Wikipedia

Ezetimibe

Ezetimibe,sold under the brand nameZetiaamong others, is amedicationused to treathigh blood cholesteroland certain otherlipid abnormalities.[3][4]Generally it is used together with dietary changes and astatin.[5]Alone, it is less preferred than a statin.[4]It is takenby mouth.[4]It is also available in thefixed-dosecombinationsezetimibe/simvastatin,[6]ezetimibe/atorvastatin,[7]ezetimibe/rosuvastatin,[4][8]andezetimibe/bempedoic acid.[9]

Ezetimibe
Clinical data
Pronunciation/ɛˈzɛtɪmɪb,-maɪb/
Trade namesZetia, others
AHFS/Drugs.comMonograph
MedlinePlusa603015
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classCholesterol absorption inhibitor
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability35% to 65%
Protein binding>90%
MetabolismIntestinal wall,liver
Eliminationhalf-life19 h to 30 h
ExcretionKidney 11%, fecal 78%
Identifiers
  • (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.207.996Edit this at Wikidata
Chemical and physical data
FormulaC24H21F2NO3
Molar mass409.433g·mol−1
3D model (JSmol)
Melting point164 to 166 °C (327 to 331 °F)
  • Fc1ccc(cc1)[C@@H](O)CC[C@H]4C(=O)N(c2ccc(F)cc2)[C@@H]4c3ccc(O)cc3
  • InChI=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/s1checkY
  • Key:OLNTVTPDXPETLC-XPWALMASSA-NcheckY
(verify)

The most commonly reported adverse events includeupper respiratory tract infections,joint pain, diarrhea, and tiredness.[4]Serious side effects may includeanaphylaxis,liver problems,depression, and muscle breakdown.[4][5]Use inpregnancyandbreastfeedingis of unclear safety.[10]Ezetimibe works bydecreasing cholesterol absorptionin theintestines.[5]

Ezetimibe was approved for medical use in the United States in 2002.[4]It is available as ageneric medication.[5]In 2022, it was the 79th most commonly prescribed medication in the United States, with more than 8million prescriptions.[11][12]

Medical uses

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Adding ezetimibe to statin treatment ofhigh blood cholesterolhas no effect on overall mortality or cardiovascular mortality, although it significantly reduces the risk ofmyocardial infarctionandstroke.[13]Combining ezetimibe with simvastatin had no effect on overall mortality but did lower the risk of heart attack or stroke in people with priorheart attack.[14][15]Several treatment guidelines recommend adding ezetimibe in select high risk persons in whom LDL goals cannot be achieved by maximally tolerated statin alone.[16][17][18][19][20]

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.[21]

Ezetimibe is indicated in the United States as an add-on to dietary measures to reduce levels of certainlipidsin people with:[3]

A 2018 review found that ezetimibe used as sole treatment slightly lowered plasma levels oflipoprotein(a),but the effect was not large enough to be important.[22]

Ezetimibe improves thenon-alcoholic fatty liver diseaseactivity score but the available evidence indicates it does not improve outcomes of hepatic steatosis.[23]

Contraindications

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The two contraindications to taking ezetimibe are a previous allergic reaction to it, including symptoms of rash,angioedema,andanaphylaxis,and severe liver disease, especially when taken with a statin.[24]

Ezetimibe may have significant medication interactions withciclosporinand withfibratesother thanfenofibrate.[3]

Adverse effects

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Commonadverse drug reactions(≥1% of patients) associated with ezetimibe therapy include headache and/or diarrhea (steatorrhea). Infrequent adverse effects (0.1–1% of patients) includemyalgiaand/or raisedliver function test(ALT/AST) results. Rarely (<0.1% of patients),hypersensitivityreactions (rash,angioedema) ormyopathymay occur.[3]Cases of muscle problems (myalgia andrhabdomyolysis) have been reported and are included as warnings on the label for ezetimibe.[3]

SinceNPC1L1also regulatesvitamin Kuptake, the use of ezetimibe can lead to side effects inwarfarintherapy.[25]

Overdose

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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 toloose stools,abdominal pain,andfatigue.[26]

