View source for Ezetimibe

{{Short description|Medication used to treat high cholesterol}}
{{Use dmy dates|date=February 2024}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{infobox drug
| Watchedfields = changed
| verifiedrevid = 461098524
| image = Ezetimibe.svg
| image_class = skin-invert-image
| width = 
| alt = <!-- Clinical data -->
| caption = Above: molecular structure of ezetimibe
Below: 3D representation of an ezetimibe molecule
| image2 = Ezetimibe 3D.png
| pronounce = {{IPAc-en|ɛ|ˈ|z|ɛ|t|ᵻ|m|ɪ|b|,_|-|m|aɪ|b}}
| tradename = Zetia, others
| Drugs.com = {{drugs.com|monograph|ezetimibe}}
| MedlinePlus = a603015
| DailyMedID = Ezetimibe
| pregnancy_AU = B3
| pregnancy_AU_comment = <ref name="Ezetimibe AusPAR">{{cite web | title=AusPAR: Ezetimibe | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/auspar/auspar-ezetimibe | access-date=20 April 2024}}</ref>
| routes_of_administration = [[Oral administration|By mouth]]
| class = [[Cholesterol absorption inhibitor]]
| ATC_prefix = C10
| ATC_suffix = AX09
| ATC_supplemental = {{ATC|C10|BA05}} {{ATC|C10|BA06}} {{ATC|C10|BA02}}
| legal_AU = S4
| legal_AU_comment = <ref name="Ezetimibe AusPAR" />
| legal_CA = Rx-only
| legal_UK = POM
| legal_US = Rx-only
| legal_US_comment = <ref name="Zetia FDA label">{{cite web | title=Zetia- ezetimibe tablet | website=DailyMed | date=26 January 2011 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=582e1593-1e6c-4ce8-8bae-134fbc3a66f0 | access-date=13 August 2022 | archive-date=10 May 2021 | archive-url=https://web.archive.org/web/20210510134732/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=582e1593-1e6c-4ce8-8bae-134fbc3a66f0 | url-status=live }}</ref>

<!--Pharmacokinetic data-->| bioavailability = 35% to 65%
| protein_bound = >90%
| metabolism = Intestinal wall, [[liver]]
| elimination_half-life = 19 h to 30 h
| excretion = Kidney 11%, fecal 78%

<!--Identifiers-->| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 163222-33-1
| PubChem = 150311
| IUPHAR_ligand = 6816
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00973
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 132493
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = EOR26LQQ24
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D01966
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 49040
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1138

<!--Chemical data-->| IUPAC_name = (3''R'',4''S'')-1-(4-fluorophenyl)-3-[(3''S'')-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one
| C = 24
| H = 21
| F = 2
| N = 1
| O = 3
| SMILES = Fc1ccc(cc1)[C@@H](O)CC[C@H]4C(=O)N(c2ccc(F)cc2)[C@@H]4c3ccc(O)cc3
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C24H21F2NO3/c25-17-5-1-15(2-6-17)22(29)14-13-21-23(16-3-11-20(28)12-4-16)27(24(21)30)19-9-7-18(26)8-10-19/h1-12,21-23,28-29H,13-14H2/t21-,22+,23-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = OLNTVTPDXPETLC-XPWALMASSA-N
| melting_point = 164
| melting_high = 166
}}

