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{{Short description|Chemical compound}} |
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{{Use dmy dates|date=January 2023}} |
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{{cs1 config |name-list-style=vanc |display-authors=6}} |
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{{Drugbox |
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{{Drugbox |
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| Watchedfields = changed |
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| verifiedrevid = 443496449 |
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| verifiedrevid = 460016695 |
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| IUPAC_name = pentyl carbamate |
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| IUPAC_name = Pentyl carbamate |
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| image = Capecitabine-from-xtal-2009-2D-skeletal.png |
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| image = Capecitabine.svg |
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| width = 280px |
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| width = 280 |
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| alt = |
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| image2 = Capecitabine-from-xtal-2009-3D-balls.png |
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| image2 = Capecitabine-from-xtal-2009-3D-balls.png |
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| width2 = 250 |
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| alt2 = |
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<!--Clinical data--> |
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<!--Clinical data--> |
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| pronounce = {{IPAc-en|k|æ|p|ᵻ|ˈ|s|aɪ|t|ə|b|iː|n}} |
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| tradename = Xeloda |
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| tradename = Xeloda, Xitabin, Kapetral, others |
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| Drugs.com = {{drugs.com|monograph|capecitabine}} |
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| Drugs.com = {{drugs.com|monograph|capecitabine}} |
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| MedlinePlus = a699003 |
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| MedlinePlus = a699003 |
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| pregnancy_AU = D |
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| pregnancy_AU = D |
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| routes_of_administration = ] |
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| pregnancy_US = D |
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| class = ] |
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| ATC_prefix = L01 |
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| ATC_suffix = BC06 |
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| legal_AU = S4 |
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| legal_AU = S4 |
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| legal_CA = Rx-only |
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| legal_UK = POM |
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| legal_UK = POM |
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| legal_US = Rx-only |
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| legal_US = Rx-only |
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| legal_EU = Rx-only |
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| routes_of_administration = Oral |
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| legal_EU_comment = <ref>{{cite web | title=Xeloda EPAR | website=European Medicines Agency | date=2 February 2001 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/xeloda | access-date=2 July 2024}}</ref> |
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<!--Pharmacokinetic data--> |
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<!--Pharmacokinetic data--> |
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| bioavailability = Extensive |
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| bioavailability = Extensive |
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| protein_bound = < 60% |
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| protein_bound = < 60% |
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| metabolism = Hepatic, to 5'-DFCR, 5'-DFUR (inactive); neoplastic tissue, 5'-DFUR to active ] |
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| metabolism = liver, to 5'-DFCR, 5'-DFUR (inactive); neoplastic tissue, 5'-DFUR to active ] |
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| elimination_half-life = 38–45 minutes |
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| elimination_half-life = 38–45 minutes |
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| excretion = Renal 95.5%, faecal 2.6% |
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| excretion = kidney (95.5%), faecal (2.6%) |
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<!--Identifiers--> |
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<!--Identifiers--> |
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| IUPHAR_ligand = 6799 |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 154361-50-9 |
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| CAS_number = 154361-50-9 |
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| ATC_prefix = L01 |
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| ATC_suffix = BC06 |
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| PubChem = 60953 |
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| PubChem = 60953 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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<!--Chemical data--> |
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<!--Chemical data--> |
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| C=15 | H=22 | F=1 | N=3 | O=6 |
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| C=15 | H=22 | F=1 | N=3 | O=6 |
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| molecular_weight = 359.35 g/mol |
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| smiles = FC=1\C(=N/C(=O)N(C=1)2O((O)2O)C)\NC(=O)OCCCCC |
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| smiles = FC=1\C(=N/C(=O)N(C=1)2O((O)2O)C)\NC(=O)OCCCCC |
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| InChI = 1/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 |
