Ifosfamide is a prodrug that requires metabolic activation by hepatic cytochrome P450 isoenzymes to exert its cytotoxic activity. Activation occurs through hydroxylation at the ring carbon atom, forming the unstable intermediate 4-hydroxyifosfamide and its ring-opened aldo tautomer. This decomposition yields the cytotoxic and urotoxic compound acrolein, an alkylating isophosphoramide mustard, and multiple other non-toxic products. The exact mechanism of action of ifosfamide is not fully determined, but its cytotoxic action is primarily due to DNA cross-linking caused by alkylation by the isophosphoramide mustard at guanine N-7 positions. The formation of inter- and intra-strand cross-links in DNA leads to cell death.

Ifosfamide exhibits dose-dependent pharmacokinetics in humans. At single doses of 3.8 to 5 g/m², plasma concentrations decay biphasically, with a mean terminal elimination half-life of approximately 15 hours. At doses of 1.6 to 2.4 g/m²/day, plasma decay follows a monoexponential pattern, with a terminal elimination half-life of about 7 hours.

Additionally, ifosfamide exhibits time-dependent pharmacokinetics in humans. Following intravenous administration of 1.5 g/m² over 0.5 hours once daily for five 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 was observed, along with a concomitant increase in 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 to Day 1.

Ifosfamide should be administered intravenously at a dose of 1.2 g/m² per day for five consecutive days. Treatment is repeated every three weeks or after recovery from hematologic toxicity (Platelets ≥100,000/mL, WBC ≥4,000/mL).

To prevent bladder toxicity, ifosfamide should be given with extensive hydration, consisting of at least 2 liters of oral or intravenous fluids per day. A uroprotective agent, such as Mesna (Mes-D), should be used to prevent hemorrhagic cystitis. Ifosfamide should be administered as a slow intravenous infusion lasting at least 30 minutes.

Although ifosfamide has been administered to a small number of patients with compromised hepatic and/or renal function, studies to establish optimal dose schedules for such patients have not been conducted.

Ifodex is a substrate for both CYP3A4 and CYP2B6 enzymes. Inducers of CYP3A4 (e.g., carbamazepine, phenytoin, fosphenytoin, phenobarbital, rifampin, St. John’s Wort) may increase the metabolism of Ifodex to its active alkylating metabolites. CYP3A4 inducers may also enhance the formation of the neurotoxic/nephrotoxic Ifodex metabolite, chloroacetaldehyde. Therefore, patients taking Ifodex with CYP3A4 inducers should be closely monitored for toxicities, and dose adjustments should be considered.

Conversely, CYP3A4 inhibitors (e.g., ketoconazole, fluconazole, itraconazole, sorafenib, aprepitant, fosaprepitant, grapefruit, and grapefruit juice) may reduce the metabolism of Ifodex into its active alkylating metabolites, potentially decreasing its effectiveness.

Ifosfamide is contraindicated in patients with known hypersensitivity to the drug or those with urinary outflow obstruction.

Adverse Reactions from Clinical Trials

Since clinical trials are conducted under varying conditions, adverse reaction rates observed in one clinical trial may not be directly comparable to those in another and may not reflect real-world observations. The following adverse reactions and frequencies are based on 30 publications describing the clinical experience with fractionated administration of Ifodex as monotherapy, with a total dose ranging from 4 to 12 g/m² per course.

Pregnancy Category D

Ifosfamide can cause fetal harm when administered to a pregnant woman. Fetal growth retardation and neonatal anemia have been reported following exposure to ifosfamide-containing chemotherapy regimens during pregnancy.

Animal studies indicate that ifosfamide can cause gene mutations and chromosomal damage in vivo. Pregnant mice exposed to a 30 mg/m² dose of ifosfamide on Day 11 of gestation experienced increased resorptions and anomalies by Day 19. Embryo-lethal effects were observed in rats administered 54 mg/m² doses from the 6th to the 15th day of gestation. Similarly, in rabbits receiving 88 mg/m²/day doses from the 6th to the 18th day after mating, an increased number of anomalies were noted.

Women should not become pregnant, and men should not father a child during therapy with ifosfamide. Additionally, men should avoid fathering a child for up to six months after the end of treatment. If this drug is used during pregnancy, or if a patient becomes pregnant while on this medication, they should be informed of the potential risks to the fetus.

Nursing Mothers: Ifosfamide is excreted in breast milk. Due to the potential for serious adverse reactions and tumorigenicity observed in animal studies, a decision must be made to either discontinue nursing or discontinue the drug, taking into account the mother’s medical needs. Women must not breastfeed while undergoing treatment with ifosfamide.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: 

Dose selection for elderly patients should be cautious due to the greater likelihood of reduced hepatic, renal, or cardiac function and potential interactions with concomitant diseases or drug therapies.

A study of patients aged 40 to 71 years suggested that the elimination half-life of ifosfamide increases with age, primarily due to an increase in the volume of distribution. However, no significant changes in total plasma clearance or renal/non-renal clearance were observed. Since ifosfamide and its metabolites are primarily excreted by the kidney, patients with impaired renal function may be at greater risk of toxicity. Monitoring renal function is advised when selecting the appropriate dose for elderly patients.

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