Ifodex Injection is 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.
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.
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Ifosfamide should be administrated intravenously at a dose of 1.2 g/m 2 per day for 5 consecutive days. Treatment is repeated every 3 weeks or after recovery from hematologic toxicity (Platelets ≥100,000/mL, WBC ≥4,000/mL). In order to prevent bladder toxicity, ifosfamide should be given with extensive hydration consisting of at least 2 liters of oral or intravenous fluid per day. A protector, such as Mesna (Mes-D), should also be used to prevent hemorrhagic cystitis. Ifosfamide should be administrated as a slow intravenous infusion lasting a minimum of 30 minutes. Although Ifosfamide has been administrated to a small number of patients with compromised hepatic and/.or renal function, studies to establish optimal dose schedules of Ifosfamide in such patients have not been conducted.
Adverse Reactions from Clinical Trials Because clinical trials are conducted from widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The adverse reactions and frequencies below are based on 30 publications describing clinical experience with fractionated administration of Ifodex as monotherapy with a total dose of 4 to 12 g/m2 per course.
Ifosfamide is contraindicated in patients with known hypersensitivity to administration of ifosfamide and urinary outflow obstruction.
Ifodex 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 Ifodex to its active alkylating metabolites. CYP3A4 inducers may increase the formation of the neurotoxic/nephrotoxic Ifodex metabolite, chloroacetaldehyde. Closely monitor patients taking Ifodex 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 Ifodex to its active alkylating metabolites, perhaps decreasing the effectiveness of Ifodex treatment.
Myelosuppression, Immunosuppression, and Infections Treatment with Ifodex may cause myelosuppression and significant suppression of immune responses, which can lead to severe infections. Fatal outcomes of Ifodex-associated myelosuppression have been reported. Ifodex-induced myelosuppression can cause leukopenia, neutropenia, thrombocytopenia (associated with a higher risk of bleeding events), and anemia. The nadir of the leukocyte count tends to be reached approximately during the second week after administration. When Ifodex is given in combination with other chemotherapeutic/hematotoxic agents and/or radiation therapy, severe myelosuppression is frequently observed. The risk of myelosuppression is dose-dependent and is increased with administration of a single high dose compared with fractionated administration. The risk of myelosuppression is also increased in patients with reduced renal function. Severe immunosuppression has led to serious, sometimes fatal, infections. Sepsis and septic shock also have been reported. Infections reported with Ifodex include pneumonias, as well as other bacterial, fungal, viral, and parasitic infections. Latent infections can be reactivated. In patients treated with Ifodex, reactivation has been reported for various viral infections. Infections must be treated appropriately. Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the managing physician. In case of neutropenic fever, antibiotics and/or antimycotics must be given. Close hematologic monitoring is recommended. White blood cell (WBC) count, platelet count and hemoglobin should be obtained prior to each administration and at appropriate intervals after administration. Unless clinically essential, Ifodex should not be given to patients with a WBC count below 2000/microliter and/or a platelet count below 50,000/microliter. Ifodex should be given cautiously, if at all, to patients with presence of an infection, severe immunosuppression or compromised bone marrow reserve, as indicated by leukopenia, granulocytopenia, extensive bone marrow metastases, prior radiation therapy, or prior therapy with other cytotoxic agents.Central Nervous System Toxicity, Neurotoxicity Administration of Ifodex can cause CNS toxicity and other neurotoxic effects. The risk of CNS oxicity and other neurotoxic effects necessitates careful monitoring of the patient. Neurologic manifestations consisting of somnolence, confusion, hallucinations, blurred vision, psychotic ehavior, extrapyramidal symptoms, urinary incontinence, seizures, and in some instances, coma, ave been reported following Ifodex therapy. There have also been reports of peripheral europathy associated with Ifodex use. fosfamide neurotoxicity may become manifest within a few hours to a few days after first dministration and in most cases resolves within 48 to 72 hours of Ifodex discontinuation. Symptoms may persist for longer periods of time. Supportive therapy should be maintained until heir complete resolution. Occasionally, recovery has been incomplete. Fatal outcomes of CNS oxicity have been reported. Recurrence of CNS toxicity after several uneventful treatment courses as been reported. If encephalopathy develops, administration of Ifodex should be discontinued. Due to the potential for additive effects, drugs acting on the CNS (such as antiemetics, sedatives, arcotics, or antihistamines) must be used with particular caution or, if necessary, be discontinued n case of Ifodex-induced encephalopathy. Manifestations of CNS toxicity may impair a patient’s ability to operate an automobile or other eavy machinery. Renal and Urothelial Toxicity and Effects fosfamide is both nephrotoxic and urotoxic. Women should not become pregnant and men should not father a child during therapy with osfamide. Further, men should not father a child for up to 6 months after the end of therapy. If his drug is used during pregnancy, or if the patient becomes pregnant while taking Ifodex or fter treatment, the patient should be apprised of the potential hazard to a fetus. Effects on Fertility fosfamide interferes with oogenesis and spermatogenesis. Amenorrhea, azoospermia, and sterility both sexes have been reported.