Ezetimibe

(BAN, USAN, rINN)
Ezetimibe Chemical formula
Synonyms: Ezetimiba; Ézétimibe; Ezetimibum; Sch-58235. (3R,4S)-1-(pFluorophenyl)-3-[(3S)-3-(p-fluorophenyl)-3-hydroxypropyl]-4(p-hydroxyphenyl)-2-azetidinone.
Cyrillic synonym: Эзетимиб.

💊 Chemical information

Chemical formula: C24H21F2NO3 = 409.4.
CAS — 163222-33-1.
ATC — C10AX09.
ATC Vet — QC10AX09.

💊 Adverse Effects and Precautions

Ezetimibe is generally well tolerated. The most common adverse effects include headache, abdominal pain, and diarrhoea; other gastrointestinal disorders, hypersensitivity reactions including rash and angioedema, fatigue, chest pain, and arthralgia have also been reported. Rare adverse effects include raised liver enzymes or hepatitis, pancreatitis, thrombocytopenia, cholelithiasis, and cholecystitis. Myalgia has occurred in patients taking ezetimibe either alone or when added to a statin (see below). Ezetimibe should be stopped if myopathy is suspected or creatine phosphokinase increases significantly. Ezetimibe should be avoided in patients with moderate or severe hepatic impairment.
1. Jacobson TA, et al. Safety considerations with gastrointestinally active lipid-lowering drugs. Am J Cardiol 2007; 99 (Issue 6 suppl 1): 47C–55C
2. Kashani A, et al. Review of side-effect profile of combination ezetimibe and statin therapy in randomized clinical trials. Am J Cardiol 2008; 101: 1606–13.

Effects on the liver.

Ezetimibe may cause an increase in liver enzymes and there have also been reports of acute hepatitis,1sometimes developing after addition of ezetimibe to long-term statin therapy.2,3 Both auto-immune2,3 and cholestatic hepatitis3have been described. In some patients,1,2 symptoms resolved and liver enzymes normalised when ezetimibe was stopped, and in 1 patient a statin was successfully restarted.2 However, of 2 patients who had been receiving ezetimibe and atorvastatin, 1 required treatment with corticosteroids,3 while the other3 had persistent liver changes 4 months later, despite both drugs being stopped in each case.
1. Liu Q, et al. Drug-induced liver injury associated with ezetimibe therapy. Dig Dis Sci 2007; 52: 602–5.
2. van Heyningen C. Drug-induced acute autoimmune hepatitis during combination therapy with atorvastatin and ezetimibe. Ann Clin Biochem 2005; 42: 402–4
3. Stolk MF, et al. Severe hepatic side effects of ezetimibe. Clin Gastroenterol Hepatol 2006; 4: 908–11.

Effects on the pancreas.

Pancreatitis has been reported1 in patients taking ezetimibe. In one case,2 acute pancreatitis developed 2 weeks after starting ezetimibe and resolved when the drug was stopped, suggesting an immunological cause.
1. Adverse Drug Reactions Advisory Committee (ADRAC). Drug induced pancreatitis. Aust Adverse Drug React Bull 2006; 25: 22. Also available at: http://www.tga.gov.au/adr/aadrb/ aadr0612.pdf (accessed 30/05/08
2. Ahmad I, et al. Ezetimibe-induced acute pancreatitis. South Med J 2007; 100: 409–10.

Effects on skeletal muscle.

