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Revision as of 07:39, 20 October 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'DrugBank').← Previous edit		Latest revision as of 05:23, 27 December 2024 edit undoBoghog (talk | contribs)Autopatrolled, Extended confirmed users, IP block exemptions, New page reviewers, Pending changes reviewers, Rollbackers, Template editors137,738 edits consistent citation formatting; templated cite
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			{{Short description|Chemotherapy medication}}
			{{Use dmy dates|date=July 2023}}
			{{cs1 config|name-list-style=vanc|display-authors=6}}
	{{Drugbox		{{Drugbox
			| Watchedfields = changed
	| verifiedrevid = 443823794
			| verifiedrevid = 456480929
	| IUPAC_name = 5-fluoro-1''H''-pyrimidine-2,4-dione
	| image = Fluorouracil.svg		| image = Fluorouracil2DACS.svg
	| width = 120		| width = 80
			| alt =
	| image2 = Fluorouracil-3D-vdW.png
			| image2 = Fluorouracil-from-xtal-3D-bs-17.png
			| width2 = 100
			| alt2 =
	<!--Clinical data-->		<!--Clinical data-->
			| pronounce = {{IPAc-en|ˌ|f|l|ʊər|oʊ|ˈ|j|ʊər|ə|s|ɪ|l}}<ref>{{cite web |title=Fluorouracil – Definition and More from the Free Merriam-Webster Dictionary |url=http://www.merriam-webster.com/dictionary/fluorouracil |access-date=19 November 2014 |url-status=live |archive-url=https://web.archive.org/web/20141129194245/http://www.merriam-webster.com/dictionary/fluorouracil |archive-date=29 November 2014 }}</ref>
	| tradename = Carac
			| tradename = Adrucil, others
	| Drugs.com = {{drugs.com|monograph|fluorouracil}}		| Drugs.com = {{drugs.com|monograph|fluorouracil}}
	| MedlinePlus = a682708		| MedlinePlus = a682708
			| DailyMedID = Fluorouracil
	| pregnancy_AU = D		| pregnancy_AU = D
	| pregnancy_category = <br>D (intravenous), X (topical) <small>(])</small>		| pregnancy_category =
			| routes_of_administration = ], ]
			| ATC_prefix = L01
			| ATC_suffix = BC02
			| ATC_supplemental = {{ATC|L01|BC52}}
			| legal_AU = S4
			| legal_CA = Rx-only
			| legal_CA_comment = <ref>{{cite web|url=https://pdf.hres.ca/dpd_pm/00049486.PDF|title=TOLAK : Fluorouracil Cream : 4% (w/w) fluorouracil (as fluorouracil sodium)|website=Pdf.hres.ca|access-date=8 June 2022|archive-date=10 June 2022|archive-url=https://web.archive.org/web/20220610030126/https://pdf.hres.ca/dpd_pm/00049486.PDF|url-status=live}}</ref>
			| legal_UK = POM
	| legal_US = Rx-only		| legal_US = Rx-only
	| routes_of_administration = ] (infusion or ]) and topical
	<!--Pharmacokinetic data-->		<!--Pharmacokinetic data-->
	| bioavailability = 28 to 100%		| bioavailability = 28 to 100%
	| protein_bound = 8 to 12%		| protein_bound = 8 to 12%
	| metabolism = Intracellular and ] (]-mediated)		| metabolism = Intracellular and ] (]-mediated)
	| elimination_half-life = 10 to 20 minutes		| elimination_half-life = 16 minutes
	| excretion = ]		| excretion = ]
	<!--Identifiers-->		<!--Identifiers-->
			| IUPHAR_ligand = 4789
	| CASNo_Ref = {{cascite|correct|CAS}}
			| CAS_number_Ref = {{cascite|correct|??}}
	| CAS_number = 51-21-8		| CAS_number = 51-21-8
	| ATC_prefix = L01
	| ATC_suffix = BC02
	| PubChem = 3385		| PubChem = 3385
	| DrugBank_Ref = {{drugbankcite|correct|drugbank}}		| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
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	<!--Chemical data-->		<!--Chemical data-->
			| IUPAC_name = 5-Fluoro-1''H'',3''H''-pyrimidine-2,4-dione
	| C=4 | H=3 | F=1 | N=2 | O=2
			| C=4 | H=3 | F=1 | N=2 | O=2
	| molecular_weight = 130.077 g/mol
	| smiles = c1c(c(=O)c(=O)1)F		| smiles = O=C1NC(=O)NC=C1F
	| InChI = 1/C4H3FN2O2/c5-2-1-6-4(9)7-3(2)8/h1H,(H2,6,7,8,9)
	| InChIKey = GHASVSINZRGABV-UHFFFAOYAG
	| StdInChI_Ref = {{stdinchicite|correct|chemspider}}		| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChI = 1S/C4H3FN2O2/c5-2-1-6-4(9)7-3(2)8/h1H,(H2,6,7,8,9)		| StdInChI = 1S/C4H3FN2O2/c5-2-1-6-4(9)7-3(2)8/h1H,(H2,6,7,8,9)
	| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}		| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChIKey = GHASVSINZRGABV-UHFFFAOYSA-N		| StdInChIKey = GHASVSINZRGABV-UHFFFAOYSA-N
	| melting_point = 282 - 283		| melting_point = 282–283
	}}		}}
			<!-- Definition and medical uses -->
	'''Fluorouracil (5-FU or f5U)''' (sold under the brand names '''Adrucil, Carac, Efudix, Efudex''' and '''Fluoroplex''') is a ] that is a ] which is used in the treatment of ]. It is a ] and works through irreversible inhibition of ]. It belongs to the family of drugs called ]s. It is typically administered with ].
