HOLOXAN FOR INJECTION 1 g/25 ml

INJECTION, POWDER, FOR SOLUTION

**Dosage and administration:** 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. The administration of uroprotection with mesna (Uroprotector®, Uromitexan®) as directed, should be maintained. 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:  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. The handling and preparation of ifosfamide should always be in accordance with current guidelines on safe handling of cytotoxic agents. Skin reactions associated with accidental exposure to ifosfamide may occur. To minimize the risk of dermal exposure, always wear impervious gloves when handling vials and solutions containing ifosfamide. If ifosfamide solution contacts the skin or mucosa, immediately wash the skin thoroughly with soap and water or rinse the mucosa with copious amounts of water. 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, hematotoxicity) and should be considered when determining the dosage in such patients. - **Ifosfamide and its metabolites are dialyzable. In patients requiring dialysis, use of a consistent interval between ifosfamide administration and dialysis should be considered.** 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. Use in Elderly Patients In elderly patients, monitoring for toxicities and the need for dose adjustment should reflect the higher frequency of decreased hepatic, renal, cardiac, or other organ function, and concomitant diseases or other drug therapy in this population.