Muscle disorders such as myalgia and myopathy are well known to occur with lipid regulating drugs such as statins and fibrates and have also been reported with ezetimibe, both alone,1,2 and when added to treatment with statins;1,3 rhabdomyolysis has also occurred, but is rare in patients taking ezetimibe alone. Up to August 2005, the Australian Adverse Drug Reactions Advisory Committee4 had received 44 reports of muscle disorders with ezetimibe, including myalgia, muscle cramp, weakness and pain; in 5 of these cases a statin was also being taken.
1. Simard C, Poirier P. Ezetimibe-associated myopathy in monotherapy and in combination with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Can J Cardiol 2006; 22: 141–4
2. Havranek JM, et al. Monotherapy with ezetimibe causing myopathy. Am J Med 2006; 119: 285–6
3. Fux R, et al. Ezetimibe and statin-associated myopathy. Ann Intern Med 2004; 140: 671–2
4. Adverse Drug Reactions Advisory Committee (ADRAC). Ezetimibe and muscle disorders. Aust Adverse Drug React Bull 2005; 24: 15. Also available at: http://www.tga.health.gov.au/ adr/aadrb/aadr0508.pdf (accessed 30/05/08)

💊 Interactions

Colestyramine reduces the absorption of ezetimibe and should not be given at the same time of day. Ciclosporin has been reported to increase the plasma concentration of ezetimibe (see below) and patients receiving both drugs should be carefully monitored; the effect may be greater in patients with severe renal impairment. An increased INR has been reported in patients given ezetimibe and oral anticoagulants.

Ciclosporin.

Pharmacokinetic studies1 have shown that plasma-ezetimibe concentrations are higher in renal transplant patients taking ciclosporin than in historical controls, and there has been a report2 of a supratherapeutic response to ezetimibe in a heart transplant patient taking ciclosporin. Ezetimibe causes a small increase in plasma-ciclosporin concentrations,3 but the clinical relevance of this is not clear.
1. Bergman AJ, et al. Interaction of single-dose ezetimibe and steady-state cyclosporine in renal transplant patients. J Clin Pharmacol 2006; 46: 328–36
2. Koshman SL, et al. Supratherapeutic response to ezetimibe administered with cyclosporine. Ann Pharmacother 2005; 39: 1561–5
3. Bergman AJ, et al. Effects of ezetimibe on cyclosporine pharmacokinetics in healthy subjects. J Clin Pharmacol 2006; 46: 321–7.

💊 Pharmacokinetics

Ezetimibe is rapidly absorbed when given orally and undergoes extensive conjugation in the small intestine and liver to an active glucuronide metabolite, which is the main circulating form. Both ezetimibe and the glucuronide are more than 90% bound to plasma proteins. Ezetimibe is excreted primarily in the faeces via bile and undergoes enterohepatic recycling; after an oral dose, about 78% is excreted in the faeces, mainly as ezetimibe, and about 11% is excreted in the urine, mainly as the glucuronide. The elimination half-life for both ezetimibe and the glucuronide is about 22 hours.
Ezetimibe is distributed into breast milk in rats.
1.
Kosoglou T, et al. Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin Pharmacokinet 2005; 44: 467–94.

💊 Uses and Administration

Ezetimibe is an inhibitor of intestinal sterol absorption and inhibits the absorption of cholesterol and plant sterols. It is used to reduce total cholesterol, low-density lipoprotein (LDL)-cholesterol, and apolipoprotein B in the management of hyperlipidaemias (below), and to reduce sitosterol and campesterol in patients with homozygous familial sitosterolaemia. It is given orally in a usual dose of 10 mg once daily.
1. Sudhop T, von Bergmann K. Cholesterol absorption inhibitors for the treatment of hypercholesterolaemia. Drugs 2002; 62: 2333–47
2. Mauro VF, Tuckerman CE. Ezetimibe for management of hypercholesterolemia. Ann Pharmacother 2003; 37: 839–48.

Hyperlipidaemias.