			'''Fluorouracil''' ('''5-FU''', '''5-fluorouracil'''), sold under the brand name '''Adrucil''' among others, is a ] ] medication used to treat ].<ref name=AHFS2016/> By ] it is used for treatment of ], ], ], ], ], and ].<ref name=AHFS2016>{{cite web|title=Fluorouracil|url=https://www.drugs.com/monograph/fluorouracil.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161220192631/https://www.drugs.com/monograph/fluorouracil.html|archive-date=20 December 2016}}</ref> As a cream it is used for ], ], and skin ].<ref name=AHFS2016Top>{{cite web|title=Fluorouracil topical|url=https://www.drugs.com/monograph/fluorouracil-topical.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161226054457/https://www.drugs.com/monograph/fluorouracil-topical.html|archive-date=26 December 2016}}</ref><ref>{{cite journal | vauthors = Moore AY | title = Clinical applications for topical 5-fluorouracil in the treatment of dermatological disorders | journal = The Journal of Dermatological Treatment | volume = 20 | issue = 6 | pages = 328–335 | date = 2009 | pmid = 19954388 | doi = 10.3109/09546630902789326 | s2cid = 218896998 }}</ref>
			<!-- Side effects and mechanism -->
	== Uses ==
			Side effects of use by injection are common.<ref name=AHFS2016/> They may include inflammation of the mouth, loss of appetite, ], hair loss, and inflammation of the skin.<ref name=AHFS2016/> When used as a cream, irritation at the site of application usually occurs.<ref name=AHFS2016Top/> Use of either form in ] may harm the fetus.<ref name=AHFS2016/> Fluorouracil is in the ] and ] families of medications.<ref name=BNF69>{{cite book|title=British national formulary : BNF 69|date=2015|publisher=British Medical Association|isbn=9780857111562|page=590|edition=69}}</ref><ref>{{cite book| vauthors = Airley R |title=Cancer Chemotherapy: Basic Science to the Clinic|date=2009|publisher=John Wiley & Sons|isbn=9780470092569|page=76|url=https://books.google.com/books?id=wjjYyYpfiQ8C&pg=PA76|language=en|url-status=live|archive-url=https://web.archive.org/web/20171105200744/https://books.google.com/books?id=wjjYyYpfiQ8C&pg=PA76|archive-date=5 November 2017}}</ref> How it works is not entirely clear, but it is believed to involve blocking the action of ] and thus stopping the production of ].<ref name=AHFS2016/>
	The chemotherapy agent 5-FU (fluorouracil), which has been in use against cancer for about 40 years, acts in several ways, but principally as a ]. Interrupting the action of this enzyme blocks synthesis of the pyrimidine ], which is a nucleotide required for ]. ] methylates deoxyuridine monophosphate (dUMP) into ] (dTMP). Administration of 5-FU causes a scarcity in dTMP, so rapidly dividing cancerous cells undergo cell death via ].<ref>{{cite journal |author=Longley DB, Harkin DP, Johnston PG |title=5-fluorouracil: mechanisms of action and clinical strategies |journal=Nat. Rev. Cancer |volume=3 |issue=5 |pages=330–8 |year=2003 |month=May |pmid=12724731 |doi=10.1038/nrc1074 |url=http://www.nature.com/nrc/journal/v3/n5/full/nrc1074.html}}</ref>
			<!-- History, society and culture -->
	Like many anti-cancer drugs, 5-FU's effects are felt system wide but fall most heavily upon rapidly dividing cells that make heavy use of their nucleotide synthesis machinery, such as cancer cells (other parts of the body with rapidly dividing cells include the cells lining the digestive tract).
			Fluorouracil was patented in 1956 and came into medical use in 1962.<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|language=en|url-status=live|archive-url=https://web.archive.org/web/20170911002644/https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA511|archive-date=11 September 2017}}</ref> It is on the ].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> In 2022, it was the 270th most commonly prescribed medication in the United States, with more than 900,000 prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Fluorouracil Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Fluorouracil | access-date = 30 August 2024 }}</ref>
			==Medical uses==
	Some of its principal uses are in ], and ], in which it has been the established form of ] for decades (]-containing drugs approved for human use in the US since 1978 are also very well established). It is also sometimes used in the treatment of inflammatory breast cancer, an especially aggressive form of breast cancer.
			{{Multiple image
			| perrow = 1
			| total_width = 200
			| direction = vertical
			| image1 = Efudix immediately post-treatment.jpg
			| width1 = 190px
			| alt1 = Male forearm showing oval scabbed skin patch with scales and reddening
			| caption1 = Effect of topical skin treatment with 5-fluorouracil cream after a standard 30-day treatment, before commencement of the healing phase (months two and three)
			| image2 = Efudix effect three plus years post-treatment.jpg
			| width2 = 190px
			| alt2 = Male forearm showing healed skin with a creamy, shiny patch having pigmentation loss
			| caption2 = Healed skin three+ years after treatment, showing some pigmentation loss
			}}
			Fluorouracil has been given systemically for ], ], ], ], ], ] and ]s (especially ]s).<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> It has also been given topically (on the skin) for ], skin cancers and ]<ref name = AMH/> (a type of ]), and as eye drops for treatment of ].<ref>{{cite journal | vauthors = Joag MG, Sise A, Murillo JC, Sayed-Ahmed IO, Wong JR, Mercado C, Galor A, Karp CL | title = Topical 5-Fluorouracil 1% as Primary Treatment for Ocular Surface Squamous Neoplasia | journal = Ophthalmology | volume = 123 | issue = 7 | pages = 1442–1448 | date = July 2016 | pmid = 27030104 | pmc = 4921289 | doi = 10.1016/j.ophtha.2016.02.034 }}</ref> Other uses include ocular injections into a previously created ] ] to inhibit healing and cause scarring of tissue, thus allowing adequate ] flow to reduce intraocular pressure.
