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Ezetimibe

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Ezetimibe
Clinical data
Trade namesZetia
AHFS/Drugs.comMonograph
MedlinePlusa603015
Pregnancy
category
  • AU: C
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability35–65%
Protein binding>90%
MetabolismIntestinal wall, hepatic
Elimination half-life19–30 hours
ExcretionRenal 11%, faecal 78%
Identifiers
  • (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.207.996 Edit this at Wikidata
Chemical and physical data
FormulaC24H21F2NO3
Molar mass409.4 g·mol−1 g·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/s1 checkY
  • Key:OLNTVTPDXPETLC-XPWALMASSA-N checkY
  (verify)

Ezetimibe /ɛˈzɛt[invalid input: 'i-']mɪb/ is a drug that lowers plasma cholesterol levels. It acts by decreasing cholesterol absorption in the small intestine. It may be used alone (marketed as Zetia or Ezetrol), when other cholesterol-lowering medications are not tolerated, or together with statins (e.g., ezetimibe/simvastatin, marketed as Vytorin and Inegy) when statins alone do not control cholesterol.

Until November 2014 when the results of the IMPROVE-IT trial were announced at the annual meeting of the AHA[2] no studies had showed that ezetimibe reduced heart attack, stroke, or death. It failed to slow the progression of atherosclerosis in two trials. There is controversy regarding whether these results are broadly representative of those to be expected in most patients treated with ezetimibe in clinical practice. It is recommended as second line therapy for those intolerant of statins or unable to achieve target LDL cholesterol levels on statins alone by several major medical group practice guidelines, but not by those of the America Heart Association/American College of Cardiology.

Pharmacology

Ezetimibe localises at the brush border of the small intestine, where it inhibits the absorption of cholesterol from the intestine. Specifically, it appears to bind to a critical mediator of cholesterol absorption, the Niemann-Pick C1-like 1 (NPC1L1) protein on the gastrointestinal tract epithelial cells[3] as well as in hepatocytes.[4] In addition to this direct effect, decreased cholesterol absorption leads to an upregulation of LDL-receptors on the surface of cells and an increased LDL-cholesterol uptake into cells, thus decreasing levels of LDL in the blood plasma which contribute to atherosclerosis and cardiovascular events.[5]

Clinical use

Indications

Ezetimibe is indicated as an adjunct to dietary measures in the management of:

On 9 June 2006, US regulators approved the use of ezetimibe in combination with fenofibrate to treat mixed hyperlipidaemia.

Adverse effects

Common adverse drug reactions (≥1% of patients) associated with ezetimibe therapy include: headache and/or diarrhea (steathorrea). Infrequent adverse effects (0.1–1% of patients) include: myalgia and/or raised liver function test (ALT/AST) results. Rarely (<0.1% of patients), hypersensitivity reactions (rash, angioedema) or myopathy may occur.[6]

In 2005, the manufacturer of Ezetrol, Merck Frosst/Schering Pharmaceuticals issued a warning through Health Canada associating Ezetrol (ezetimibe) with "myalgia, rhabdomyolysis, hepatitis, pancreatitis, and thrombocytopenia". Also noted were possible changes in liver function tests as described above and longer clotting times if the patient is currently on warfarin while on the cholesterol-lowering medication.[7]

Additional adverse effects include gastrointestinal disturbances, fatigue, rarely arthralgia; AND very rarely, cholelithiasis, cholecystitis, raised creatine kinase.[8]

Contraindications

The two contraindications to taking ezetimibe are a previous allergic reaction including rash, angioedema, and anaphylaxis, and severe liver disease, especially when taken with a statin. [9]

Efficacy

A clinical study suggests, in combination with statins, Niaspan, a slow-release form of niacin, is more effective than ezetimibe at reducing arterial plaque buildup.[10]

Pharmacokinetics

Ezetimibe is available as 10-mg tablets; the recommended dose is one tablet once daily without regard to meals for all its approved indications. 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 h. 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 the Cmax of ezetimibe by 38%. The absolute bioavailability cannot be determined, since ezetimibe is insoluble in aqueous media suitable for injection. Ezetimibe and its active metabolite are highly bound to human plasma proteins (90%).

