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Purine analoguesIn useDerivative of an earlier drugNeeds review

Fludarabine

Also known as fludarabine phosphate, Fludara, 2-fluoro-ara-A

A purine nucleoside analogue, resistant to adenosine deaminase, given as fludarabine phosphate. The US label lists B-cell chronic lymphocytic leukaemia that has not responded to, or has progressed during treatment with, an alkylating-agent regimen.

From discovery to approval

  1. c. 1977 · Earliest report found

    The earliest report found whose title names the compound is a 1977 paper on the biologic activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine, 'a metabolically stable analog' of ara-A (title only). A 1969 paper on nucleosides of 2-fluoroadenine (title only) may describe earlier chemistry; this was not confirmed.[2][3][4]

  2. 1991-04-18 · FDA regular · 14 years after first description

    Fludara (fludarabine phosphate for injection), NDA 020038, original approval, classed as a new molecular entity with priority review in the Drugs@FDA history. The original label and letter are not available there, so the indication at approval is not stated here. The type regular is an inference: no accelerated-approval wording was found. The July 2010 label lists B-cell chronic lymphocytic leukaemia not responding to, or progressing during, at least one alkylating-agent regimen.[5]

  3. 2008-12-18 · FDA accelerated · 31 years after first description

    Adult patients with B-cell CLL whose disease has not responded to or has progressed during or after treatment with at least one standard alkylating-agent containing regimen (approved under the accelerated approval regulations, 21 CFR 314.510)[6]

  4. 2011-12-31 · FDA withdrawn · 34 years after first description

    Accelerated approval for B-cell CLL after an alkylating-agent regimen, listed as withdrawn (the FDA list gives the withdrawal date as the Federal Register effective date or the label-update date, whichever came first)[7]

How it works

Fludarabine phosphate is converted to 2-fluoro-ara-A and then phosphorylated inside cells to the active triphosphate, which appears to inhibit DNA polymerase alpha, ribonucleotide reductase and DNA primase. The label says the mechanism is not completely characterised.[1]

Where it came from and why

A 1986 phase I report describes fludarabine phosphate as an adenosine deaminase-resistant analogue of ara-A that had entered clinical trials. The 1977 title calls the nucleoside a metabolically stable analogue of ara-A.

Cancers

  • B-cell chronic lymphocytic leukaemia

    In a randomised trial of 509 untreated patients, fludarabine gave higher response rates and longer remission and progression-free survival than chlorambucil; overall survival did not differ significantly.[8]

  • Acute leukaemia

    In a phase I and II study in relapsed or refractory leukaemia, 4 of 9 patients on the higher doses reached complete remission, but severe delayed CNS toxicity occurred in 5 patients at the two highest dose levels.[9]

Family and partners

Drugs derived from it: Clofarabine

Worth knowing

  • In 33 patients with chronic lymphocytic leukaemia treated with single-agent fludarabine, 11 (33%) had complete remission and the total response rate was 79%; the authors call it the most cytoreductive single agent so far studied in CLL.[10]
  • In the randomised comparison, complete remission was 20% with fludarabine and 4% with chlorambucil, and median progression-free survival was 20 months against 14 months.[8]
  • A generic US label states that doses about four times the recommended CLL dose (96 mg/m2/day for 5 to 7 days) were associated with delayed blindness, coma and death, and that 13 of 36 patients (36%) at those doses developed this severe neurotoxicity.[11]
  • A 2006 review groups fludarabine, cladribine and clofarabine as drugs that mainly require phosphorylation by the deoxynucleoside salvage pathways, in contrast to pentostatin, which does not need phosphorylation.[12]
  • A 1986 phase I study in acute leukaemia found a maximum tolerated dose of 40 mg/m2/day for a 5-day infusion, with fatal neurotoxicity above that dose.[4]

On this site

References

  1. U.S. Food and Drug Administration. Fludara (fludarabine phosphate) for injection, prescribing information, NDA 020038/S-033 (action date 29 July 2010). Source
  2. Brockman RW, Schabel FM Jr, Montgomery JA. Biologic activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine, a metabolically stable analog of 9-beta-D-arabinofuranosyladenine. Biochem Pharmacol. 1977;26(22):2193-6. PubMedDOI
  3. Montgomery JA, Hewson K. Nucleosides of 2-fluoroadenine. J Med Chem. 1969;12(3):498-504. PubMedDOI
  4. Spriggs DR, Stopa E, Mayer RJ, Schoene W, Kufe DW. Fludarabine phosphate (NSC 312878) infusions for the treatment of acute leukemia: phase I and neuropathological study. Cancer Res. 1986;46(11):5953-8. PubMed
  5. U.S. Food and Drug Administration. Drugs@FDA: Approval date(s) and history, NDA 020038 (Fludara, fludarabine phosphate). Accessed 20 October 2026. Source
  6. U.S. Food and Drug Administration. Approval letter, NDA 22-273, fludarabine phosphate 10 mg tablets (Oforta), Antisoma. 18 December 2008. Source
  7. FDA. Withdrawn | Cancer Accelerated Approvals. Listing, content current as of 5 October 2026 (accessed 19 October 2026). Source
  8. Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000;343(24):1750-7. PubMedDOI
  9. Warrell RP Jr, Berman E. Phase I and II study of fludarabine phosphate in leukemia: therapeutic efficacy with delayed central nervous system toxicity. J Clin Oncol. 1986;4(1):74-9. PubMedDOI
  10. Keating MJ, Kantarjian H, O'Brien S, Koller C, Talpaz M, Schachner J, et al. Fludarabine: a new agent with marked cytoreductive activity in untreated chronic lymphocytic leukemia. J Clin Oncol. 1991;9(1):44-9. PubMedDOI
  11. Fresenius Kabi USA, LLC. Fludarabine phosphate injection: prescribing information. DailyMed, set ID cf5255cc-91fd-4132-973b-764dba142eae, published 21 October 2024. Read 26 October 2026. Source
  12. Robak T, Lech-Maranda E, Korycka A, Robak E. Purine nucleoside analogs as immunosuppressive and antineoplastic agents: mechanism of action and clinical activity. Curr Med Chem. 2006;13(26):3165-89. PubMedDOI