Capecitabine

Capecitabine
Names
Pronunciation/kæpɪˈsaɪtəbiːn/
Trade namesXeloda, Xitabin, Kapetral, others
IUPAC name
  • Pentyl [1-(3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)-5-fluoro-2-oxo-1H-pyrimidin-4-yl]carbamate
Clinical data
Drug classChemotherapy agent
Main usesBreast cancer, gastric cancer, colorectal cancer[1]
Side effectsAbdominal pain, vomiting, diarrhea, weakness, rashes[2]
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
    Routes of
    use    		By mouth
    Defined daily doseNot established[3]
    External links
    AHFS/Drugs.comMonograph
    US NLMCapecitabine
    MedlinePlusa699003
    Legal
    License data
    Legal status
    Pharmacokinetics
    BioavailabilityExtensive
    Protein binding< 60%
    Metabolismliver, to 5'-DFCR, 5'-DFUR (inactive); neoplastic tissue, 5'-DFUR to active fluorouracil
    Elimination half-life38–45 minutes
    ExcretionKidney (95.5%), faecal (2.6%)
    Chemical and physical data
    FormulaC15H22FN3O6
    Molar mass359.354 g·mol−1
    3D model (JSmol)
    SMILES
    • FC=1\C(=N/C(=O)N(C=1)[C@@H]2O[C@@H]([C@@H](O)[C@H]2O)C)\NC(=O)OCCCCC
    InChI
    • InChI=1S/C15H22FN3O6/c1-3-4-5-6-24-15(23)18-12-9(16)7-19(14(22)17-12)13-11(21)10(20)8(2)25-13/h7-8,10-11,13,20-21H,3-6H2,1-2H3,(H,17,18,22,23)/t8-,10-,11-,13-/m1/s1 checkY
    • Key:GAGWJHPBXLXJQN-UORFTKCHSA-N checkY

    Capecitabine, sold under the brand name Xeloda among others, is a chemotherapy medication used to treat breast cancer, gastric cancer, and colorectal cancer.[1] For breast cancer it is often used together with docetaxel.[2] It is taken by mouth.[2]

    Common side effects include abdominal pain, vomiting, diarrhea, weakness, and rashes.[2] Other severe side effects include blood clotting problems, allergic reactions, heart problems such as cardiomyopathy, and low blood cell counts.[2] It is not recommended in people with kidney problems.[2] Use during pregnancy may result in harm to the baby.[2] Capecitabine, inside the body, is converted to 5-fluorouracil (5-FU) through which it acts.[2] It belongs to the class of medications known as fluoropyrimidines, which also includes 5-fluorouracil and tegafur.[4]

    Capecitabine was patented in 1992 and approved for medical use in 1998.[5] It is on the World Health Organization's List of Essential Medicines.[6] The wholesale cost in the developing world is about US$122.64–195.66 per cycle of medication.[7] In the United Kingdom it costs the NHS about £210.67 per cycle.[1] In the United States it costs about $1,892.00 as of 2016.[8]

    Medical uses

    It is used in the treatment of the following cancers:[9][10][11]

    • Colorectal cancer (either as neoadjuvant therapy with radiation, adjuvant therapy or for metastatic cases)
    • Breast cancer (metastatic or as monotherapy/combotherapy; this is licensed as a second-line treatment in the UK)
    • Gastric cancer (off-label in the US; this is a licensed indication in the UK)
    • Oesophageal cancer (off-label in the US)

    Dosage

    The defined daily dose is not established[3]

    Side effects

    Fingerprints absent on red smooth fingertips after seven cycles of capecitabine

    Adverse effects by frequency:[12][13][14][15]

    Very common (>10% frequency)

    Notes on adverse effects:

    1. ↑ Includes: anaemia, lymphopenia, neutropenia and thrombocytopenia

    Contraindications

    Contraindications include:[14]

    Drug interactions

    Drugs it is known to interact with include:[14]

    • Sorivudine or its analogues, such as, brivudine.
    • CYP2C9 substrates, including, warfarin and other coumarin-derivatives anticoagulants
    • Phenytoin, as it increases the plasma concentrations of phenytoin.
    • Calcium folinate may enhance the therapeutic effects of capecitabine by means of synergising with its metabolite, 5-FU. It may also induce more severe diarrhoea by means of this synergy.[9]

