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Pyrimidine analogues and fluoropyrimidinesIn useRational designNeeds review

Capecitabine

Also known as Xeloda

An oral fluoropyrimidine carbamate designed to be converted to fluorouracil in three enzyme steps, the last concentrated in tumour tissue. Its 2025 US label lists colorectal, breast, gastric, oesophageal and pancreatic cancer.

From discovery to approval

  1. c. 1998 · Earliest report found

    A 1998 European Journal of Cancer paper by Miwa and colleagues describes the design of capecitabine, an oral prodrug converted to fluorouracil by carboxylesterase, then cytidine deaminase, then thymidine phosphorylase. A 2000 paper describes its design and synthesis from N4-substituted 5'-deoxy-5-fluorocytidine derivatives.[2][3][4]

  2. 1998-04-30 · FDA accelerated

    Treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen, or resistant to paclitaxel and for whom further anthracycline therapy may be contraindicated. The letter says the application was reviewed according to the regulations for accelerated approval and approved under 21 CFR 314.520.[5]

  3. 2001-02-02 · EMA regular · 3 years after first description

    Marketing authorisation valid throughout the EU, issued 2 February 2001 according to the EPAR product page. The page lists adjuvant stage III colon cancer, metastatic colorectal cancer, first-line advanced gastric cancer with a platinum regimen, and locally advanced or metastatic breast cancer; it does not state which indications were authorised in 2001. The page mentions neither conditional approval nor exceptional circumstances, so the type regular is an inference.[6]

  4. 2001-04-30 · FDA regular · 3 years after first description

    First-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred (supplements S-006 and S-009; S-009 was a labeling supplement on renal impairment). The letter, a scanned image, says combination chemotherapy has shown a survival benefit over fluorouracil with leucovorin alone and that a survival benefit over that regimen has not been shown with capecitabine monotherapy. It has no accelerated-approval wording, so the type regular is an inference.[7]

  5. 2001-09-07 · FDA converted · 3 years after first description

    In combination with docetaxel for locally advanced or metastatic breast cancer after failure of prior anthracycline-containing chemotherapy (supplement S-010; the letter also covers S-011, a warfarin labeling supplement). The letter states that the NDA was approved under 21 CFR 314.510 and that approval of the supplement fulfils the commitments made under that regulation; it does not use the word converted. The date is the electronic signature date on the letter (9/7/01), which matches the action date in Drugs@FDA.[8]

  6. 2005-03-30 · EMA regular · 7 years after first description

    Extension of indication (variation II/0009) to the adjuvant treatment of patients following surgery of stage III (Dukes' stage C) colon cancer. Opinion 17 February 2005; Commission decision 30 March 2005 (EPAR procedural-steps table). The central marketing authorisation was issued on 2 February 2001.[9]

  7. 2005-06-15 · FDA regular · 7 years after first description

    Single-agent adjuvant treatment of patients with Dukes' C colon cancer who have undergone complete resection of the primary tumour when treatment with fluoropyrimidine therapy alone is preferred (supplement S-016). The letter states that Xeloda was non-inferior to 5-FU/LV for disease-free survival and that, although neither Xeloda nor combination chemotherapy prolongs overall survival, combination chemotherapy has been demonstrated to improve disease-free survival compared with 5-FU/LV.[10]

How it works

It is metabolised to fluorouracil in the body. Metabolites then injure cells in two ways: FdUMP, with a folate cofactor, binds thymidylate synthase and blocks thymidylate formation, and FUTP is mistakenly incorporated into RNA, interfering with RNA processing and protein synthesis.[1]

Where it came from and why

A 2000 paper says the aim was an orally available fluoropyrimidine with better efficacy and safety than parenteral fluorouracil: a prodrug that passes intact through the intestine and is converted to fluorouracil by enzymes high in liver and then in tumours. Tissue measurements of the three enzymes guided the design.