<!-- Definition and medical uses -->
'''Ezetimibe''', sold under the brand name '''Zetia''' among others, is a [[medication]] used to treat [[high blood cholesterol]] and certain other [[dyslipidemia|lipid abnormalities]].<ref name="Zetia FDA label" /><ref name=AHFS2019>{{cite web |title=Ezetimibe Monograph for Professionals |url=https://www.drugs.com/monograph/ezetimibe.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=13 April 2019 |archive-date=17 June 2019 |archive-url=https://web.archive.org/web/20190617034725/https://www.drugs.com/monograph/ezetimibe.html |url-status=live }}</ref> Generally it is used together with dietary changes and a [[statin]].<ref name=BNF76/> Alone, it is less preferred than a statin.<ref name=AHFS2019/> It is taken [[Oral administration|by mouth]].<ref name=AHFS2019/> It is also available in the [[fixed-dose]] combinations [[ezetimibe/simvastatin]],<ref>{{cite web | title=Vytorin- ezetimibe and simvastatin tablet | website=DailyMed | date=1 June 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=89b860d2-de83-468e-b7e8-76aeec2edca2 | access-date=13 August 2022 | archive-date=14 August 2022 | archive-url=https://web.archive.org/web/20220814023845/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=89b860d2-de83-468e-b7e8-76aeec2edca2 | url-status=live }}</ref> [[ezetimibe/atorvastatin]],<ref>{{cite web | title=Liptruzet (ezetimibe and atorvastatin) tablets for oral useInitial U.S. Approval: 2013 | website=DailyMed | date=30 September 2016 | url=https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=257849 | access-date=13 August 2022 | archive-date=14 August 2022 | archive-url=https://web.archive.org/web/20220814023846/https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=257849 | url-status=live }}</ref> [[ezetimibe/rosuvastatin]],<ref name=AHFS2019/><ref>{{cite web | title=Roszet- rosuvastatin and ezetimibe tablet Roszet (- rosuvastatin and ezetimibe tablet | website=DailyMed | date=15 September 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1653b3c4-2b2a-408b-918a-c687918c6265 | access-date=13 August 2022 | archive-date=14 August 2022 | archive-url=https://web.archive.org/web/20220814023845/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1653b3c4-2b2a-408b-918a-c687918c6265 | url-status=live }}</ref> and [[ezetimibe/bempedoic acid]].<ref>{{cite web | title=Nexlizet- bempedoic acid and ezetimibe tablet, film coated | website=DailyMed | date=24 September 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3fa2108c-0300-47b8-9d34-f762af7c93c6 | access-date=13 August 2022}}</ref>

<!-- Side effects and mechanisms -->
The most commonly reported adverse events include [[upper respiratory tract infections]], joint pain, diarrhea, and tiredness.<ref name=AHFS2019/> Serious side effects may include [[anaphylaxis]], [[liver problems]], depression, and muscle breakdown.<ref name=AHFS2019/><ref name=BNF76/> Use in [[pregnancy]] and [[breastfeeding]] is of unclear safety.<ref>{{cite web |title=Ezetimibe (Zetia) Use During Pregnancy |url=https://www.drugs.com/pregnancy/ezetimibe.html |website=Drugs.com |access-date=13 April 2019 |archive-date=13 April 2019 |archive-url=https://web.archive.org/web/20190413032023/https://www.drugs.com/pregnancy/ezetimibe.html |url-status=live }}</ref> Ezetimibe works by [[cholesterol absorption inhibitor|decreasing cholesterol absorption]] in the [[intestine]]s.<ref name=BNF76>{{cite book|title=British national formulary : BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=9780857113382|pages=196|edition=76}}</ref>

<!-- History and culture -->
Ezetimibe was approved for medical use in the United States in 2002.<ref name="AHFS2019"/> It is available as a [[generic medication]].<ref name=BNF76/> In 2023, it was the 70th most commonly prescribed medication in the United States, with more than 9{{nbsp}}million prescriptions.<ref name="Top300Drugs">{{cite web | title=Top 300 of 2023 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=12 August 2025 | archive-date=12 August 2025 | archive-url=https://web.archive.org/web/20250812130026/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Ezetimibe Drug Usage Statistics, United States, 2013 - 2023 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Ezetimibe | access-date = 18 August 2025 }}</ref>