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| InChIKey = GAGWJHPBXLXJQN-UORFTKCHBD |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 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 |
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| StdInChI = 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 |
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| StdInChIKey = GAGWJHPBXLXJQN-UORFTKCHSA-N |
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| StdInChIKey = GAGWJHPBXLXJQN-UORFTKCHSA-N |
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}} |
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}} |
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'''Capecitabine''' (]) ({{IPAc-en|icon|k|eɪ|p|ˈ|s|aɪ|t|ə|b|iː|n}}) (Xeloda, Roche) is an orally-administered chemotherapeutic agent used in the treatment of ] ] and ]s. Capecitabine is a ], that is enzymatically converted to ] in the tumor, where it inhibits ] and slows growth of tumor tissue. The activation of capecitabine follows a pathway with three enzymatic steps and two intermediary metabolites, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR), to form 5-fluorouracil. |
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<!-- Definition and medical uses --> |
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==Indications== |
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'''Capecitabine''', sold under the brand name '''Xeloda''' among others, is a ] used to treat ], ] and ].<ref name=BNF69>{{cite book|title=British national formulary : BNF 69|date=2015|publisher=British Medical Association|isbn=9780857111562|pages=585, 588|edition=69}}</ref> For breast cancer it is often used together with ].<ref name=AHFS2016/> It is taken ].<ref name=AHFS2016>{{cite web|title=Capecitabine|url=https://www.drugs.com/monograph/capecitabine.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20160415200439/http://www.drugs.com/monograph/capecitabine.html|archive-date=15 April 2016}}</ref> |
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Capecitabine is FDA-approved for: |
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* Adjuvant in '']'' Stage III Dukes' C - used as first-line monotherapy. |
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* ''Metastatic colorectal cancer'' - used as first-line monotherapy, if appropriate. |
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* ''Metastatic ]'' - used in combination with ], after failure of ]-based treatment. Also as monotherapy, if the patient has failed ]-based treatment, and if anthracycline-based treatment has either failed or cannot be continued for other reasons (i.e., the patient has already received the maximum lifetime dose of an anthracycline). |
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<!-- Side effects and mechanism --> |
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In the UK, capecitabine is approved by the ] (NICE) for colon and colorectal cancer, and locally advanced or metastatic breast cancer.<ref></ref> |
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Common side effects include abdominal pain, vomiting, ], weakness, and rashes.<ref name=AHFS2016/> Other severe side effects include blood clotting problems, ], heart problems such as ], and ].<ref name=AHFS2016/> Use during ] may result in harm to the fetus.<ref name=AHFS2016/> Capecitabine, inside the body, is converted to ] (5-FU) through which it acts.<ref name=AHFS2016/> It belongs to the class of medications known as ]s, which also includes ] and ].<ref name="pmid23988873">{{cite journal | vauthors = Caudle KE, Thorn CF, Klein TE, Swen JJ, McLeod HL, Diasio RB, Schwab M | title = Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing | journal = Clinical Pharmacology and Therapeutics | volume = 94 | issue = 6 | pages = 640–645 | date = December 2013 | pmid = 23988873 | pmc = 3831181 | doi = 10.1038/clpt.2013.172 }}</ref> |
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On March 29,2007, the European Commission approved Capecitabine, in combination with platinum-based therapy (with or without epirubicin), for the first-line treatment of advanced stomach cancer. |
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<!-- History and culture --> |
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==Dose== |
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Capecitabine was patented in 1992 and approved for medical use in 1998.<ref name=Fis2006>{{cite book| vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery|date=2006|publisher=John Wiley & Sons|isbn=9783527607495|page=511|url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA511|access-date=30 August 2017|archive-date=12 January 2023|archive-url=https://web.archive.org/web/20230112070704/https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA511|url-status=live}}</ref> It is on the ].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> |
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The usual starting dose is 2,500 mg/m<sup>2</sup>/day in two divided doses, 12 hours apart. One cycle includes two weeks of treatment followed by one week without treatment. Cycles can be repeated every three weeks. |
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===Dose adjustments=== |
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==Medical uses== |
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Capecitabine is ] for |
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* For mild renal dysfunction (] 30-50 mL/min), it is recommended to reduce dose by 25%. |
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* adjuvant treatment of people with Stage III colon cancer as a single agent or as a component of a combination chemotherapy regimen;<ref name="FDA Xeloda">{{cite web | title=FDA approves updated drug labeling including new indications and dosing regimens for capecitabine tablets under Project Renewal | website=U.S. Food and Drug Administration | date=15 December 2022 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-updated-drug-labeling-including-new-indications-and-dosing-regimens-capecitabine | access-date=26 January 2023 | archive-date=27 January 2023 | archive-url=https://web.archive.org/web/20230127005901/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-updated-drug-labeling-including-new-indications-and-dosing-regimens-capecitabine | url-status=live }} {{PD-notice}}</ref> |
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* For severe renal dysfunction (creatinine clearance <30 mL/min), treatment is not recommended. |
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* perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy;<ref name="FDA Xeloda" /> |