Ezetimibe inhibits the absorption of dietary cholesterol1 and, although there is a compensatory increase in cholesterol synthesis in the liver,1 overall plasma LDL-cholesterol concentrations are reduced.2 Ezetimibe may be used alone in the management of hyperlipidaemias but use with lipid regulating drugs that act by reducing cholesterol synthesis may produce additive effects. In patients already taking statins, addition of ezetimibe results in a further reduction in LDLcholesterol,3 which may increase the number of patients achieving lipid targets, or allow lower doses of statins to be used. However, the clinical relevance of this is unclear; a study4 in patients with familial hypercholesterolaemia found no difference in the progression of carotid atherosclerosis (measured by intimamedia thickness) in those given ezetimibe with simvastatin compared with those given simvastatin alone, despite a larger reduction in LDL-cholesterol. Similar effects on LDL-cholesterol have been reported5 for ezetimibe with fibrates. As well as inhibiting cholesterol absorption, ezetimibe also blocks the absorption of plant sterols such as campesterol and sitosterol, and may be effective in patients with sitosterolaemia,6an inherited disorder in which increased absorption of plant sterols leads to premature atherosclerosis.
1. Sudhop T, et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation 2002; 106: 1943–8
2. Knopp RH, et al. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J 2003; 24: 729–41
3. Pearson TA, et al. A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the ezetimibe add-on to statin for effectiveness (EASE) trial. Mayo Clin Proc 2005; 80: 587–95
4. Kastelein JJP, et al. The ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008; 358: 1431–43
5. McKenney JM, et al. Safety and efficacy of long-term co-administration of fenofibrate and ezetimibe in patients with mixed hyperlipidemia. J Am Coll Cardiol 2006; 47: 1584–7
6. Salen G, et al. Ezetimibe effectively reduces plasma plant sterols in patients with sitosterolemia. Circulation 2004; 109: 966–71.

💊 Preparations

Proprietary Preparations

Arg.: Acotral; Alin; Alipas; Cerclerol; Cetrakam; Coracil; Ezetrol; Ixacor; Lipimibe; Nalecol; Sinterol; Trilip; Vadel; Zetia; Austral.: Ezetrol; Austria: Ezetrol; Belg.: Ezetrol; Braz.: Ezetrol; Zetia; Canad.: Ezetrol; Chile: Ezetrol; Zient; Cz.: Ezetrol; Zient; Denm.: Ezetrol; Fin.: Ezetrol; Fr.: Ezetrol; Ger.: Ezetrol; Gr.: Ezetrol; Hong Kong: Ezetrol; Hung.: Ezetrol; India: Ezetib; Ezzicad†; Imbibe; Indon.: Ezetrol; Irl.: Ezetrol; Israel: Ezetrol; Malaysia: Ezetrol; Mex.: Ezetrol; Zient; Neth.: Ezetrol; Norw.: Ezetrol; NZ: Ezetrol; Philipp.: Ezetrol; Port.: Ezetrol; Rus.: Ezetrol (Эзетрол); S.Afr.: Ezetrol; Singapore: Ezetrol; Spain: Ezetrol; Swed.: Ezetrol; Switz.: Ezetrol; Thai.: Ezetrol; UK: Ezetrol; USA: Zetia; Venez.: Ezetrol; Zetia; Zient. Multi-ingredient: Arg.: Alipas Duo; Ampliar Duo; Ateroclar Duo; Labistatin Duo; Liparex Duo; Lipibec Duo; Liponorm Duo; Redusterol Duo; Torimibe; Vasotenal EZ; Vytorin; Austral.: Vytorin; Austria: Inegy; Vytorin; Braz.: Vytorin; Zetsim; Chile: Adacai; Vytorin; Zintrepid; Cz.: Inegy; Fr.: Inegy; Ger.: Inegy; Gr.: Inegy; Vytorin; Hong Kong: Vytorin; Hung.: Inegy; India: Zetitor†; Indon.: Vytorin; Irl.: Inegy; Ital.: Inegy; Vytorin; Malaysia: Vytorin; Mex.: Vytorin; Zintrepid; Neth.: Inegy; Vytorin; Norw.: Inegy; NZ: Vytorin; Philipp.: Vytorin; Port.: Inegy; Singapore: Vytorin; UK: Inegy; USA: Vytorin; Venez.: Adacai; Vytorin; Zintrepid.
Published February 17, 2019.