==Medical uses==
Several treatment guidelines recommend adding ezetimibe in select high risk persons in whom LDL goals cannot be achieved by maximally tolerated statin alone.<ref name="AlenghatDavis2019">{{cite journal | vauthors = Alenghat FJ, Davis AM | title = Management of Blood Cholesterol | journal = JAMA | volume = 321 | issue = 8 | pages = 800–801 | date = February 2019 | pmid = 30715135 | pmc = 6679800 | doi = 10.1001/jama.2019.0015 }}</ref><ref>{{cite journal | vauthors = Catapano AL, Reiner Z, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, Chapman M, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF, Wood D | display-authors = 6 | title = ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) | journal = Atherosclerosis | volume = 217 | issue = 1 | pages = 3–46 | date = July 2011 | pmid = 21882396 | doi = 10.1016/j.atherosclerosis.2011.06.011 }}</ref><ref>{{cite journal | vauthors = Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K, Iida M, Kihara S, Kinoshita M, Maruyama C, Ohta T, Okamura T, Yamashita S, Yokode M, Yokote K | display-authors = 6 | title = Executive summary of the Japan Atherosclerosis Society (JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan -2012 version | journal = Journal of Atherosclerosis and Thrombosis | volume = 20 | issue = 6 | pages = 517–523 | year = 2013 | pmid = 23665881 | doi = 10.5551/jat.15792 | doi-access = free | title-link = doi }}</ref><ref>{{cite web |url=http://www.nice.org.uk/Guidance/CG181++++ |title=Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease &#124; Guidance and guidelines &#124; NICE |archive-url=https://web.archive.org/web/20141119180833/http://www.nice.org.uk/guidance/CG181 |archive-date=19 November 2014 |url-status=dead }}</ref><ref>{{cite journal | title = An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia--full report | journal = Journal of Clinical Lipidology | volume = 8 | issue = 1 | pages = 29–60 | year = 2014 | pmid = 24528685 | doi = 10.1016/j.jacl.2013.12.005 | doi-access = free | title-link = doi | vauthors = Grundy SM, Arai H, Barter P, Bersot TP, Betteridge DJ, Carmena R | collaboration=Expert Dyslipidemia Panel of the International Atherosclerosis Society | hdl = 11655/15470 | hdl-access = free }}</ref>

Adding ezetimibe to statin treatment of [[high blood cholesterol]] has no effect on overall mortality or cardiovascular mortality, although it significantly reduces the risk of [[myocardial infarction]] and [[stroke]].<ref>{{cite journal | vauthors = Savarese G, De Ferrari GM, Rosano GM, Perrone-Filardi P | title = Safety and efficacy of ezetimibe: A meta-analysis | journal = International Journal of Cardiology | volume = 201 | pages = 247–252 | date = December 2015 | pmid = 26301648 | doi = 10.1016/j.ijcard.2015.08.103 }}</ref> Combining ezetimibe with simvastatin had no effect on overall mortality but did lower the risk of heart attack or stroke in people with prior [[acute coronary syndrome|heart attack]].<ref name=Phan/><ref>{{cite journal | vauthors = Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, De Ferrari GM, Ruzyllo W, De Lucca P, Im K, Bohula EA, Reist C, Wiviott SD, Tershakovec AM, Musliner TA, Braunwald E, Califf RM | display-authors = 6 | title = Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes | journal = The New England Journal of Medicine | volume = 372 | issue = 25 | pages = 2387–2397 | date = June 2015 | pmid = 26039521 | doi = 10.1056/NEJMoa1410489 | hdl-access = free | hdl = 11573/1150638 | doi-access = free | title-link = doi }}</ref> 

Initiation of ezetimibe along with high-intensity statin therapy at the time of an acute coronary syndrome (ACS) event was associated with significantly better cholesterol reduction at day 7, 1-month, 3-months, and 1-year post-ACS event; which translated into significantly lower recurrent cardiovascular events (death from any cause, major ACS, non-fatal stroke, non-fatal myocardial infarction, and ischemic stroke) post the index event of ACS. <ref>{{cite journal | vauthors = Mahajan K, Nagendra L, Dhall A, Dutta D | title = Impact of early initiation of ezetimibe in patients with acute coronary syndrome: A systematic review and meta-analysis. | journal = Eur J Intern Med | date = Feb 2024 | volume = 124 | pages = S0953-6205(24)00049-9 | pmid = 38336550 | doi = 10.1016/j.ejim.2024.02.004 | doi-access = free }}</ref>

Ezetimibe is indicated in the United States as an add-on to dietary measures to reduce levels of certain [[lipids]] in people with:<ref name="Zetia FDA label" />
*Primary [[hyperlipidemia]], alone or with a statin
*Mixed hyperlipidemia, in combination with [[fenofibrate]]
*[[Homozygous]] [[familial hypercholesterolemia]], in combination with specific statins
*Homozygous [[sitosterolemia]]