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* There is no recommendation for hepatic dysfunction. |
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* treatment of people with unresectable or metastatic colorectal cancer as a single agent or as a component of a combination chemotherapy regimen;<ref name="FDA Xeloda" /> |
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* For elderly patients, lower doses may be required due to higher incidences of serious adverse reactions. |
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* treatment of people with advanced or metastatic breast cancer as a single agent if an anthracycline- or taxane-containing chemotherapy is not indicated;<ref name="FDA Xeloda" /> |
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* Patients with ] (a.k.a. DPD deficiency), a pharmacogenetic syndrome affecting capecitabine detoxification process in the liver, should have their dosage tailored. |
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* treatment of people with advanced or metastatic breast cancer in combination with docetaxel after disease progression on prior anthracycline-containing chemotherapy;<ref name="FDA Xeloda" /> |
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* treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen;<ref name="FDA Xeloda" /> |
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* treatment of adults with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease as a component of a combination regimen;<ref name="FDA Xeloda" /> |
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* adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen.<ref name="FDA Xeloda" /> |
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==Side effects== |
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==Adverse effects== |
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Adverse effects by frequency:<ref name=DM>{{cite web|title=XELODA (capecitabine) tablet, film coated |work=DailyMed|publisher=Genentech, Inc.|date=December 2013|access-date=25 January 2014|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a1de8bba-3b1d-4c9d-ab8a-32d2c05e67c8|url-status=live|archive-url=https://web.archive.org/web/20140201232002/http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a1de8bba-3b1d-4c9d-ab8a-32d2c05e67c8|archive-date=1 February 2014}}</ref><ref name=EMA>{{cite web|title=Capecitabine Teva : EPAR – Product Information|work=European Medicines Agency|publisher=Teva Pharma B.V.|date=10 January 2014|access-date=25 January 2014|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002362/WC500127288.pdf|url-status=live|archive-url=https://web.archive.org/web/20140204011552/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002362/WC500127288.pdf|archive-date=4 February 2014}}</ref><ref name=EMC>{{cite web|title=Capecitabine 150mg – Summary of Product Characteristics (SPC)|work=electronic Medicines Compendium|publisher=Zentiva|date=23 December 2013|access-date=25 January 2014|url=http://www.medicines.org.uk/emc/medicine/28462/SPC/Capecitabine+150mg/|url-status=dead|archive-url=https://web.archive.org/web/20140201205125/http://www.medicines.org.uk/emc/medicine/28462/SPC/Capecitabine+150mg/|archive-date=1 February 2014}}</ref><ref name=TGA>{{cite web|title=NAME OF THE MEDICINE XELODA® Capecitabine|work=TGA eBusiness Services|publisher=Roche Products Pty Limited|date=5 December 2013|access-date=25 January 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03462-3|format=PDF|url-status=live|archive-url=https://web.archive.org/web/20170911002644/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03462-3|archive-date=11 September 2017}}</ref> |
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Potential major adverse reactions include: |
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* Cardiovascular: ] changes, ], ] (these may be more common in patients with pre-existing coronary artery disease) |
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* Dermatological: ] (numbness, tingling, pain, redness, or blistering of the palms of the hands and soles of the feet). This can lead to the disappearance of ] in some patients.<ref> </ref> <ref></ref> |
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* Gastrointestinal: ] (sometimes severe), ], ] |
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* Hematological: ], ], ] |
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* Hepatic: ] |
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;Very common (>10% frequency): |
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==Drug interactions== |
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{{div col|colwidth=18em}} |
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* May interact with ] and increase bleeding risk. |
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* Appetite loss |
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* May inhibit ] CYP2C9 enzyme, and therefore increase levels of ] such as ] and other substrates of CYP2C9. |
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* Diarrhea |
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* The concomitant use of ] is not recommended. In a controlled study, leucovorin increased the toxicity of capecitabine without any apparent advantage in response rate. |
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* Vomiting |
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* Nausea |
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* ] |
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* Abdominal pain |
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* Fatigue |
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* ] |
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* ]<ref name = "Notes">Reddening, swelling, numbness and ] on palms and soles</ref> |
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* ] |
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* Fever |
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* Pain |
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* Headache |
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* ] |
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* ] |
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* ] |
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* ] |
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* Eye irritation |
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* Myelosuppression<ref group = "Note">Includes: ], ], ] and ]</ref> |
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{{div col end}} |