Ezetimibe is primarily metabolized in the liver and the small intestine via glucuronide conjugation with subsequent renal and biliary excretion. 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 on cytochrome P-450 isoenzymes, which explains its limited number of drug interactions. No dose adjustment is needed in patients with renal insufficiency 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 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

Patient information

Ezetimibe may be taken with or without food at the same time each day. Colestipol or cholestyramine should not be taken within four hours of ezetimibe . In cases of liver disease, another cholesterol-lowering medication may be more appropriate. Patients who are are pregnant or plan on becoming pregnant should consult their physicians. [11] Additionally, these medications may have significant medication interactions: Cyclosporine, fenofibrate, or other fibrates.[12]

Clinical trial controversy

The utility of ezetimibe as a primary lipid-lowering agent, or in conjunction with statins, is controversial. While clearly efficacious in reducing LDL cholesterol, it has not been demonstrated to have an impact on patient outcomes such mortality or risk of a major cardiovascular event.

Additionally, the ACC guidelines advise physicians to focus on patient cardiovascular risk factors instead of specific LDL levels. Therefore, until ezetimibe is shown to have a measurable clinical impact, it should remain a second-, or more likely, third-line agent, critics say.[13]

The ENHANCE trial of Vytorin (ezetimibe and simvastatin) was designed to show that ezetimibe could reduce the growth of fatty plaques in arteries. While the ENHANCE trial did not have the power to detect significant differences in death, it measured the difference in artery thickness (in the carotid and femoral intima-media) to detect reductions in atherosclerotic plaque. At the end of two years, no significant difference was found in artery thickness between patients taking simvastatin and ezetimibe versus patients taking simvastatin alone.[14] Reviewers of the ENHANCE trial have raised the possibility that it did not last long enough for ezetimibe to work. Also, many patients had already been treated on statins for a long time, so their artery thickness was already lower. Perhaps if they had not used statins, ezetimibe might have had a greater effect.[15] Results from the trial have provoked three large clinical-outcome trials.[16]

The ARBITER-6 trial compared the effiacy of ezetimibe to that of niacin as an add-on to statin therapy. The trial was performed in people with coronary artery disease whose LDL levels were well-controlled by statin monotherapy, but whose HDL levels were lower than recommended by contemporaneous treatment guidelines. The primary outcome measure of the trial was the change in artery wall thickness (a measure of atherosclerosis). The study was stopped early after 14 months, at which point niacin but not ezetimibe had been shown to produce a reduction in artery wall thickness. This result has been interpreted as supporting the finding of no effect of ezetimibe on atherosclerosis progression in the ENHANCE trial. Alternatively, a 2014 review argues that the results of the trial were somewhat predictable given that niacin is a potent HDL raising agent, ezetimibe acts primarily by lowering LDL, and the trial population had normal LDL but low HDL. According to this argument, the results of this trial are not generalizable to those whose LDL levels are not adequately controlled by statins.[17][18] enrolled patients with coronary artery disease, or an equivalent risk condition such as diabetes, who were already taking statins. They were randomized to additionally take either extended-release niacin or ezetimibe, and the primary end point was change in artery wall thickness. Both drugs reduced LDL cholesterol levels. Niacin reduced artery wall thickness, but ezetimibe paradoxically increased artery wall thickness. Patients on ezetimibe also had more major cardiovascular events. The trial was terminated early after 208 volunteers had completed the study.

