Ifosfamide Injection is indicated for use in combination with other approved anticancer agents as third-line chemotherapy for germ cell testicular cancer. It should be administered together with mesna to prevent hemorrhagic cystitis.

Ifosfamide is a prodrug that requires activation by hepatic cytochrome P450 enzymes to produce its cytotoxic effects. Activation occurs through hydroxylation at the ring carbon, forming unstable intermediates such as 4-hydroxyifosfamide and its ring-opened aldo tautomer. These intermediates break down to generate cytotoxic and urotoxic compounds like acrolein, along with alkylating isophosphoramide mustard and other inactive products. Although the exact mechanism is not fully defined, ifosfamide mainly acts by forming DNA cross-links through alkylation at the guanine N-7 position. These inter- and intra-strand DNA cross-links ultimately lead to cell death. Ifosfamide shows dose-dependent pharmacokinetics. After single doses of 3.8–5 g/m², plasma levels decline biphasically with an average terminal half-life of approximately 15 hours. At doses of 1.6–2.4 g/m²/day, elimination follows a monoexponential pattern with a half-life of about 7 hours. It also demonstrates time-dependent pharmacokinetics. Following intravenous administration of 1.5 g/m² over 0.5 hours daily for 5 days in patients with neoplastic disease, the median elimination half-life decreased from 7.2 hours on Day 1 to 4.6 hours on Day 5, while median clearance increased from 66 mL/min on Day 1 to 115 mL/min on Day 5. No significant change in volume of distribution was observed between Day 1 and Day 5.

Ifosfamide should be administered intravenously at a dose of 1.2 g/m² per day for 5 consecutive days. The treatment cycle may be repeated every 3 weeks or after recovery from hematologic toxicity (Platelets ≥100,000/mL, WBC ≥4,000/mL). To reduce bladder toxicity, adequate hydration should be ensured, with at least 2 liters of oral or intravenous fluids per day. A uroprotective agent such as mesna (Mes-D) must also be used to prevent hemorrhagic cystitis. Ifosfamide should be given as a slow intravenous infusion over a minimum duration of 30 minutes. Although it has been administered to a limited number of patients with impaired hepatic and/or renal function, appropriate dose adjustment guidelines for such patients have not been clearly established.

Ifosfamide is metabolized by CYP3A4 and CYP2B6 enzymes. Drugs that induce CYP3A4 (such as carbamazepine, phenytoin, fosphenytoin, phenobarbital, rifampin, and St. John’s Wort) may increase the metabolism of ifosfamide into its active metabolites, including potentially toxic ones like chloroacetaldehyde. Patients receiving such combinations should be closely monitored, and dose adjustments may be required. Conversely, CYP3A4 inhibitors (such as ketoconazole, fluconazole, itraconazole, sorafenib, aprepitant, fosaprepitant, grapefruit, and grapefruit juice) may reduce the conversion of ifosfamide into its active metabolites, possibly decreasing its therapeutic effectiveness

Ifosfamide is contraindicated in patients with known hypersensitivity to ifosfamide and in those with urinary outflow obstruction.

Adverse Reactions from Clinical Trials: Since clinical trials are performed under different conditions, the rates of adverse reactions observed in one study cannot be directly compared with those from another and may not reflect real-world clinical practice. The following adverse reaction data are derived from approximately 30 published studies describing clinical experience with fractionated ifosfamide monotherapy at total doses of 4 to 12 g/m² per treatment course.

Pregnancy Category D. Ifosfamide may cause fetal harm when administered during pregnancy. Reports have shown fetal growth retardation and neonatal anemia following exposure to ifosfamide-containing regimens. Animal studies indicate that ifosfamide can induce gene mutations and chromosomal damage in vivo. Pregnancy Category D. Ifosfamide may cause fetal harm when administered during pregnancy. Reports indicate fetal growth restriction and neonatal anemia following exposure to ifosfamide-containing chemotherapy. Animal studies suggest that ifosfamide can induce gene mutations and chromosomal damage. In pregnant mice, fetal death and abnormalities were observed when administered at 30 mg/m² on day 11 of gestation. In rats, embryo-lethal effects occurred at doses of 54 mg/m² during days 6–15 of gestation, and embryotoxic effects were noted at 18 mg/m². Rabbits exposed to 88 mg/m²/day from gestation days 6–18 also showed embryotoxicity. The frequency of abnormalities was higher compared to controls. Women should avoid pregnancy during treatment with ifosfamide. Men should avoid fathering a child during treatment and for at least 6 months after completion. If the drug is used during pregnancy or pregnancy occurs during therapy, patients should be informed of potential fetal risks. Nursing Mothers: Ifosfamide is excreted in breast milk. Due to the risk of serious adverse reactions and tumorigenicity observed in animal studies, a decision should be made to discontinue breastfeeding or discontinue the drug, considering the importance of therapy. Breastfeeding is not recommended during treatment. Pediatric Use: Safety and effectiveness have not been established in pediatric patients. Geriatric Use: Dose selection in elderly patients should be cautious due to possible reductions in hepatic, renal, or cardiac function and concomitant diseases or therapies. Studies in patients aged 40–71 years show that elimination half-life increases with age, likely due to increased volume of distribution. No significant changes in total plasma clearance or renal/non-renal clearance were observed. Since ifosfamide and its metabolites are primarily excreted by the kidneys, patients with impaired renal function may have increased risk of toxic reactions. Dose adjustments and renal monitoring may be required.

Myelosuppression, Immunosuppression, and Infections: Treatment with ifosfamide may lead to myelosuppression and significant suppression of immune responses, increasing the risk of severe infections. Fatal infections linked with myelosuppression have been reported. Dose-dependent myelosuppression may cause leukopenia, neutropenia, thrombocytopenia (with increased bleeding risk), and anemia. The lowest leukocyte count is typically observed in the second week after administration, with recovery usually occurring within approximately one week. Severe immunosuppression may predispose patients to serious infections such as pneumonia, urinary tract infections, and other bacterial, viral, fungal, or parasitic infections. Latent infections may also reactivate. Preventive antibacterial, antiviral, or antifungal therapy may be considered in certain cases. In cases of neutropenic fever, antibiotic treatment should be initiated promptly. Dose adjustment or delay may be necessary based on hematologic recovery. Ifosfamide should be used cautiously in patients with reduced bone marrow function or prior cytotoxic therapy. Neurological toxicity, including somnolence, confusion, hallucinations, blurred vision, and coma, has been reported and requires close monitoring. CNS toxicity may appear within hours to days after administration and may resolve within 48–72 hours after discontinuation, although recovery may sometimes be incomplete. Recurrent CNS toxicity has been reported. Encephalopathy can occur and may be severe. Concomitant use of CNS depressants (e.g., antiemetics, sedatives, narcotics) should be done cautiously. Renal and urotoxic effects may also occur. Patients should avoid pregnancy during treatment and for up to 6 months after therapy. Effects on fertility, including impaired spermatogenesis, have been observed.

Cytotoxic chemotherapy

Store in the original container at 2°C to 8°C. Protect from light. Keep out of the reach of children.