Pharmacology

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Mechanism of action

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Ezetimibe inhibits the absorption of cholesterol from thesmall intestineand decreases the amount of cholesterol normally available to liver cells. The lower levels of cholesterol in the liver cells leads them to absorb more cholesterol from circulation and thus lowering the levels of circulating cholesterol. It blocks the critical mediator of cholesterol absorption, theNiemann-Pick C1-like 1(NPC1L1) protein on thegastrointestinal tractepithelialcells, as well as inhepatocytes;it blocksaminopeptidase Nand interrupts acaveolin 1–annexin A2complex involved in trafficking cholesterol.[14]

Pharmacokinetics

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Within 4–12 hours of the oral administration of a 10-mg dose to fasting adults, the attained mean ezetimibe peak plasma concentration (Cmax) was 3.4–5.5 ng/ml. Following oral administration, ezetimibe is absorbed and extensively conjugated to a phenolic glucuronide (active metabolite). Mean Cmax(45–71 ng/ml) of ezetimibe-glucuronide is attained within 1–2 hours. The concomitant administration of food (high-fat vs. nonfat meals) has no effect on the extent of absorption of ezetimibe. However, coadministration with a high-fat meal increases its Cmaxby 38%. The absolutebioavailabilitycannot 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%).[3]

Ezetimibe is primarily metabolized in the liver and the small intestine via glucuronide conjugation with subsequent renal and biliary excretion.[27]Both the parent compound and its active metabolite are eliminated from plasma with a half-life around 22 hours, allowing for once-daily dosing. Ezetimibe lacks significant inhibitor or inducer effects oncytochrome P450isoenzymes, which explains its limited number of drug interactions. No dose adjustment is needed in patients withchronic kidney diseaseor mild hepatic dysfunction (Child-Pugh score5–6). 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 meanAUCvalues for total ezetimibe are increased about 1.7-fold, 3-to-4-fold, and 5-to-6-fold, respectively, compared to healthy subjects.[3]