			==Contraindications==
	5-FU is also used in ophthalmic surgery, specifically to augment ] (an operation performed to lower the intraocular pressure in patients with ]) in patients deemed to be at high risk for failure. 5-FU acts as an anti-scarring agent in this regard, since excessive scarring at the trabeculectomy site is the main cause for failure of the surgery.
			Fluorouracil is contraindicated in patients who are severely debilitated and in patients with ] due to either radiotherapy or chemotherapy.<ref name = EMC/> It is likewise contraindicated in pregnant or breastfeeding women.<ref name = EMC/>
			Non-topical use, i.e. administration by injection, should be avoided in patients who do not have malignant illnesses.<ref name="EMC" />
	Fluorouracil can be used topically (as a cream) for treating ] and some types of ]s of the skin. It is often referred to by its trade names ''Efudex'', ''Carac'' or ''Fluoroplex''.
			in 2020, the EU and UK license was updated to state that fluorouracil was contra-indicated in patients that "have a known complete absence of dihydropyrimidine dehydrogenase (DPD) activity"<ref>{{Cite web |title=Fluorouracil 50 mg/ml Injection - Summary of Product Characteristics (SmPC) - (emc) |url=https://www.medicines.org.uk/emc/product/3791/smpc |access-date=2024-12-26 |website=www.medicines.org.uk}}</ref>. In US, as of 2024, there is no specific contraindication on the package inserts however, there is a cautionary warning: "Increased risk of serious or fatal adverse reactions in patients with low or absent Dipyrimidine Dehydrogenase activity: withhold or permanently discontinue fluorouracil in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of dipyrimidine dehydrogenase (DPD) activity.
	Due to Fluorouracil's toxicity and the fact that it can be manufactured using the same reaction as uracil, its precursor, 5-Fluoroorotic Acid, is commonly used in laboratories to screen against organisms capable of synthesizing uracil.
			No fluorouracil dose has been proven safe in patients with absent DPD activity"<ref name=":0">{{Cite web |title=Drugs@FDA: FDA-Approved Drugs |url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=012209 |access-date=2024-12-26 |website=www.accessdata.fda.gov |language=en}}</ref>
	It is a key component in ].
			Within the UK, DPYD testing to check for this contraindication is now routine practice<ref>{{Cite web | vauthors = Robinson J |date=2022-05-05 |title=Cancer pharmacogenomics testing: are we hitting the mark? |url=https://pharmaceutical-journal.com/article/feature/cancer-pharmacogenomics-testing-are-we-hitting-the-mark |access-date=2024-12-26 |website=The Pharmaceutical Journal |language=en-US}}</ref>, this is not the case in the US<ref>{{cite journal | vauthors = Koo K, Pasternak AL, Henry NL, Sahai V, Hertz DL | title = Survey of US Medical Oncologists' Practices and Beliefs Regarding <i>DPYD</i> Testing Before Fluoropyrimidine Chemotherapy | journal = JCO Oncology Practice | volume = 18 | issue = 6 | pages = e958-e965 | date = June 2022 | pmid = 35239419 | pmc = 9191302 | doi = 10.1200/OP.21.00874 }}</ref>.
	== Synthesis ==
	5-FU was designed, synthesized and patented by Charles Heidelberger in 1957.<ref>{{cite journal |title=Awards, Appointments, Announcements |journal=J Natl Cancer Inst |volume=91 |issue=15 |pages=1278–80 |year=1999 |doi=10.1093/jnci/91.15.1278 |url=http://jnci.oxfordjournals.org/content/91/15/1278.full}}</ref><ref>{{cite journal |author=Chu E |title=Ode to 5-Fluorouracil |journal=Clinical Colorectal Cancer |volume=6 |issue=9 |pages=609 |date=September 2007 |doi=10.3816/CCC.2007.n.029 |url=http://cigjournals.metapress.com/content/b464v2u31594jj28/}}</ref><ref>National Academy of Sciences, Biographical Memoirs,80:135</ref>
			==Adverse effects==
	Since ] is a normal component of RNA, the rationale behind the development of the drug was that cancer cells, with their increased genetic instability, might be more sensitive to 'decoy' molecules that mimic the natural compound than normal cells. The scientific goal in this case was to synthesize a drug which demonstrated specific uracil antagonism. The drug proved to have anti-tumor capabilities.
			Adverse effects by frequency include:<ref name = AMH/><ref name=EMC>{{cite web|title=Fluorouracil 50 mg/ml Injection – Summary of Product Characteristics|work=electronic Medicines Compendium|publisher=Hospira UK Ltd|date=24 August 2011|access-date=24 January 2014|url=http://www.medicines.org.uk/emc/medicine/636/SPC/Fluorouracil++50+mg+ml++Injection/|url-status=live|archive-url=https://web.archive.org/web/20140201204538/http://www.medicines.org.uk/emc/medicine/636/SPC/Fluorouracil++50+mg+ml++Injection/|archive-date=1 February 2014}}</ref><ref name=TGA>{{cite web|title=DBL Fluorouracil Injection BP|work=TGA eBusiness Services|publisher=Hospira Australia Pty Ltd|date=21 June 2012|access-date=24 January 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-02952-3|format=PDF|url-status=live|archive-url=https://web.archive.org/web/20170128034658/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-02952-3|archive-date=28 January 2017}}</ref><ref name=DM>{{cite web|title=ADRUCIL (fluorouracil) injection |work=DailyMed|publisher=Teva Parenteral Medicines, Inc.|date=August 2012|access-date=24 January 2014|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b90e0da7-f702-4f09-9488-74f2bb20e9ac|url-status=live|archive-url=https://web.archive.org/web/20140201231133/http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b90e0da7-f702-4f09-9488-74f2bb20e9ac|archive-date=1 February 2014}}</ref><ref name=MSRIV>{{cite web|title=Adrucil (fluorouracil) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=24 January 2014|url=http://reference.medscape.com/drug/adrucil-fluorouracil-342092#showall|url-status=live|archive-url=https://web.archive.org/web/20140202174903/http://reference.medscape.com/drug/adrucil-fluorouracil-342092#showall|archive-date=2 February 2014}}</ref>
			===During systemic use===
	When elemental fluorine is reacted with ], 5-fluorouracil is produced. 5-Fluorouracil masquerades as uracil during the nucleic acid replication process. Because 5-Fluorouracil is similar in shape to, but does not perform the same chemistry as uracil the drug inhibits RNA replication enzymes, thereby eliminating RNA synthesis and stopping the growth of cancerous cells.
