HOLOXAN

What it is

HOLOXAN is ifosfamide supplied as a powder for concentrate for solution for infusion, available in strengths of 500mg, 1g and 2g per vial. Ifosfamide is a chemotherapeutic agent related chemically to the nitrogen mustards and is a synthetic analogue of cyclophosphamide.

Approved indications

HOLOXAN is indicated for tumours sensitive to ifosfamide either as a single agent or in combination with other chemotherapeutic agents, including germ cell tumours, sarcomas, and lymphomas. Anti-tumour activity has been shown in ovarian and cervical cancers. Some activity has also been seen in lung and breast cancer.

Dosing overview

The usual total dose for each course is either 8–10 g/m² fractionated equally as single daily doses over five days, or 5–6 g/m² (maximum 10 g) given as a 24 hour infusion. Courses are normally repeated at intervals of 2–4 weeks for intermittent therapy or 3–4 weeks for 24 hour infusions depending on the haematological and biochemical status of the patient. HOLOXAN should always be given concurrently with the uroprotector UROMITEXAN (mesna).

Key safety warnings

Urotoxic side effects, especially haemorrhagic cystitis, have been frequently associated with the use of HOLOXAN, and outflow disturbances in the efferent urinary tract, cystitis, infections and electrolyte imbalances must be excluded or rectified before start of therapy. The use of mesna has been demonstrated to reduce the incidence of urinary tract complications from 40% to 3.5%. Administration of ifosfamide can cause CNS toxicity including encephalopathy and other neurotoxic effects, with some data suggesting that CNS toxicity is related to impaired renal function, pre-treatment with nephrotoxic drugs such as cisplatin, post-renal obstructions, and prior nephrectomy. Encephalopathy may occur very commonly, developing within a few hours up to a few days after treatment initiation, and is usually reversible, disappearing spontaneously within a few days after the last administration. Large cumulative doses of ifosfamide (in particular for children below 3 years of age) are a pre-disposing factor for nephrotoxicity, so glomerular and tubular kidney function must be evaluated and checked before commencement of therapy, as well as during and after treatment. Since ifosfamide is associated with myelosuppression, leucocyte, erythrocyte and platelet counts should be carried out prior to each administration and at appropriate intervals, with a reduction in the leucocyte count beginning on approximately day 5, nadir being reached after 8 to 10 days, and recovery occurring after 10 to 14 days with usual complete recovery after 2 to 3 weeks.

Contraindications

HOLOXAN is contraindicated in patients with known hypersensitivity to ifosfamide, severely impaired bone marrow function (especially in patients previously treated with cytotoxic agents or radiotherapy), inflammation of the urinary bladder (cystitis), impaired renal function and/or obstructions of the urine flow, severe hepatic impairment, acute infections, and fertility, pregnancy and lactation.

PBS listing

HOLOXAN powder for intravenous injection 1 g is listed on the PBS with 2 items, unrestricted restriction type, and an ex-manufacturer price of A$38.24.

Regulatory history

HOLOXAN ifosfamide was first listed on the ARTG on 21 October 1993, with three strengths registered: 500 mg, 1 g, and 2 g powder for injection vials.