References

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  1. ^ab"AusPAR: Ezetimibe".Therapeutic Goods Administration (TGA).21 June 2022.Retrieved20 April2024.
  2. ^"FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)".nctr-crs.fda.gov.FDA.Retrieved22 October2023.
  3. ^abcdefgh"Zetia- ezetimibe tablet".DailyMed.26 January 2011.Archivedfrom the original on 10 May 2021.Retrieved13 August2022.
  4. ^abcdefg"Ezetimibe Monograph for Professionals".Drugs.com.American Society of Health-System Pharmacists.Archivedfrom the original on 17 June 2019.Retrieved13 April2019.
  5. ^abcdBritish national formulary: BNF 76(76 ed.). Pharmaceutical Press. 2018. p. 196.ISBN9780857113382.
  6. ^"Vytorin- ezetimibe and simvastatin tablet".DailyMed.1 June 2022.Archivedfrom the original on 14 August 2022.Retrieved13 August2022.
  7. ^"Liptruzet (ezetimibe and atorvastatin) tablets for oral useInitial U.S. Approval: 2013".DailyMed.30 September 2016.Archivedfrom the original on 14 August 2022.Retrieved13 August2022.
  8. ^"Roszet- rosuvastatin and ezetimibe tablet Roszet (- rosuvastatin and ezetimibe tablet".DailyMed.15 September 2021.Archivedfrom the original on 14 August 2022.Retrieved13 August2022.
  9. ^"Nexlizet- bempedoic acid and ezetimibe tablet, film coated".DailyMed.24 September 2021.Retrieved13 August2022.
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  11. ^"The Top 300 of 2022".ClinCalc.Archivedfrom the original on 30 August 2024.Retrieved30 August2024.
  12. ^"Ezetimibe Drug Usage Statistics, United States, 2013 - 2022".ClinCalc.Retrieved30 August2024.
  13. ^Savarese G, De Ferrari GM, Rosano GM, Perrone-Filardi P (December 2015). "Safety and efficacy of ezetimibe: A meta-analysis".International Journal of Cardiology.201:247–252.doi:10.1016/j.ijcard.2015.08.103.PMID26301648.
  14. ^abPhan BA, Dayspring TD, Toth PP (2012)."Ezetimibe therapy: mechanism of action and clinical update".Vascular Health and Risk Management.8:415–427.doi:10.2147/VHRM.S33664.PMC3402055.PMID22910633.
  15. ^Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. (June 2015)."Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes".The New England Journal of Medicine.372(25): 2387–2397.doi:10.1056/NEJMoa1410489.hdl:11573/1150638.PMID26039521.{{cite journal}}:CS1 maint: overridden setting (link)
  16. ^Alenghat FJ, Davis AM (February 2019)."Management of Blood Cholesterol".JAMA.321(8): 800–801.doi:10.1001/jama.2019.0015.PMC6679800.PMID30715135.
  17. ^Catapano AL, Reiner Z, De Backer G, Graham I, Taskinen MR, Wiklund O, et al. (July 2011). "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)".Atherosclerosis.217(1): 3–46.doi:10.1016/j.atherosclerosis.2011.06.011.PMID21882396.{{cite journal}}:CS1 maint: overridden setting (link)
  18. ^Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, et al. (2013)."Executive summary of the Japan Atherosclerosis Society (JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan -2012 version".Journal of Atherosclerosis and Thrombosis.20(6): 517–523.doi:10.5551/jat.15792.PMID23665881.{{cite journal}}:CS1 maint: overridden setting (link)
  19. ^"Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease | Guidance and guidelines | NICE".Archived fromthe originalon 19 November 2014.
  20. ^Grundy SM, Arai H, Barter P, Bersot TP, Betteridge DJ, Carmena R, et al. (Expert Dyslipidemia Panel of the International Atherosclerosis Society) (2014)."An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia--full report".Journal of Clinical Lipidology.8(1): 29–60.doi:10.1016/j.jacl.2013.12.005.PMID24528685.
  21. ^Mahajan K, Nagendra L, Dhall A, Dutta D (February 2024)."Impact of early initiation of ezetimibe in patients with acute coronary syndrome: A systematic review and meta-analysis".Eur J Intern Med.124:S0953-6205(24)00049-9.doi:10.1016/j.ejim.2024.02.004.PMID38336550.
  22. ^Awad K, Mikhailidis DP, Katsiki N, Muntner P, Banach M (March 2018). "Effect of Ezetimibe Monotherapy on Plasma Lipoprotein(a) Concentrations in Patients with Primary Hypercholesterolemia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials".Drugs.78(4): 453–462.doi:10.1007/s40265-018-0870-1.PMID29396832.S2CID207489460.
  23. ^Lee HY, Jun DW, Kim HJ, Oh H, Saeed WK, Ahn H, et al. (March 2019)."Ezetimibe decreased nonalcoholic fatty liver disease activity score but not hepatic steatosis".The Korean Journal of Internal Medicine.34(2): 296–304.doi:10.3904/kjim.2017.194.PMC6406097.PMID29551054.{{cite journal}}:CS1 maint: overridden setting (link)
  24. ^"Ezetimibe".Medline Plus.U.S. National Library of Medicine, National Institutes of Health, U.S. Department of Health and Human Services. 27 October 2014.Archivedfrom the original on 5 July 2016.Retrieved21 March2018.
  25. ^Takada T, Yamanashi Y, Konishi K, Yamamoto T, Toyoda Y, Masuo Y, et al. (February 2015). "NPC1L1 is a key regulator of intestinal vitamin K absorption and a modulator of warfarin therapy".Science Translational Medicine.7(275): 275ra23.doi:10.1126/scitranslmed.3010329.PMID25696002.S2CID5951911.{{cite journal}}:CS1 maint: overridden setting (link)
  26. ^"Ezetimibe - National Library of Medicine HSDB Database".toxnet.nlm.nih.gov.National Library of Medicine.Archivedfrom the original on 12 June 2018.Retrieved29 May2018.
  27. ^Basha SJ, Naveed SA, Tiwari NK, Shashikumar D, Muzeeb S, Kumar TR, et al. (June 2007). "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 of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences.853(1–2): 88–96.doi:10.1016/j.jchromb.2007.02.053.PMID17442643.{{cite journal}}:CS1 maint: overridden setting (link)
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