XIFOS2

It is an alkylating drug indicated for use in combination with certain other approved antineoplastic agents for third-line chemotherapy of germ cell testicular cancer. It should be used in combination with mesna for prophylaxis of hemorrhagic cystitis

Cytotoxic Chemotherapy

Ifosfamide is a prodrug that requires metabolic activation by hepatic cytochrome P450 isoenzymes to exert its cytotoxic activity. Activation occurs by hydroxylation at the ring carbon atom forming the unstable intermediate 4-hydroxyifosfamide and its ring-opened aldo tautomer, which decomposes to yield the cytotoxic and urotoxic compound acrolein and an alkylating isophosphoramide mustard as well as multiple other nontoxic products. The exact mechanism of action of ifosfamide has not been determined, but its cytotoxic action is primarily through DNA crosslinks caused by alkylation by the isophosphoramide mustard at guanine N-7 positions. The formation of inter- and intra-strand cross-links in the DNA results in cell death. Ifosfamide exhibits dose-dependent pharmacokinetics in humans. At single doses of 3.8 to 5 g/m2, the plasma concentrations decay biphasically and the mean terminal elimination half-life is about 15 hours. At doses of 1.6 to 2.4 g/m2/day, the plasma decay is monoexponential and the terminal elimination half-life is about 7 hours. Ifosfamide exhibits time-dependent pharmacokinetics in humans. Following intravenous administration of 1.5 g/m2 over 0.5 hours once daily for 5 days to 15 patients with neoplastic disease, a decrease in the median elimination half-life from 7.2 hours on Day 1 to 4.6 hours on Day 5 occurred with a concomitant increase in the median clearance from 66 mL/min on Day 1 to 115 mL/min on Day 5. There was no significant change in the volume of distribution on Day 5 compared with Day 1.

Dosage and duration of treatment and/or treatment intervals depend on the scheme of combination therapy,the patient’s general state of health and organ function,and the results of laboratory monitoring. ? It should be administered as a slow intravenous infusion lasting a minimum of 30 minutes at a dose of 1.2 grams per m2 per day for 5 consecutive days. ? Treatment is repeated every 3 weeks or after recovery from hematologic toxicity. ? To prevent bladder toxicity,It should be given with extensive hydration consisting of at least 2 liters of oral or intravenous fluid per day. ? Mesna should be used to reduce the incidence of hemorrhagic cystitis.

Ifosfamide is a substrate for both CYP3A4 and CYP2B6. Inducers of CYP3A4 CYP3A4 inducers (e.g., carbamazepine, phenytoin, fosphenytoin, phenobarbital, rifampin, St. John’s Wort) may increase the metabolism of ifosfamide to its active alkylating metabolites. CYP3A4 inducers may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde. Closely monitor patients taking ifosfamide with CYP3A4 inducers for toxicities and consider dose adjustment.Inhibitors of CYP3A4 CYP3A4 inhibitors (e.g., ketoconazole, fluconazole, itraconazole, sorafenib, aprepitant, fosaprepitant, grapefruit, grape fruit juice) may decrease the metabolism of ifosfamide to its active alkylating metabolites, perhaps decreasing the effectiveness of ifosfamide treatment.

Known hypersensitivity to administration of ifosfamide. ? Urinary outflow obstruction.

Alopecia,nausea/vomiting,leukopenia,anemia,CNS toxicity,hematuria,and infection

Pregnancy: fetal growth retardation and neonatal anemia

No specific antidote for ifosfamide is known. Patients who receive an overdose should be closely monitored for the development of toxicities. Serious consequences of overdosage include manifestations of dose-dependent toxicities such as CNS toxicity, nephrotoxicity, myelosuppression, and mucositis [see Warnings and Precautions (5)]. Management of overdosage would include general supportive measures to sustain the patient through any period of toxicity that might occur, including appropriate state-of-the-art treatment for any concurrent infection, myelosuppression, or other toxicity. Ifosfamide as well as ifosfamide metabolites are dialyzable. Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with overdose.

Store the vial in original carton at 2°-8° C. Protect from light. Keep out of reach of children.