A 2018 review found that ezetimibe used as sole treatment slightly lowered plasma levels of [[lipoprotein(a)]], but the effect was not large enough to be important.<ref>{{cite journal | vauthors = Awad K, Mikhailidis DP, Katsiki N, Muntner P, Banach M | title = Effect of Ezetimibe Monotherapy on Plasma Lipoprotein(a) Concentrations in Patients with Primary Hypercholesterolemia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials | journal = Drugs | volume = 78 | issue = 4 | pages = 453–462 | date = March 2018 | pmid = 29396832 | doi = 10.1007/s40265-018-0870-1 | s2cid = 207489460 }}</ref>

Ezetimibe improves the [[non-alcoholic fatty liver disease]] activity score but the available evidence indicates it does not improve outcomes of hepatic steatosis.<ref>{{cite journal | vauthors = Lee HY, Jun DW, Kim HJ, Oh H, Saeed WK, Ahn H, Cheung RC, Nguyen MH | display-authors = 6 | title = Ezetimibe decreased nonalcoholic fatty liver disease activity score but not hepatic steatosis | journal = The Korean Journal of Internal Medicine | volume = 34 | issue = 2 | pages = 296–304 | date = March 2019 | pmid = 29551054 | pmc = 6406097 | doi = 10.3904/kjim.2017.194 }}</ref>

==Contraindications==
The two contraindications to taking ezetimibe are a previous allergic reaction to it, including symptoms of rash, [[angioedema]], [[anaphylaxis]], and severe liver disease, especially when taken with a statin.<ref name=MedlinePlus>{{cite web | publisher = U.S. National Library of Medicine, National Institutes of Health, U.S. Department of Health and Human Services. | date = 27 October 2014 | url = https://www.medlineplus.gov/druginfo/meds/a603015.html | work = Medline Plus | title = Ezetimibe | access-date = 21 March 2018 | archive-date = 5 July 2016 | archive-url = https://web.archive.org/web/20160705112630/https://www.nlm.nih.gov/medlineplus/druginfo/meds/a603015.html | url-status = live }}</ref>

Ezetimibe may have significant medication interactions with [[ciclosporin]] and with [[fibrate]]s other than [[fenofibrate]].<ref name="Zetia FDA label" />

==Adverse effects==
Common [[adverse drug reaction]]s (≥1% of patients) associated with ezetimibe therapy include headache and/or diarrhea ([[steatorrhea]]). Infrequent adverse effects (0.1–1% of patients) include [[myalgia]] and/or raised [[liver function test]] ([[alanine aminotransferase|ALT]]/[[aspartate aminotransferase|AST]]) results. Rarely (<0.1% of patients), [[hypersensitivity]] reactions (rash, [[angioedema]]) or [[myopathy]] may occur.<ref name="Zetia FDA label" /> Cases of muscle problems (myalgia and [[rhabdomyolysis]]) have been reported and are included as warnings on the label for ezetimibe.<ref name="Zetia FDA label" />

Since [[NPC1L1]] also regulates [[vitamin K]] uptake, the use of ezetimibe can lead to side effects in [[warfarin]] therapy.<ref>{{cite journal |vauthors = Takada T, Yamanashi Y, Konishi K, Yamamoto T, Toyoda Y, Masuo Y, Yamamoto H, Suzuki H |display-authors = 6 |title = NPC1L1 is a key regulator of intestinal vitamin K absorption and a modulator of warfarin therapy |journal = Science Translational Medicine |volume = 7 |issue = 275 |pages = 275ra23 |date = February 2015 |pmid = 25696002 |doi = 10.1126/scitranslmed.3010329 |s2cid = 5951911}}</ref>

==Overdose==
The incidence of overdose with ezetimibe is rare; subsequently, few data exist on the effects of overdose. However, an acute overdose of ezetimibe is expected to produce an exaggeration of its usual effects, leading to [[diarrhea|loose stools]], [[abdominal pain]], and [[Fatigue (medical)|fatigue]].<ref name="Toxnet Zetia">{{cite web|title=Ezetimibe - National Library of Medicine HSDB Database|url=https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+7737|website=toxnet.nlm.nih.gov|publisher=National Library of Medicine|access-date=29 May 2018|archive-date=12 June 2018|archive-url=https://web.archive.org/web/20180612112735/https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+7737|url-status=dead}}</ref>

