Ifosfamide

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Cat Number

API3778732

CAS Number

3778-73-2

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CAS Number

3778-73-2

EINECS

223-237-3

Storage

Store at 2-8℃

Synonyms

Isophosphamide; Iphosphamide; Isofosfamide; Ifex; Ifosfamid; Isoendoxan; ASTA Z 4942; Ifosfamida; Ifosfamidum; MJF 9325

Molecular Formula

C7H15Cl2N2O2P

Molecular Weight

261.09

Smiles

C1CN(P(=O)(OC1)NCCCl)CCCl

Appearance

White crystalline powder

Melting Point

48℃

Boiling Point

336.1℃

General Description

Ifosfamide is a nitrogen mustard alkylating agent belonging to the oxazaphosphorine class, structurally analogous to cyclophosphamide. It is a prodrug that requires hepatic activation to exert its cytotoxic effects. This agent is administered intravenously and is distinguished by its greater water solubility and distinct metabolic pathway compared to its parent compound.

Mechanism of Action

Following hepatic cytochrome P450-mediated activation, ifosfamide generates active metabolites, primarily ifosfamide mustard, that alkylate DNA at the N-7 position of guanine. This cross-linking results in DNA strand breakage and inhibition of DNA replication, leading to cell cycle non-specific cytotoxicity. A concurrent metabolite, acrolein, is responsible for urothelial toxicity but does not contribute to antitumor activity.

Application

It is FDA-approved for the treatment of germ cell testicular cancer in combination with other chemotherapeutic agents. It also has established utility in the management of sarcomas, lymphomas, and cervical cancer as part of combination regimens. Concurrent administration of mesna is mandatory to prevent hemorrhagic cystitis, a dose-limiting toxicity associated with the urinary excretion of acrolein.

Long‑term outcomes of paclitaxel, ifosfamide, and cisplatin (TIP) as second‑line salvage therapy were evaluated in 104 patients with relapsed germ cell tumors. After a median follow‑up of 8.9 years, 5‑year progression‑free and overall survival rates were 66% and 69%, respectively. Favorable response (complete response or partial response with negative tumor markers) occurred in 79% of favorable‑risk and 76% of unfavorable‑risk patients. Five‑year overall survival was 72% in favorable‑risk and 56% in unfavorable‑risk patients. TIP is an effective second‑line regimen with comparable outcomes across risk strata, supporting its continued use while awaiting results from the randomized TIGER trial comparing TIP with high‑dose chemotherapy.

Fig. 1 OS by IPFSG group in all patients (panel A) and favorable cohort (panel B). (Gleeson JP, et al., 2024)

References

Gleeson JP, et al. Paclitaxel, Ifosfamide, and Cisplatin as Initial Salvage Chemotherapy for Germ Cell Tumors: Long-Term Follow-Up and Outcomes for Favorable- and Unfavorable-Risk Disease. J Clin Oncol. 2024; 42(26):3130-3139.

A phase III randomized trial compared paclitaxel/carboplatin (PC) versus paclitaxel/ifosfamide (PI) in 536 patients with uterine carcinosarcoma (UCS) and 101 with ovarian carcinosarcoma (OCS). In UCS patients, PC was noninferior to PI, with median overall survival of 37 versus 29 months (HR 0.87; 90% CI, 0.70‑1.075; P<0.01 for noninferiority). Progression‑free survival was significantly better with PC (16 vs. 12 months; HR 0.73; P<0.01). Toxicity profiles differed: more hematologic toxicity with PC, more confusion and hemorrhage with PI. The authors conclude that PC should be the standard regimen for UCS.

Fig. 2 Forest plot of treatment effect on OS by subgroup of (A) all eligible patients with UCS and (B) all eligible patients with OCS. (Powell MA, et al., 2022)

References

Powell MA, et al. Randomized Phase III Trial of Paclitaxel and Carboplatin Versus Paclitaxel and Ifosfamide in Patients With Carcinosarcoma of the Uterus or Ovary: An NRG Oncology Trial. J Clin Oncol. 2022; 40(9):968-977.

Does Ifosfamide require refrigerated storage as an alkylating agent?

Yes, it must be stored at 2-8°C. As a nitrogen mustard derivative, it is thermally labile and susceptible to degradation at higher temperatures.

Is Ifosfamide sensitive to moisture during handling and storage?

Yes, it is hygroscopic and can hydrolyze in the presence of moisture. Our packaging includes moisture-barrier bags with desiccant to ensure long-term stability.

What is the stability of Ifosfamide after reconstitution for intravenous administration?

Reconstituted solutions have limited stability. We provide detailed in-use stability data for various diluents and storage conditions.

How is the degradation product chloroacetaldehyde monitored?

Chloroacetaldehyde is a key degradation and metabolite marker. We use a specific GC or HPLC method to monitor its formation during stability studies.