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Notes on adverse effects: |
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==Formulation== |
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{{reflist|group = "Note"}} |
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Capecitabine (as brand-name Xeloda) is available in light peach 150 mg tablets and peach 500 mg tablets. |
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===Contraindications=== |
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==References== |
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Contraindications include:<ref name = EMC/> |
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* Lacy, Charles F; Armstrong, Lora L; Goldman, Morton P; Lance, Leonard L (2004). ''Lexi-Comp's Drug Information Handbook'' (12th Edition). Lexi-Comp Inc. ISBN 1-59195-083-X |
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* History of hypersensitivity to fluorouracil, capecitabine or any of its excipients |
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* Fischer, David S; Knobf, M Tish; Durivage, Henry J; Beaulieu, Nancy J (2003). ''The Cancer Chemotherapy Handbook'' (6th Edition). Mosby. ISBN 0-323-01890-4 |
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* ] (see ]) |
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* Retrieved 6/05 |
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* Pregnancy and lactation |
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* Mercier C, Ciccolini J (2007). "Severe or lethal toxicities upon capecitabine intake: is DPYD genetic polymorphism the ideal culprit?". Trends in pharmacological sciences 28 (12): 597–598. doi:10.1016/j.tips.2007.09.009. PMID 18001850. |
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* Severe ], ], or ] |
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* Severe hepatic impairment or severe renal impairment |
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* Treatment with ] or its chemically related analogues, such as ] |
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===Drug interactions=== |
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Drugs it is known to interact with include:<ref name = EMC/> |
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* ] or its analogues, such as, ]. |
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* ] substrates, including, ] and other coumarin-derivatives anticoagulants |
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* ], as it increases the plasma concentrations of phenytoin. |
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* ] 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.<ref name="AMH">{{cite book | veditors = Rossi S | isbn = 978-0-9805790-9-3 | title = Australian Medicines Handbook | place = Adelaide | publisher = The Australian Medicines Handbook Unit Trust | year = 2013 | edition = 2013 }}</ref> |
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===Pharmacogenetics=== |
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The ] (DPD) enzyme is responsible for the detoxifying metabolism of fluoropyrimidines, a class of drugs that includes capecitabine, ] and ].<ref name="pmid23988873"/> ]s within the DPD gene (''DPYD'') can lead to reduced or absent DPD activity, and individuals who are ] or ] for these variations may have partial or complete ]; an estimated 0.2% of individuals have complete ].<ref name="pmid23988873"/><ref name="pmid21919607">{{cite journal | vauthors = Amstutz U, Froehlich TK, Largiadèr CR | title = Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity | journal = Pharmacogenomics | volume = 12 | issue = 9 | pages = 1321–1336 | date = September 2011 | pmid = 21919607 | doi = 10.2217/pgs.11.72 }}</ref> 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 ], ] and ].<ref name="pmid23988873"/><ref name="pmid21919607"/> |
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==Mechanism of action== |
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{{FluoropyrimidineActivity WP1601|highlight=Capecitabine}} |
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Capecitabine is metabolised to 5-FU which in turn is a ] inhibitor, hence inhibiting the synthesis of ] (ThMP), the active form of thymidine which is required for the ''de novo'' synthesis of DNA.<ref name=MSR>{{cite web|title=Xeloda (capecitabine) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|date=25 January 2014|url=http://reference.medscape.com/drug/xeloda-capecitabine-342211#showall|url-status=live|archive-url=https://web.archive.org/web/20140202175324/http://reference.medscape.com/drug/xeloda-capecitabine-342211#showall|archive-date=2 February 2014}}</ref> |
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==Drug synthesis== |
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] |
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==Society and culture== |
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=== Brand names === |
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{{unreferenced section|date=August 2020}} |
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One of the brand names is Xeloda, marketed by ]. |
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Others include Xitabin, Capcibin, Kapetral and Pecaset by ]. |
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== References == |
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{{reflist}} |
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{{reflist}} |
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== Further reading == |
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==External links== |
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* {{cite book | title=Medical Genetics Summaries | chapter=Capecitabine Therapy and DPYD Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK385155/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | publisher=] (NCBI) | year=2016 | pmid=28520372 | id=Bookshelf ID: NBK385155 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ }} |
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* (patient information, tools, and resources) |
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* (patient information) |
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{{Chemotherapeutic agents}} |
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{{Chemotherapeutic agents}} |
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{{Portal bar | Medicine}} |
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{{Authority control}} |
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