Holoxan Dosage/Direction for Use

The treatment should only be administered by an experienced oncologist. The dosage must be adapted to each patient individually. In single-drug therapy of adults, the most common treatment is based on fractionated doses. In the absence of individual prescriptions, the following recommen­dations may serve as a guideline.
In general, Holoxan is given intravenously in divided doses of 1.2-2.4 g/m² body surface (up to 60 mg/kg of body weight) daily for 5 consecutive days (the duration of these infusions is about 30-120 minutes, depending on the volume). Holoxan may also be given in a single high dose, usually as a 24-hours-prolonged infusion. The dosage is generally 5 g/m² body surface (125 mg/kg body weight) and should not exceed more than 8 g/m² body surface (200 mg/kg body weight) per cycle. A single high dose may cause higher haemato-, uro-, nephro- and CNS toxicity.
Care should be taken to ensure that the ifosfamide concentration of the solution does not exceed 4 percent.
In combination-therapy with other cytostatics, the dose should be adapted to the type of therapeutic scheme.
Remarks: Because of its urotoxicity, ifosfamide should as a matter of principle be used in combination with mesna. Other toxicities and the therapeutic effects of ifosfamide will not be influenced by mesna. Should cystitis with micro and macrohaematuria develop during therapy, the treatment should be discontinued until the patient has recovered.
Because the cytostatic effect of ifosfamide occurs only after activation in the liver, there is no danger of injuring the tissue in the case of paravenous injections.
Administration and duration of treatment: The therapy cycles may be repeated every 3-4 weeks. The intervals will depend on the blood count and on the recovery from any adverse reactions or side-effects.
Regular blood counts, regular checks of renal function and regular urinalysis including urinary sediment are necessary.
Timely administration of antiemetics is indicated, and the additional influences on the CNS in combination with Holoxan should be taken into consideration.
Preparation of the solution: The handling of Holoxan should always be in accordance with the safety precautions used for the handling of cytotoxic agents.
To prepare a 4% isotonic solution ready for injection, water for injection is added to the dry sub­stance in the following amounts: See Table 2.

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The substance dissolves readily if the vials are vigorously shaken for 0.5 to 1 min after addition of the water for injection. If the substance fails to dissolve immediately and completely, it is advisable to allow the solution to stand for a few minutes. The prepared solution can be kept for up to approx. 24 hours if stored at a temperature not exceeding +8°C (refrigerator). The Holoxan solution for short-term intravenous infusion (approx. 30-120 min) is prepared by diluting the above solution with 250 ml Ringer's solution or 5% glucose solution or physiological saline. For longer infusions over one to two hours, dilution is recommended with 500 ml Ringer's solution or 5% glucose solution or physiological saline. For continuous 24-hour infusions of high-dose Holoxan, the prepared Holoxan solution, e.g., 5 g/m², must be diluted to 3 litres with 5% glucose solution and/or physiological saline.
Special remark: Because of its alkylating action, ifosfamide is a mutagenic and also a potential carcinogenic substance. Contact with the skin and mucous membranes should therefore be avoided.