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Bending the Curve Trial by Trial
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Nitrogen mustards and oxazaphosphorinesIn useDerivative of an earlier drugNeeds review

Ifosfamide

Also known as Ifex

An oxazaphosphorine that its US label calls a synthetic analogue of cyclophosphamide. The 2024 US label lists third-line combination chemotherapy of germ cell testicular cancer in adults; trials have tested it in sarcoma.

From discovery to approval

  1. 1958 or later · No earlier than

    A 2023 review calls ifosfamide the isomer of cyclophosphamide, which it dates to 1958, and says ifosfamide followed soon after. No source gives a year for ifosfamide itself; the year shown is cyclophosphamide's, a lower bound. Brock's 1989 lecture groups it with cyclophosphamide and trofosfamide as one designed family.[2][3][1]

  2. 1987-08-14 · FDA regular · 29 years after first description

    Ifex, NDA 019763, original approval, classed as a new molecular entity with priority review and orphan status in the Drugs@FDA history. The original label is not available there, so the indication at approval is not stated here; the 2024 label lists third-line combination chemotherapy of germ cell testicular cancer in adults and gives 'Initial U.S. Approval: 1988', which differs from the Drugs@FDA date. The type regular is an inference: no accelerated-approval wording was found.[4]

How it works

A prodrug activated by liver cytochrome P450 enzymes. The 2024 label says breakdown yields acrolein and an alkylating isophosphoramide mustard, that the exact mechanism is not determined, and that cytotoxicity is mainly through DNA cross-links from alkylation at guanine N-7.[1]

Where it came from and why

Brock's 1989 lecture says the oxazaphosphorines, ifosfamide included, were based on converting the reactive nitrogen mustard group into an inactive transport form that is enzymatically activated in the target organ, to widen the therapeutic range of alkylating agents.

Cancers

  • Germ cell testicular cancer

    The 2024 US label lists use in adults, with certain other approved agents, as third-line chemotherapy of germ cell testicular cancer.[1]

  • Ewing sarcoma and primitive neuroectodermal tumour of bone

    In a randomised trial of 518 patients aged 30 or younger, adding ifosfamide and etoposide to standard chemotherapy improved outcome in non-metastatic disease but not in metastatic disease, as reported by the authors.[5]

  • Advanced soft-tissue sarcoma

    A 2014 abstract says doxorubicin and ifosfamide have been used for soft-tissue sarcoma for more than 30 years; in the EORTC 62012 trial the combination did not significantly improve overall survival over doxorubicin alone.[6]

Family and partners

Derived from: Cyclophosphamide

Worth knowing

  • A 2023 review concludes that ifosfamide causes encephalopathy in susceptible patients and cyclophosphamide does not, through a combination of several metabolites; it reports that methylene blue appears generally effective for prevention and treatment.[2]
  • The 2024 US label carries a boxed warning headed myelosuppression, encephalopathy, nephrotoxicity and urotoxicity.[1]
  • Brock's 1989 lecture says mesna, introduced as a regional uroprotector, removes the risk of therapy-limiting urotoxic effects of oxazaphosphorines.[3]
  • The EORTC 62012 abstract reports a median progression-free survival of 7.4 months with intensified doxorubicin plus ifosfamide against 4.6 months with doxorubicin alone (hazard ratio 0.74, 95% CI 0.60 to 0.90), while overall survival, the primary endpoint, did not differ significantly (hazard ratio 0.83, 95.5% CI 0.67 to 1.03).[6]

On this site

References

  1. U.S. Food and Drug Administration. Ifex (ifosfamide), prescribing information, NDA 019763 supplement 021 (action date 2 December 2024; label revised 12/2024). Source
  2. Idle JR, Beyoğlu D. Ifosfamide - History, efficacy, toxicity and encephalopathy. Pharmacol Ther. 2023;243:108366. PubMedDOI
  3. Brock N. Oxazaphosphorine cytostatics: past-present-future. Seventh Cain Memorial Award lecture. Cancer Res. 1989;49(1):1-7. PubMed
  4. U.S. Food and Drug Administration. Drugs@FDA: Approval date(s) and history, letters, labels, reviews for NDA 019763 (Ifex, ifosfamide). Page read 2026-10-26. Source
  5. Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003;348(8):694-701. PubMedDOI
  6. Judson I, Verweij J, Gelderblom H, Hartmann JT, Schöffski P, Blay JY, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol. 2014;15(4):415-23. PubMedDOI