The SANDS trial compared compared standard care (treat to targeted LDL-C < 100 mg/dL and systolic blood pressure targeted to <130 mm Hg) to aggressive treatment (treat to LDL <70 mg/dL and blood pressure <115 mg Hg) in people with diabetes. Ezetimibe was added on to statin therapy as needed to meet LDL cholesterol targets. The artery wall thickness was compared between the standard treatment group, the aggressive treatment group, and between people receiving statins only vs. a statin plus ezetimibe. The people in this trial had a greater baseline artery wall thickness than those in the ENHANCE trial. As measured by artery wall thickness, atherosclerosis progressed in the standard treatment group but partially regressed in the aggressive therapy group, irrespective of whether LDL lowering was achieved by using a higher statin dose or by adding on ezetimibe. In a multi-variable analysis, the most important predictor of atherosclerosis progression or regression was LDL level.[19]

Until November 2014 when the results of the IMPROVE-IT trial were announced at the annual meeting of the AMA[2] no trial had demonstrated a reduction in cardiovascular events with ezetimibe alone or ezetimibe plus a statin vs. a statin alone. This question was examined in the IMPROVE-IT trial, which compared treatment with ezetimibe vs. placebo on top of a background regimen of intensive statin therapy in people who have had recent episodes of acute coronary syndrome.[20]

As of mid-2014, treatment guidelines of the American Heart Association/American College of Cardiology[21] recommend that people with dyslipidemia be treated with a statin. These guidelines recommend increasing the statin dose in certain populations, but do not recognize target serum cholesterol levels or recommend the use of non-statin cholesterol lowering drugs. Guidelines issued by the European Society of Cardiology/European Atherosclerosis Society,[22] the Japan Atherosclerosis Society,[23] the National Institute for Health and Clinical Excellence,[24] and the International Atherosclerosis Society[25] recommend ezetimibe as one of several second line treatment options for people who are intolerant of statins or who are unable to reach serum LDL goals using statins alone.

Chemical properties

Ezetimibe is highly soluble in alcohols (methanol, ethanol, 1-propanol, 2-propanol, etc.) and insoluble in water.

Degradation behaviour: HPLC studies on ezetimibe under different stress conditions suggested the following degradation behaviour.

  • Acidic condition: The drug gradually decreased with time on heating at 80°C in 1 M HCl by forming degradation products. The rate of hydrolysis in acid was slower as compared to that of alkali or water.
  • Neutral (water) condition: Upon heating, the drug solution in water at 80°C for 1 h, almost complete degradation of the drug was observed.
  • In alkali: The drug was found to be highly labile to alkaline hydrolysis. The reaction in 0.1 M NaOH at 80°C was so fast, all of the drug was degraded in 0 min. Subsequently, studies were performed in 0.01 M NaOH at 40°C and complete degradation of the drug was observed in 4 h.
  • Oxidative conditions: The drug was stable to hydrogen peroxide (3 and 20%) at room temperature.
  • Photolytic conditions: No major degradation product was observed after exposure of drug solution in 1 M HCl to sunlight for 2 d, only minor degradation products were formed. The nature of degradation in light and dark was found to be similar, indicating that light had no effect on the degradation of the drug in acid. However, the samples in water degraded under sunlight for 2 d. Corresponding rate of degradation in dark was much slower.
  • Solid-state study: The solid-state studies showed ezetimibe was stable to the effect of temperature. When the drug powder was exposed to dry heat at 50°C for 45 d and at 60°C for 7 d, no decomposition of the drug was seen.

