Capecitabine

Last updated

Capecitabine
Capecitabine.svg
Capecitabine-from-xtal-2009-3D-balls.png
Clinical data
Pronunciation /kæpɪˈstəbn/
Trade names Xeloda, Xitabin, Kapetral, others
AHFS/Drugs.com Monograph
MedlinePlus a699003
Pregnancy
category
  • AU:D
Routes of
administration
By mouth
Drug class Antineoplastic agent
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Extensive
Protein binding < 60%
Metabolism liver, to 5'-DFCR, 5'-DFUR (inactive); neoplastic tissue, 5'-DFUR to active fluorouracil
Elimination half-life 38–45 minutes
Excretion kidney (95.5%), faecal (2.6%)
Identifiers
  • Pentyl [1-(3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)-5-fluoro-2-oxo-1H-pyrimidin-4-yl]carbamate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.112.980 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C15H22FN3O6
Molar mass 359.354 g·mol−1
3D model (JSmol)
  • 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=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 Yes check.svgY
  • Key:GAGWJHPBXLXJQN-UORFTKCHSA-N Yes check.svgY
   (verify)

Capecitabine, sold under the brand name Xeloda among others, is a anticancer medication used to treat breast cancer, gastric cancer and colorectal cancer. [3] For breast cancer it is often used together with docetaxel. [4] It is taken by mouth. [4]

Contents

Common side effects include abdominal pain, vomiting, diarrhea, weakness, and rashes. [4] Other severe side effects include blood clotting problems, allergic reactions, heart problems such as cardiomyopathy, and low blood cell counts. [4] Use during pregnancy may result in harm to the fetus. [4] Capecitabine, inside the body, is converted to 5-fluorouracil (5-FU) through which it acts. [4] It belongs to the class of medications known as fluoropyrimidines, which also includes 5-FU and tegafur. [5]

Capecitabine was patented in 1992 and approved for medical use in 1998. [6] It is on the World Health Organization's List of Essential Medicines. [7]

Medical uses

Capecitabine is indicated for

Adverse effects

Adverse effects by frequency: [9] [10] [11] [12]

Very common (>10% frequency)

Notes on adverse effects:

Contraindications

Contraindications include: [11]

In 2020, the EU and UK license was updated to state that capecitabine was contra-indicated in patients that "have a known complete absence of dihydropyrimidine dehydrogenase (DPD) activity". [14] In US, as of 2024, there is no specific contraindication on the package inserts however, there is a cautionary warning: "Patients with certain homozygous or compound heterozygous variants in the DPYD gene are at increased risk for acute early-onset toxicity and serious, including fatal, adverse reactions due to XELODA (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). XELODA is not recommended for use in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete absence of DPD activity. Withhold or permanently discontinue based on clinical assessment. No XELODA dose has been proven safe in patients with complete absence of DPD activity. " [15]

Within the UK, DPYD testing to check for this contraindication is now routine practice, [16] this is not the case in the US. [17]

Drug interactions

Drugs it is known to interact with include: [11]

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. [5] 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. [5] [19] 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. [5] [19]

Mechanism of action

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

[[File:
FluoropyrimidineActivity WP1601.png go to articlego to articlego to articlego to pathway articlego to pathway articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to PubChem Compoundgo to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to pathway articlego to pathway articlego to articlego to articlego to articlego to articlego to articlego to WikiPathwaysgo to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to article
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FluoropyrimidineActivity WP1601.png go to articlego to articlego to articlego to pathway articlego to pathway articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to PubChem Compoundgo to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to pathway articlego to pathway articlego to articlego to articlego to articlego to articlego to articlego to WikiPathwaysgo to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to article
|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. [20]

Drug synthesis

Capecitabine Synthesis.svg

Overdose

Uridine Triacetate is a potential antidote for cases of suspected overdose. [21]

Society and culture

Brand names

One of the brand names is Xeloda, marketed by Genentech.

Others include Xitabin, Capcibin, Kapetral and Pecaset by Eurolab.

Related Research Articles

Fluorouracil, sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pancreatic cancer, breast cancer, and cervical cancer. As a cream it is used for actinic keratosis, basal cell carcinoma, and skin warts.

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Irinotecan, sold under the brand name Camptosar among others, is an anti-cancer medication used to treat colon cancer and small cell lung cancer. For colon cancer it is used either alone or with fluorouracil. For small cell lung cancer it is used with cisplatin. It is given intravenously.