			Common (> 1% frequency):{{div col|colwidth=18em}}
			* Nausea
			* Vomiting
			* Diarrhea (see below for details)
			* ]
			* Headache
			* ]
			* Myelosuppression (see below for details)
			* Alopecia (hair loss)
			* Photosensitivity
			* Maculopapular eruption
			* Itch
			* Cardiotoxicity (see below for details)
			* Persistent ]<ref>{{cite web | url = http://medsfacts.com/study-5FU%28FLUOROURACIL%29-causing-HICCUPS.php | work = MedsFacts | title = Meta-analysis covering adverse side effect reports of 5fu(fluorouracil) patients who developed hiccups | archive-url = https://web.archive.org/web/20140905143353/http://medsfacts.com/study-5FU%28FLUOROURACIL%29-causing-HICCUPS.php | archive-date=5 September 2014 }}</ref>
			* Mood disorders (irritability, anxiety, depression)
			{{div col end}}
			Uncommon (0.1–1% frequency):
	== Mode of action ==
			{{div col|colwidth=18em}}
	As a ] analogue, it is transformed inside the cell into different cytotoxic metabolites which are then incorporated into ] and ], finally inducing ] arrest and ] by inhibiting the cell's ability to synthesize DNA. It is an ] specific drug and only active during certain cell cycles. In addition to being incorporated in DNA and RNA, the drug has been shown to inhibit the activity of the ], an ] complex of which the activity is essential for cell survival.
			* ]
			* GI ulceration and bleeding
			* ]
			* Nail disorders
			* Vein pigmentation
			* Confusion
			* Cerebellar syndrome
			* ]
			* Visual changes
			* ]
			* Lacrimation (the expulsion of tears without any emotional or physiologic reason)
			{{div col end}}
			Rare (< 0.1% frequency):
	] is a ] that is converted into 5-FU in the tissues. It can be administered orally.
			* ]
			* Allergic reactions
			* Fever without signs of infection
			* Mania, reversible dementia<ref>{{cite journal | vauthors = Ha JH, Hwang DY, Yu J, Park DH, Ryu SH | title = Onset of Manic Episode during Chemotherapy with 5-Fluorouracil | journal = Psychiatry Investigation | volume = 8 | issue = 1 | pages = 71–73 | date = March 2011 | pmid = 21519541 | pmc = 3079190 | doi = 10.4306/pi.2011.8.1.71 }}</ref><ref>Park H. J., Choi Y. T., Kim I. H., Hah J. C.; A case of reversible dementia associated with depression in a patient on 5-FU or its analogue drugs. J. Korean Neuropsychiatr. Assoc. 1987;30:199–202.</ref>
			Diarrhea is severe and may be dose-limiting and is exacerbated by co-treatment with ].<ref name = AMH/> ] tends to peak about 9–14 days after beginning treatment.<ref name = AMH/> ] tends to peak about 7–17 days after the beginning of treatment and tends to recover about 10 days after its peak.<ref name = AMH/> ] is a fairly common side effect, usually manifesting as ] or symptoms associated with ], but about 0.55% of those receiving the drug will develop life-threatening cardiotoxicity.<ref name="MD">{{cite web|title=Fluorouracil: Martindale: The Complete Drug Reference|date=9 January 2017|url=https://www.medicinescomplete.com/mc/martindale/current/1836-x.htm|access-date=14 August 2017| veditors = Brayfield A |publisher=Pharmaceutical Press|website=MedicinesComplete|location=London, UK|archive-date=28 August 2021|archive-url=https://web.archive.org/web/20210828090019/https://about.medicinescomplete.com/wp-content/plugins/revslider/public/assets/js/extensions/revolution.extension.slideanims.min.js?version=5.4.5|url-status=live}}</ref> Life-threatening cardiotoxicity includes: ], ] and ], secondary to transmural ischaemia.<ref name="MD"/>
	== Adverse effects ==
	]s include ], ], ], ] and ].
