contact with the medicinal product and provides additional transport protection, which increases the safety for the medical and pharmaceutical personnel.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Before parenteral administration, the substance must be completely dissolved.

The following protective recommendations are advised during handling due to the toxic nature of the substance:

Reconstitution and administration must be undertaken only by trained personnel. Pregnant staff and breastfeeding mothers should be excluded.

Protective clothing, goggles, masks and disposable PVC or latex gloves should be worn.

A designated area should be defined for reconstitution (preferably under a laminar-airflow system). The work surface should be protected by a disposable, plastic backed absorbent paper. Accidental contact with the skin or eyes should be treated immediately by copious lavage with water. Soap and water should then be used on non-mucous membranes. Spillage should be removed by dry or moist disposable towels.

Care must be taken in the disposal of all waste material (syringes, needles and disposable towels etc.) Used items should be placed in appropriate secure containers in readiness for destruction in an appropriate high-temperature incinerator with an after-burner.