    Pharmacogenetics

    The dihydropyrimidine dehydrogenase (DPD) enzyme is responsible for the detoxifying metabolism of fluoropyrimidines, a class of drugs that includes capecitabine, 5-fluorouracil and tegafur.[4] Genetic variations within the DPD gene (DPYD) can lead to reduced or absent DPD activity, and individuals who are heterozygous or homozygous for these variations may have partial or complete DPD deficiency; an estimated 0.2% of individuals have complete DPD deficiency.[4][17] Those with partial or complete DPD deficiency have a significantly increased risk of severe or even fatal drug toxicities when treated with fluoropyrimidines; examples of toxicities include myelosuppression, neurotoxicity and hand-foot syndrome.[4][17]

    Mechanism of action

    Click on genes, proteins and metabolites below to link to respective articles.[§ 1]

    [[File:
    FluoropyrimidineActivity_WP1601
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    FluoropyrimidineActivity_WP1601
    |alt=Fluorouracil (5-FU) Activity edit]]
    Fluorouracil (5-FU) Activity edit
    1. ↑ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601".

    Capecitabine is metabolised to 5-FU which in turn is a thymidylate synthase inhibitor, hence inhibiting the synthesis of thymidine monophosphate (ThMP), the active form of thymidine which is required for the de novo synthesis of DNA.[10]

    Society and culture

    One of the brandnames is Xeloda, marketed by Genentech.

    Others include Xitabin, Capcibin, and Kapetral.

    References

    1. 1 2 3 British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. pp. 585, 588. ISBN 9780857111562.
    2. 1 2 3 4 5 6 7 8 "Capecitabine". The American Society of Health-System Pharmacists. Archived from the original on 15 April 2016. Retrieved 8 December 2016.
    3. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 22 January 2021. Retrieved 18 September 2020.
    4. 1 2 3 4 Caudle KE, Thorn CF, Klein TE, Swen JJ, McLeod HL, Diasio RB, Schwab M (December 2013). "Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing". Clinical Pharmacology and Therapeutics. 94 (6): 640–5. doi:10.1038/clpt.2013.172. PMC 3831181. PMID 23988873.
    5. ↑ Fischer, Janos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 511. ISBN 9783527607495. Archived from the original on 2020-12-06. Retrieved 2017-08-30.
    6. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
    7. ↑ "Capecitabine". International Drug Price Indicator Guide. Archived from the original on 22 January 2018. Retrieved 8 December 2016.
    8. ↑ "NADAC as of 2016-12-07 | Data.Medicaid.gov". Centers for Medicare and Medicaid Services. Archived from the original on 21 December 2016. Retrieved 19 December 2016.
    9. 1 2 Rossi S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
    10. 1 2 "Xeloda (capecitabine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. 25 January 2014. Archived from the original on 2 February 2014.
    11. ↑ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8.
    12. ↑ "XELODA (capecitabine) tablet, film coated [Genentech, Inc.]". DailyMed. Genentech, Inc. December 2013. Archived from the original on 1 February 2014. Retrieved 25 January 2014.
    13. ↑ "Capecitabine Teva : EPAR – Product Information" (PDF). European Medicines Agency. Teva Pharma B.V. 10 January 2014. Archived (PDF) from the original on 4 February 2014. Retrieved 25 January 2014.
    14. 1 2 3 "Capecitabine 150mg – Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Zentiva. 23 December 2013. Archived from the original on 1 February 2014. Retrieved 25 January 2014.
    15. ↑ "NAME OF THE MEDICINE XELODA® Capecitabine" (PDF). TGA eBusiness Services. Roche Products Pty Limited. 5 December 2013. Archived from the original on 11 September 2017. Retrieved 25 January 2014.
    16. ↑ Reddening, swelling, numbness and desquamation on palms and soles
    17. 1 2 Amstutz U, Froehlich TK, Largiadèr CR (September 2011). "Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity". Pharmacogenomics. 12 (9): 1321–36. doi:10.2217/pgs.11.72. PMID 21919607.

    Further reading

    External sites:
    Identifiers:


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