			===During topical use===
	5-FU injection and topical even in small doses cause both acute ] damage and progressively worsening delayed degeneration of the CNS in mice. This latter effect is caused by 5-FU-induced damage to the ] that produce the insulating ] sheaths.<ref> by Dr. Mark D. Noble, University of Rochester</ref>
			Common (> 1% frequency):<ref name = AMH/><ref name=MSRT>{{cite web|title=Efudex, Carac (fluorouracil topical) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=24 January 2014|url=http://reference.medscape.com/drug/efudex-carac-fluorouracil-topical-343545#showall|url-status=live|archive-url=https://web.archive.org/web/20140202174906/http://reference.medscape.com/drug/efudex-carac-fluorouracil-topical-343545#showall|archive-date=2 February 2014}}</ref>
			{{div col|colwidth=18em}}
			* Local pain
			* Itchiness
			* Burning
			* Stinging
			* Crusting
			* Weeping
			* Dermatitis
			* Photosensitivity
			{{div col end}}
			Uncommon (0.1–1% frequency):
	When using a pyrimidine-based drug, users must be aware that some people have a genetic inability to metabolize them. Current theory points to nearly 8% of the population having what is termed ]. There are laboratory tests to determine the relative activity of the DPD enzyme. Many labs offer DPD testing: Laboratory Corporation of America was one of the first to make the test available commercially on a large scale (Test Number 511176). ] in ] also offers a test. In addition to full sequence analysis of the DPYD gene, Myriad performs an analysis of the TYMS gene which accounts for moderate gastrointestinal toxicities. Coventry Diagnostics in ] and DNAVision (]) have quantitative analyses. GenPath diagnostics in ] is also offering this test as a part of their pharmacogenomics effort. Additionally, EntroGen now offers genotyping reagents to clinical laboratories interested in developing an in-house DPYD mutation screen. It is expected that with a potential 500,000 people in North America using the pyrimidine-based 5-FU, this form of testing will increase.
			* Hyper- or hypopigmentation
			* Scarring
			===Neurological damage===
	The typical starting dose of capecitabine is 2,500&nbsp;mg/m2 per day in Europe and 2,000&nbsp;mg/m2 per day in the US. Probably the main action of 5-FU occurs when a 5-FU metabolite binds to thymidylate synthase. This binding is stable only in the presence of methylenetetrahydrofolate. It is speculated that this may explain why people in the US—a country that mandates adding folic acid to some foods—apparently require a lower dose of capecitabine than people in Europe—countries that do not mandate added folic acid.<ref>{{cite journal |author=Midgley R, Kerr DJ |title=Capecitabine: have we got the dose right? |journal=Nat Clin Pract Oncol |volume=6 |issue=1 |pages=17–24 |year=2009 |month=January |pmid=18936793 |doi=10.1038/ncponc1240 |url=http://www.nature.com/nrclinonc/journal/v6/n1/full/ncponc1240.html}}
			The United States package insert warns that acute cerebellar syndrome has been observed following injection of fluorouracil and may persist after cessation of treatment. Symptoms include ], ], and ].<ref>{{cite web|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=e0794add-67a7-4308-93e9-f889472716cc|title=Adrucil (Fluorouracil) Injection |url-status=live|archive-url=https://web.archive.org/web/20140814024152/http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=e0794add-67a7-4308-93e9-f889472716cc|archive-date=14 August 2014}}</ref>
	</ref><ref>{{cite web |author=Midgley, Rachel |title=Regional Variation in Capecitabine Metabolism and Toxicity |publisher=Medscape.com |url=http://www.medscape.com/viewarticle/583704_3}}
	</ref>
			==Potential overdose==
	The body converts both folic acid and ] to methylenetetrahydrofolate.
			There is very little difference between the minimum effective dose and maximum tolerated dose of 5-FU, and the drug exhibits marked individual pharmacokinetic variability.<ref name="dose monitoring">{{cite journal | vauthors = Gamelin E, Boisdron-Celle M | title = Dose monitoring of 5-fluorouracil in patients with colorectal or head and neck cancer--status of the art | journal = Critical Reviews in Oncology/Hematology | volume = 30 | issue = 1 | pages = 71–79 | date = March 1999 | pmid = 10439055 | doi = 10.1016/s1040-8428(98)00036-5 }}</ref><ref name="dosing strategies">{{cite journal | vauthors = Felici A, Verweij J, Sparreboom A | title = Dosing strategies for anticancer drugs: the good, the bad and body-surface area | journal = European Journal of Cancer | volume = 38 | issue = 13 | pages = 1677–1684 | date = September 2002 | pmid = 12175683 | doi = 10.1016/s0959-8049(02)00151-x }}</ref><ref name="role of body">{{cite journal | vauthors = Baker SD, Verweij J, Rowinsky EK, Donehower RC, Schellens JH, Grochow LB, Sparreboom A | title = Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001 | journal = Journal of the National Cancer Institute | volume = 94 | issue = 24 | pages = 1883–1888 | date = December 2002 | pmid = 12488482 | doi = 10.1093/jnci/94.24.1883 | doi-access = free }}</ref> Therefore, an identical dose of 5-FU may result in a therapeutic response with acceptable toxicity in some patients and unacceptable and possibly life-threatening toxicity in others.<ref name="dose monitoring"/> Both overdosing and underdosing are of concern with 5-FU, although several studies have shown that the majority of colorectal cancer patients treated with 5-FU are underdosed based on today's dosing standard, body surface area (BSA).