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<span class="mw-page-title-main">Dihydropyrimidine dehydrogenase deficiency</span> Medical condition

Dihydropyrimidine dehydrogenase deficiency is an autosomal recessive metabolic disorder in which there is absent or significantly decreased activity of dihydropyrimidine dehydrogenase, an enzyme involved in the metabolism of uracil and thymine.

Panitumumab, sold under the brand name Vectibix, is a fully human monoclonal antibody specific to the epidermal growth factor receptor.

<span class="mw-page-title-main">Dihydropyrimidine dehydrogenase (NADP+)</span> Class of enzymes

In enzymology, a dihydropyrimidine dehydrogenase (NADP+) (EC 1.3.1.2) is an enzyme that catalyzes the chemical reaction

Tegafur/uracil is a chemotherapy drug combination used in the treatment of cancer, primarily bowel cancer.

<span class="mw-page-title-main">Tegafur</span> Chemical compound

Tegafur is a chemotherapeutic prodrug of 5-fluorouracil (5-FU) used in the treatment of cancers. It is a component of the combination drug tegafur/uracil. When metabolised, it becomes 5-FU.

Ramucirumab, sold under the brand name Cyramza, is a fully human monoclonal antibody (IgG1) used for the treatment of cancer. Ramucirumab is a human vascular endothelial growth factor receptor 2 (VEGFR2) antagonist. Ramucirumab was developed by ImClone Systems. It was isolated from a native phage display library from Dyax.

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<span class="mw-page-title-main">Uridine triacetate</span> Chemical compound

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References

  1. "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  2. "Xeloda EPAR". European Medicines Agency. 2 February 2001. Retrieved 2 July 2024.
  3. British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. pp. 585, 588. ISBN   9780857111562.
  4. 1 2 3 4 5 6 "Capecitabine". The American Society of Health-System Pharmacists. Archived from the original on 15 April 2016. Retrieved 8 December 2016.
  5. 1 2 3 4 Caudle KE, Thorn CF, Klein TE, Swen JJ, McLeod HL, Diasio RB, et al. (December 2013). "Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing". Clinical Pharmacology and Therapeutics. 94 (6): 640–645. doi:10.1038/clpt.2013.172. PMC   3831181 . PMID   23988873.
  6. Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 511. ISBN   9783527607495. Archived from the original on 12 January 2023. Retrieved 30 August 2017.
  7. 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.
  8. 1 2 3 4 5 6 7 8 "FDA approves updated drug labeling including new indications and dosing regimens for capecitabine tablets under Project Renewal". U.S. Food and Drug Administration. 15 December 2022. Archived from the original on 27 January 2023. Retrieved 26 January 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
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  10. "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.
  11. 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.
  12. "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.
  13. Reddening, swelling, numbness and desquamation on palms and soles
  14. ATC code (23 April 2021). "Summary of Product Characteristics (SmPC)". (emc). Retrieved 5 January 2025.
  15. "FDA approves updated drug labeling including new indications". U.S. Food and Drug Administration. 1 October 2024. Retrieved 5 January 2025.
  16. Robinson J (5 May 2022). "Cancer pharmacogenomics testing: are we hitting the mark?". The Pharmaceutical Journal. Retrieved 26 December 2024.
  17. Koo K, Pasternak AL, Henry NL, Sahai V, Hertz DL (June 2022). "Survey of US Medical Oncologists' Practices and Beliefs Regarding DPYD Testing Before Fluoropyrimidine Chemotherapy". JCO Oncology Practice. 18 (6): e958 –e965. doi:10.1200/OP.21.00874. PMC   9191302 . PMID   35239419.
  18. Rossi S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN   978-0-9805790-9-3.
  19. 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): 1321–1336. doi:10.2217/pgs.11.72. PMID   21919607.
  20. "Xeloda (capecitabine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. 25 January 2014. Archived from the original on 2 February 2014.
  21. Ma WW, Saif WM, Cartwright TH, Fakih M, El-Rayes BF, King T, et al. (20 May 2016). "Uridine triacetate as a lifesaving antidote for overdoses and severe early-onset 5-fluorouracil and capecitabine toxicities". Journal of Clinical Oncology. 34 (15_suppl): e21689 –e21689. doi:10.1200/JCO.2016.34.15_suppl.e21689. ISSN   0732-183X.

Further reading