==Pharmacology==
===Mechanism of action===
Ezetimibe inhibits the absorption of cholesterol from the [[small intestine]] and decreases the amount of cholesterol normally available to liver cells. The lower levels of cholesterol in the liver cells lead them to absorb more cholesterol from circulation thus lowering the levels of circulating cholesterol. It blocks the critical mediator of cholesterol absorption, the [[NPC1L1|Niemann-Pick C1-like 1]] (NPC1L1) protein on the [[gastrointestinal tract]] [[epithelial]] cells, as well as in [[hepatocyte]]s; it blocks [[Alanine aminopeptidase|aminopeptidase N]] and interrupts a [[caveolin 1]]–[[annexin A2]] complex involved in trafficking cholesterol.<ref name=Phan>{{cite journal |vauthors = Phan BA, Dayspring TD, Toth PP |title = Ezetimibe therapy: mechanism of action and clinical update |journal = Vascular Health and Risk Management |volume = 8 |pages = 415–427 |year = 2012 |pmid = 22910633 |pmc = 3402055 |doi = 10.2147/VHRM.S33664 |doi-access = free }}</ref>

===Pharmacokinetics===
Within 4–12 hours of the oral administration of a 10-mg dose to fasting adults, the attained mean ezetimibe peak plasma concentration ([[Cmax (pharmacology)|C<sub>max</sub>]]) was 3.4–5.5&nbsp;ng/ml. Following oral administration, ezetimibe is absorbed and extensively conjugated to a phenolic glucuronide (active metabolite). Mean C<sub>max</sub> (45–71&nbsp;ng/ml) of ezetimibe-glucuronide is attained within 1–2 hours. The concomitant administration of food (high-fat vs. nonfat meals) does not affect the extent of absorption of ezetimibe. However, coadministration with a high-fat meal increases its C<sub>max</sub> by 38%. The absolute [[bioavailability]] cannot be determined, since ezetimibe is insoluble in aqueous media suitable for injection. Ezetimibe and its active metabolites are highly bound to human plasma proteins (90%).<ref name="Zetia FDA label" />

Ezetimibe is primarily metabolized in the liver and the small intestine via glucuronide conjugation with subsequent renal and biliary excretion.<ref>{{cite journal | vauthors = Basha SJ, Naveed SA, Tiwari NK, Shashikumar D, Muzeeb S, Kumar TR, Kumar NV, Rao NP, Srinivas N, Mullangi R, Srinivas NR | display-authors = 6 | title = Concurrent determination of ezetimibe and its phase-I and II metabolites by HPLC with UV detection: quantitative application to various in vitro metabolic stability studies and for qualitative estimation in bile | journal = Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences | volume = 853 | issue = 1–2 | pages = 88–96 | date = June 2007 | pmid = 17442643 | doi = 10.1016/j.jchromb.2007.02.053 }}</ref> Both the parent compound and its active metabolite are eliminated from plasma with a half-life of around 22 hours, allowing for once-daily dosing. Ezetimibe lacks significant inhibitor or inducer effects on [[cytochrome P450]] isoenzymes, which explains its limited number of drug interactions. No dose adjustment is needed in patients with [[chronic kidney disease]] or mild hepatic dysfunction ([[Child-Pugh score]] 5–6). Due to insufficient data, the manufacturer does not recommend ezetimibe for patients with moderate to severe hepatic impairment (Child-Pugh score 7–15). In patients with mild, moderate, or severe hepatic impairment, the mean [[Area under the curve (pharmacokinetics)|AUC]] values for total ezetimibe are increased about 1.7-fold, 3-to-4-fold, and 5-to-6-fold, respectively, compared to healthy subjects.<ref name="Zetia FDA label" />

== References ==
{{Reflist}}

{{Lipid modifying agents}}
{{Merck&Co}}
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[[Category:Lipid-lowering agents]]
[[Category:Beta-lactams]]
[[Category:Drugs developed by Merck & Co.]]
[[Category:4-Fluorophenyl compounds]]
[[Category:4-Hydroxyphenyl compounds]]
[[Category:Drugs developed by Schering-Plough]]
[[Category:Wikipedia medicine articles ready to translate]]