Cancers

  • Breast cancer

    The first US approval, in 1998, covered metastatic breast cancer resistant to paclitaxel and an anthracycline-containing regimen; in 2001 it was approved with docetaxel after anthracycline failure. The 2025 label lists advanced or metastatic breast cancer.[5]

  • Colorectal cancer

    The 2025 US label lists adjuvant treatment of stage III colon cancer, perioperative treatment of locally advanced rectal cancer with chemoradiotherapy, and unresectable or metastatic colorectal cancer. A 2001 FDA letter approved first-line use in metastatic colorectal cancer when fluoropyrimidine therapy alone is preferred; a 2005 letter approved single-agent adjuvant use in Dukes' C colon cancer.[1]

  • Gastric, oesophageal and gastro-oesophageal junction cancer

    The 2025 US label lists unresectable or metastatic gastric, oesophageal or gastro-oesophageal junction cancer as part of combination chemotherapy, including HER2-overexpressing disease with other agents.[1]

  • Pancreatic cancer

    The 2025 US label lists adjuvant treatment of pancreatic adenocarcinoma as part of a combination regimen.[1]

Family and partners

Derived from: Fluorouracil (5-FU)

Worth knowing

  • The 1998 FDA letter, which says the application was reviewed according to the regulations for accelerated approval, approved capecitabine under 21 CFR 314.520 for metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing regimen, or to paclitaxel when further anthracycline therapy may be contraindicated.[5]
  • A 2001 FDA letter approving capecitabine with docetaxel in breast cancer states that the approval fulfils the commitments made under 21 CFR 314.510.[8]
  • The 1998 design paper reports that carboxylesterase was almost exclusively located in human liver and hepatoma, cytidine deaminase was concentrated in liver and solid tumours, and thymidine phosphorylase was more concentrated in various tumours than in normal tissue.[2]
  • A 1999 review reports that in 24 human cancer xenograft models capecitabine was effective over a wider dose range than fluorouracil, UFT or the intermediate 5'-deoxy-5-fluorouridine, and that xenograft susceptibility correlated with tumour thymidine phosphorylase levels.[4]
  • The 2025 US label carries a boxed warning for serious adverse reactions or death in patients with complete DPD deficiency, and advises testing for DPYD variants before starting treatment unless immediate treatment is necessary.[1]

On this site

References

  1. U.S. Food and Drug Administration. Xeloda (capecitabine) tablets, prescribing information (NDA 020896, supplement 052, revised 10/2025). Source
  2. Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer. 1998;34(8):1274-81. PubMedDOI
  3. Shimma N, Umeda I, Arasaki M, Murasaki C, Masubuchi K, Kohchi Y, et al. The design and synthesis of a new tumor-selective fluoropyrimidine carbamate, capecitabine. Bioorg Med Chem. 2000;8(7):1697-706. PubMedDOI
  4. Ishitsuka H, Shimma N, Horii I. [Discovery and development of novel anticancer drug capecitabine]. Yakugaku Zasshi. 1999;119(12):881-97. PubMedDOI
  5. U.S. Food and Drug Administration. Approval letter, NDA 20-896, Xeloda (capecitabine) tablets, Hoffmann-La Roche Inc., 30 April 1998. Source
  6. European Medicines Agency. Xeloda (capecitabine): European public assessment report, product page (marketing authorisation issued 02/02/2001; adjuvant stage III colon cancer indication listed). Page read 22 October 2026. Source
  7. U.S. Food and Drug Administration. Supplement approval letter, NDA 20-896/S-006, S-009, Xeloda (capecitabine) tablets, first-line metastatic colorectal cancer, Hoffmann-La Roche Inc., 30 April 2001 (scanned image in the Drugs@FDA approval package). Source
  8. U.S. Food and Drug Administration. Supplement approval letter, NDA 20-896/S-010, S-011, Xeloda (capecitabine) tablets with docetaxel, Hoffmann-La Roche Inc., September 2001 (action date 7 September 2001 in Drugs@FDA). Source
  9. European Medicines Agency. Xeloda: EPAR, procedural steps taken and scientific information after the authorisation. Variation II/0009, extension of indication to the adjuvant treatment of patients following surgery of stage III (Dukes' stage C) colon cancer: opinion 17/02/2005, Commission decision 30/03/2005 (column order confirmed from the table header). PDF read 22 October 2026. Source
  10. U.S. Food and Drug Administration. Supplement approval letter, NDA 20-896/S-016, Xeloda (capecitabine), Hoffmann-La Roche Inc. Electronic signature dated 15 June 2005. Source
  11. U.S. Food and Drug Administration. Drugs@FDA: Approval date(s) and history, letters, labels, reviews for NDA 020896 (capecitabine; Xeloda). Page read 2026-10-26. Source
  12. Malet-Martino M, Martino R. Clinical studies of three oral prodrugs of 5-fluorouracil (capecitabine, UFT, S-1): a review. Oncologist. 2002;7(4):288-323. PubMedDOI
  13. Twelves C, Wong A, Nowacki MP, Abt M, Burris H 3rd, Carrato A, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;352(26):2696-704. PubMedDOI