<ref name="dose adjustment">{{cite journal | vauthors = Capitain O, Asevoaia A, Boisdron-Celle M, Poirier AL, Morel A, Gamelin E | title = Individual fluorouracil dose adjustment in FOLFOX based on pharmacokinetic follow-up compared with conventional body-area-surface dosing: a phase II, proof-of-concept study | journal = Clinical Colorectal Cancer | volume = 11 | issue = 4 | pages = 263–267 | date = December 2012 | pmid = 22683364 | doi = 10.1016/j.clcc.2012.05.004 }}</ref><ref name="body surface area">{{cite journal | vauthors = Saam J, Critchfield GC, Hamilton SA, Roa BB, Wenstrup RJ, Kaldate RR | title = Body surface area-based dosing of 5-fluoruracil results in extensive interindividual variability in 5-fluorouracil exposure in colorectal cancer patients on FOLFOX regimens | journal = Clinical Colorectal Cancer | volume = 10 | issue = 3 | pages = 203–206 | date = September 2011 | pmid = 21855044 | doi = 10.1016/j.clcc.2011.03.015 }}</ref><ref name="multicenter evaluation">{{cite journal | vauthors = Beumer JH, Boisdron-Celle M, Clarke W, Courtney JB, Egorin MJ, Gamelin E, Harney RL, Hammett-Stabler C, Lepp S, Li Y, Lundell GD, McMillin G, Milano G, Salamone SJ | title = Multicenter evaluation of a novel nanoparticle immunoassay for 5-fluorouracil on the Olympus AU400 analyzer | journal = Therapeutic Drug Monitoring | volume = 31 | issue = 6 | pages = 688–694 | date = December 2009 | pmid = 19935361 | doi = 10.1097/FTD.0b013e3181b9b8c0 | s2cid = 220558482 }}</ref><ref>{{cite journal | vauthors = Goldberg RM, Rothenberg ML, Van Cutsem E, Benson AB, Blanke CD, Diasio RB, Grothey A, Lenz HJ, Meropol NJ, Ramanathan RK, Becerra CH, Wickham R, Armstrong D, Viele C | title = The continuum of care: a paradigm for the management of metastatic colorectal cancer | journal = The Oncologist | volume = 12 | issue = 1 | pages = 38–50 | date = January 2007 | pmid = 17227899 | doi = 10.1634/theoncologist.12-1-38 | s2cid = 21638678 | doi-access = free }}</ref> The limitations of BSA-based dosing prevent oncologists from being able to accurately titer the dosage of 5-FU for the majority of individual patients, which results in sub-optimal treatment efficacy or excessive toxicity.<ref name="dose adjustment"/><ref name="body surface area"/>
	Each of those precursors amplify the effect of 5-FU in one animal study.<ref>
	{{cite journal |author=Raghunathan K, Priest DG |title=Modulation of fluorouracil antitumor activity by folic acid in a murine model system |journal=Biochem. Pharmacol. |volume=58 |issue=5 |pages=835–9 |year=1999 |month=September |pmid=10449194 |url=http://linkinghub.elsevier.com/retrieve/pii/S0006-2952(99)00157-4 |doi=10.1016/S0006-2952(99)00157-4}}
	</ref> However, another animal study seemed to indicate that, given the same 5-FU treatment, that a special diet containing no folic acid (0 ppm) worked better than the normal diet.<ref>
	{{cite journal |author=Tucker JM, Davis C, Kitchens ME, ''et al.'' |title=Response to 5-fluorouracil chemotherapy is modified by dietary folic acid deficiency in Apc(Min/+) mice |journal=Cancer Lett. |volume=187 |issue=1–2 |pages=153–62 |year=2002 |month=December |pmid=12359363 |url=http://linkinghub.elsevier.com/retrieve/pii/S0304383502004020 |doi=10.1016/S0304-3835(02)00402-0}}</ref>
			Numerous studies have found significant relationships between concentrations of 5-FU in blood plasma and both desirable or undesirable effects on patients.<ref>{{cite journal | vauthors = Ploylearmsaeng SA, Fuhr U, Jetter A | title = How may anticancer chemotherapy with fluorouracil be individualised? | journal = Clinical Pharmacokinetics | volume = 45 | issue = 6 | pages = 567–592 | year = 2006 | pmid = 16719540 | doi = 10.2165/00003088-200645060-00002 | s2cid = 36534309 }}</ref><ref>{{cite journal | vauthors = van Kuilenburg AB, Maring JG | title = Evaluation of 5-fluorouracil pharmacokinetic models and therapeutic drug monitoring in cancer patients | journal = Pharmacogenomics | volume = 14 | issue = 7 | pages = 799–811 | date = May 2013 | pmid = 23651027 | doi = 10.2217/pgs.13.54 }}</ref> Studies have also shown that dosing based on the concentration of 5-FU in plasma can greatly increase desirable outcomes while minimizing negative side effects of 5-FU therapy.<ref name="dose adjustment"/><ref name="individual fluorouracil">{{cite journal | vauthors = Gamelin E, Delva R, Jacob J, Merrouche Y, Raoul JL, Pezet D, Dorval E, Piot G, Morel A, Boisdron-Celle M | title = Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial of patients with metastatic colorectal cancer | journal = Journal of Clinical Oncology | volume = 26 | issue = 13 | pages = 2099–2105 | date = May 2008 | pmid = 18445839 | doi = 10.1200/jco.2007.13.3934 | s2cid = 9557055 | doi-access = free }}</ref> One such test that has been shown to successfully monitor 5-FU plasma levels and which "may contribute to improved efficacy and safety of commonly used 5-FU-based chemotherapies" is the My5-FU test.<ref name="multicenter evaluation"/><ref>{{cite web|url=http://Mycaretests.com|title=Customizing Chemotherapy for Better Cancer Care|publisher=MyCare Diagnostics|url-status=dead|archive-url=https://web.archive.org/web/20140428135326/http://www.mycaretests.com/|archive-date=28 April 2014}}</ref><ref>{{cite web|url=http://bettercancercare.com|title=A Brief History of BSA Dosing|publisher=MyCare Diagnostics|url-status=live|archive-url=https://web.archive.org/web/20140428195606/http://bettercancercare.com/|archive-date=28 April 2014}}</ref>
	Folic acid may amplify the desired action and the toxicity of 5-FU.