See also

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ a b "Study Finds Alternative to Statins in Preventing Heart Attacks and Strokes" article by Gina Kolata in The New York Times November 17, 2014
  3. ^ Garcia-Calvo M, Lisnock J, Bull HG, Hawes BE, Burnett DA, Braun MP, et al. The target of ezetimibe is Niemann-Pick C1-like 1 (NPC1L1). Proc Natl Acad Sci U S A 2005;102(23):8132-7. PMID 15928087
  4. ^ Temel, Ryan E., Tang, Weiqing, Ma, Yinyan, Rudel, Lawrence L., Willingham, Mark C., Ioannou, Yiannis A., Davies, Joanna P., Nilsson, Lisa-Mari, Yu, Liqing. Hepatic Niemann-Pick C1-like 1 regulates biliary cholesterol concentration and is a target of ezetimibe J. Clin. Invest. 2007 0: JCI30060
  5. ^ DiPiro JT, Talbert RL, Yee GC, Marzke GR, Wells BG, Posey LM, editors. Pharmacotherapy:a pathophysiologic approach. 7th ed. New York: The McGraw-Hill Companies, Inc.; 2008.
  6. ^ a b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
  7. ^ http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/public/_2005/ezetrol_pa-ap-eng.php
  8. ^ http://www.bnf.org/bnf/bnf/current/128035.htm?q="ezetimibe"#_hit
  9. ^ http://www.nlm.nih.gov/medlineplus/druginfo/meds/a603015.html
  10. ^ Singer, Natasha (November 15, 2009). "Study Raises Questions About Cholesterol Drug's Benefit". The New York Times. Retrieved November 16, 2009.
  11. ^ http://www.nlm.nih.gov/medlineplus/druginfo/meds/a603015.html
  12. ^ http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021445s033lbl.pdf
  13. ^ Mitka M. Ezetimibe prescribing fails to keep up with evidence. JAMA. 2014 Apr 2;311(13):1279-80. doi: 10.1001/jama.2014.2896. PMID 24647479
  14. ^ Kastelein JJP, Akdim F, Stroes ESG, Zwinderman AH, Bots ML, Stalenhoef AFH, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. The New England Journal of Medicine: 2008; 358(14) 1431-1443.
  15. ^ http://www.nejm.org/doi/full/10.1056/NEJMe0801608
  16. ^ Phan BA, Dayspring TD, Toth PP (2012). "Ezetimibe therapy: mechanism of action and clinical update". Vasc Health Risk Manag. 8: 415–27. doi:10.2147/VHRM.S33664. PMC 3402055. PMID 22910633.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  17. ^ Phan BA, Dayspring TD, Toth PP (2012). "Ezetimibe therapy: mechanism of action and clinical update". Vasc Health Risk Manag. 8: 415–27. doi:10.2147/VHRM.S33664. PMC 3402055. PMID 22910633.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  18. ^ Taylor A.J., Villnes T.C., Stanek E.J.; et al. (26 November 2009). "Extended-Release Niacin or Ezetimibe and Carotid Intima-Media Thickness". N Engl J Med. 361 (22): 2113–22. doi:10.1056/NEJMoa0907569. PMID 19915217. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  19. ^ Phan BA, Dayspring TD, Toth PP (2012). "Ezetimibe therapy: mechanism of action and clinical update". Vasc Health Risk Manag. 8: 415–27. doi:10.2147/VHRM.S33664. PMC 3402055. PMID 22910633.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  20. ^ Phan BA, Dayspring TD, Toth PP (2012). "Ezetimibe therapy: mechanism of action and clinical update". Vasc Health Risk Manag. 8: 415–27. doi:10.2147/VHRM.S33664. PMC 3402055. PMID 22910633.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  21. ^ Stone NJ, Robinson JG, Lichtenstein AH; et al. (2014). "2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines". Circulation. 129 (25 Suppl 2): S1–45. doi:10.1161/01.cir.0000437738.63853.7a. PMID 24222016. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  22. ^ Catapano AL, Reiner Z, De Backer G; et al. (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. PMID 21882396. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  23. ^ Teramoto T, Sasaki J, Ishibashi 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". J. Atheroscler. Thromb. 20 (6): 517–23. PMID 23665881. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  24. ^ "Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease | Guidance and guidelines | NICE".
  25. ^ "An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia--full report". J Clin Lipidol. 8 (1): 29–60. 2014. doi:10.1016/j.jacl.2013.12.005. PMID 24528685.
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