	The exact mechanism of interaction is unknown.<ref></ref>
			==Dangers to pets==
	When 5-FU is given ], it is typically mixed with ] in order to increase 5-FU activity. Folic acid may work as well as leucovorin, but the one human study performed (with a high dose of folic acid, from 40&nbsp;mg/m<sup>2</sup> to 140&nbsp;mg/m<sup>2</sup>) had disappointing results and concluded that further studies were needed.<ref> by Joseph I. Boullata, Vincent T. Armenti, 2007, p.207, 208</ref> There is some confusion about whether the amount of folic acid in a normal diet and multivitamins is enough to interact badly with 5-FU.<ref></ref>
			The ] has highlighted the dangers of inadvertent administration to pets.<ref>{{Cite web | work = Office of the Commissioner |date=2024-08-09 |title=Fluorouracil and Pet Safety |url=https://www.fda.gov/consumers/consumer-updates/fluorouracil-and-pet-safety | publisher = U.S. Food and Drug Administration (FDA) |language=en}}</ref> While fluorouracil is sometimes used off label to treat horses, it's administration to dogs in particular can be fatal.
			The FDA reports that it has received 20 reports of fatal outcomes in dogs following accidental ingestion of topical fluorouracil.<ref>{{Cite web | work = Center for Veterinary Medicine |date=2024-11-22 |title=Don't Expose Pets to Prescription Topical Fluorouracil Medicine for People |url=https://www.fda.gov/animal-veterinary/animal-health-literacy/dont-expose-pets-prescription-topical-fluorouracil-medicine-people#:~:text=When%20applying%20fluorouracil%20cream%20or,very%20sick%20and%20possibly%20die. | publisher = U.S. Food and Drug Administration (FDA) |language=en}}</ref>
	One study showed that 79 percent of the patients who switched from 5-FU (with leucovorin) to Xeloda (]) had serious side effects. None of the patients who switched from Xeloda to 5-FU (with leucovorin) had serious side effects. The researchers were unsure of why.<ref>
	</ref>
			== Interactions ==
	Trissel and colleagues have shown that 5-FU and leucovorin are physically incompatible when mixed in portable-pump reservoirs. <ref>{{cite journal |author=Trissel LA, Martinez JF, Xu QA |title=Incompatibility of fluorouracil with leucovorin calcium or levoleucovorin calcium |journal=Am J Health Syst Pharm |volume=52 |issue=7 |pages=710–5 |year=1995 |month=April |pmid=7627739 }}</ref> Similarly, infusion of 5-FU and leucovorin via permanent indwelling catheters is complicated by catheter blockage due to calcium carbonate formation (Ardalan and Flores, 1995). <ref>{{cite journal |author=Ardalan B, Flores MR |title=A new complication of chemotherapy administered via permanent indwelling central venous catheter |journal=Cancer |volume=75 |issue=8 |pages=2165–8 |year=1995 |month=April |pmid=7697607 |doi=10.1002/1097-0142(19950415)75:8<2165::AID-CNCR2820750821>3.0.CO;2-W }}</ref>
			It may increase the INR and prothrombin times in people on ].<ref name = EMC/> Fluorouracil's efficacy is decreased when used alongside ], which can be used to decrease fluorouracil induced stomatitis through use of allopurinol mouthwash.<ref name="pmid8192112">{{cite journal | vauthors = Porta C, Moroni M, Nastasi G | title = Allopurinol mouthwashes in the treatment of 5-fluorouracil-induced stomatitis | journal = American Journal of Clinical Oncology | volume = 17 | issue = 3 | pages = 246–247 | date = June 1994 | pmid = 8192112 | doi = 10.1097/00000421-199406000-00014 | s2cid = 26844431 }}</ref>
	== History ==
	In 1954 ] and ] found liver tumors absorbed radioactive ] more readily than normal liver cells. ], who had earlier found that fluorine in ] inhibited a vital enzyme, asked ] and ] at ] to synthesize fluorouracil.<ref>Sneader W. (2005). ''Drug Discovery'', p. 255.</ref> Some credit Heidelberger and Duschinsky with the discovery that 5-fluorouracil markedly inhibited tumors in mice.<ref>{{cite journal |author=Cohen, Seymour |title=50 years ago in cell biology: A virologist recalls his work on cell growth inhibition |journal=The Scientist |date=30 January 2008 |url=http://www.the-scientist.com/news/display/54259/}}</ref> The original 1957 report in Nature has Heidelberger as lead author, along with N.K.Chaudhuri, Peter Danneberg, Dorothy Mooren, Louis Griesbach, Robert Duschinsky, R.J. Schnitzer, E. Pleven, and J. Scheiner.<ref>{{cite journal |author=Heidelberger C, Chaudhuri NK, Danneberg P, ''et al.'' |title=Fluorinated pyrimidines, a new class of tumour-inhibitory compounds |journal=Nature |volume=179 |issue=4561 |pages=663–6 |year=1957 |month=March |pmid=13418758 |doi=10.1038/179663a0 }}</ref>
			==Pharmacology==
	== Interactive pathway map ==
			===Pharmacogenetics===
			The ] (DPD) enzyme is responsible for the detoxifying metabolism of fluoropyrimidines, a class of drugs that includes 5-fluorouracil, ], 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> ]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"/>
			===Mechanism of action===
			5-FU acts in several ways, but principally as a ]. Interrupting the action of this enzyme blocks synthesis of the pyrimidine ], which is a ] required for ]. ] methylates deoxyuridine monophosphate (dUMP) to form ] (dTMP). Administration of 5-FU causes a scarcity in dTMP, so rapidly dividing cancerous cells undergo cell death via ].<ref>{{cite journal | vauthors = Longley DB, Harkin DP, Johnston PG | title = 5-fluorouracil: mechanisms of action and clinical strategies | journal = Nature Reviews. Cancer | volume = 3 | issue = 5 | pages = 330–338 | date = May 2003 | pmid = 12724731 | doi = 10.1038/nrc1074 | s2cid = 4357553 }}</ref> Calcium folinate provides an exogenous source of reduced folinates and hence stabilises the 5-FU-TS complex, hence enhancing 5-FU's cytotoxicity.<ref>{{cite journal | vauthors = Álvarez P, Marchal JA, Boulaiz H, Carrillo E, Vélez C, Rodríguez-Serrano F, Melguizo C, Prados J, Madeddu R, Aranega A | title = 5-Fluorouracil derivatives: a patent review | journal = Expert Opinion on Therapeutic Patents | volume = 22 | issue = 2 | pages = 107–123 | date = February 2012 | pmid = 22329541 | doi = 10.1517/13543776.2012.661413 | s2cid = 2793746 }}</ref>
			==History==
			In 1954, Abraham Cantarow and Karl Paschkis found liver tumors absorbed radioactive ] more readily than did normal liver cells. ], who had earlier found that fluorine in ] inhibited a vital enzyme, asked Robert Duschinsky and Robert Schnitzer at ] to synthesize fluorouracil.<ref>{{cite book | vauthors = Sneader W | title = Drug discovery: a history. | publisher = John Wiley & Sons | date = June 2005 | page = 255 }}</ref> Some credit Heidelberger and Duschinsky with the discovery that 5-fluorouracil markedly inhibited tumors in mice.<ref>{{cite journal | vauthors = Cohen S |title=50 years ago in cell biology: A virologist recalls his work on cell growth inhibition |journal=The Scientist |date=30 January 2008 |url=http://www.the-scientist.com/news/display/54259/ |url-status=live |archive-url=https://web.archive.org/web/20100919181108/http://www.the-scientist.com/news/display/54259/ |archive-date=19 September 2010 }}</ref> The original 1957 report<ref>{{cite journal | vauthors = Chu E |title=Ode to 5-Fluorouracil |journal=Clinical Colorectal Cancer |volume=6 |issue=9 |pages=609 |date=September 2007 |doi=10.3816/CCC.2007.n.029 |url=http://cigjournals.metapress.com/content/b464v2u31594jj28/ |url-status=dead |archive-url=https://archive.today/20120714082218/http://cigjournals.metapress.com/content/b464v2u31594jj28/ |archive-date=14 July 2012 }}</ref><ref>{{cite journal | vauthors = Heidelberger C, Chaudhuri NK, Danneberg P, Mooren D, Griesbach L, Duschinsky R, Schnitzer RJ, Pleven E, Scheiner J | title = Fluorinated pyrimidines, a new class of tumour-inhibitory compounds | journal = Nature | volume = 179 | issue = 4561 | pages = 663–666 | date = March 1957 | pmid = 13418758 | doi = 10.1038/179663a0 | s2cid = 4296069 | bibcode = 1957Natur.179..663H }}</ref>
			In 1958, Anthony R. Curreri, ], Forde A. McIver, Harry A. Waisman, and Charles Heidelberger reported the first clinical findings of 5-FU's activity in cancer in humans.<ref>{{cite journal | vauthors = Jordan VC | title = A Retrospective: On Clinical Studies with 5-Fluorouracil | journal = Cancer Research | volume = 76 | issue = 4 | pages = 767–768 | date = February 2016 | pmid = 26880809 | doi = 10.1158/0008-5472.CAN-16-0150 | url = https://cancerres.aacrjournals.org/content/76/4/767 | access-date = 17 August 2019 | publisher = American Association for Cancer Research | url-status = live | doi-access = free | archive-url = https://web.archive.org/web/20210828090010/https://cancerres.aacrjournals.org/content/76/4/767 | archive-date = 28 August 2021 }}</ref>
			==Natural analogues==
			In 2003, scientists isolated 5-fluorouracil derivatives, closely related compounds, from the marine sponge, ''] fusca'', collected around ] of the ] in the ]. This is significant because fluorine-containing ] are extremely rare.<ref>{{cite journal | vauthors = Xu XH, Yao GM, Li YM, Lu JH, Lin CJ, Wang X, Kong CH | title = 5-Fluorouracil derivatives from the sponge Phakellia fusca | journal = Journal of Natural Products | volume = 66 | issue = 2 | pages = 285–288 | date = February 2003 | pmid = 12608868 | doi = 10.1021/np020034f }}</ref>
			==Interactive pathway map==
	{{FluoropyrimidineActivity WP1601}}		{{FluoropyrimidineActivity WP1601}}
	==References==		==Names==
			The name "fluorouracil" is the ], ], ] name, and ]. The form "5-fluorouracil" is often used; it shows that there is a fluorine atom on the 5th carbon of a ] ring.
			== References ==
	{{reflist}}		{{reflist}}
			== Further reading ==
			{{refbegin}}
			* {{cite book | title=Medical Genetics Summaries | chapter=Fluorouracil Therapy and DPYD Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK395610/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | publisher=] (NCBI) | year=2016 | pmid=28520376 | id=Bookshelf ID: NBK395610 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ }}
			* {{cite journal | vauthors = Latchman J, Guastella A, Tofthagen C | title = 5-Fluorouracil toxicity and dihydropyrimidine dehydrogenase enzyme: implications for practice | journal = Clinical Journal of Oncology Nursing | volume = 18 | issue = 5 | pages = 581–585 | date = October 2014 | pmid = 25253112 | pmc = 5469441 | doi = 10.1188/14.CJON.581-585 }}
			{{refend}}
	== External links ==		== External links ==
			* {{cite web | title=Fluorouracil Topical | website=MedlinePlus | url=https://medlineplus.gov/druginfo/meds/a605010.html }}
	*
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