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Ezetimib

Klassificering: A

Preparat: Ezetimib Actavis, Ezetimib Aristo, Ezetimib Krka, Ezetimib Medical Valley, Ezetimib Sandoz, Ezetimib STADA, Ezetimib/Simvastatin Krka, Ezetimibe Accord, Ezetimibe Mylan, Ezetimibe Orion, Ezetrol, Ezetrol®, Inegy®

ATC kod: C10AX09, C10BA02

Substanser: ezetimib

Sammanfattning

Randomiserande placebokontrollerade studier visar motsägelsefulla resultat huruvida det finns könsskillnader i sänkning av lipidnivåer hos patienter med hyperkolesterolemi som behandlats med ezetimib i kombination med statin.
 
Vår bedömning är att de beskrivna skillnaderna inte motiverar olika dosering eller behandling hos kvinnor och män.

Additional information

Pharmacokinetics and dosing

Healthy men and women receiving ezetimibe 20 mg for 10 days showed similar pharmacokinetics [1]. However, a study in healthy Chinese patients (6 men, 6 women) receiving a single oral dose of ezetimibe/-simvastatin 10/40 mg showed that ezetimibe AUC was higher in women, and the difference remained even after correction for body weight [2].

The original manufacturer report that ezetimibe 10 mg once daily for 10 days resulted in higher (<20%) plasma concentrations in women than in men [3]. In another study by the manufacturer, women had 13-22% higher mean Cmax and AUC of ezetimibe than men after receiving 20 mg once daily for 10 days. They concluded that the difference partly may be due to difference in body weight [4]. The difference has not been adjudicated to be large enough to warrant dosage adjustment based on sex [5].

Effects

There is a lack of studies reporting outcome data (mortality and morbidity) with an analysis of sex differences of treatment with ezetimibe [6].

Combination therapy with statins

A meta-analysis consisting of 27 double-blind, active- or placebo-controlled efficacy trials in hypercholesterolemic patients, assessed sex-related efficacy in patients treated with statin + ezetimibe (5389 men, 5142 women) or statin monotherapy (6140 men, 5607 women). Patients treated with the combination had almost twice the percentage reduction in lipid levels than patients treated with statin only, and men had slightly greater reductions than women. However, as the sex difference was very small (<2%), it’s probably of no clinical significance [7]. The finding that men had greater lipid levels reductions than women has also been seen in patients with type 2 diabetes (59 men, 76 women) [8].

Contrary to the findings in the above mentioned large meta-analysis, other studies (not included in this meta-analysis) have not reported sex differences in reduction of lipid levels [9-12]. A meta-analysis consisting of three Phase III trials comparing simvastatin-ezetimibe (591 men, 645 women) and simvastatin monotherapy (589 men, 645 women) found some reductions in lipid levels among patients treated with the combination than simvastatin only (around -52% vs. -48%), and results were similar in men and women [9]. Ezetimibe-simvastatin has also been found to reduce hs-CRP levels more than simvastatin monotherapy (-33% vs -14%), with similar reductions in men and women [11].No sex differences in the odds of achieving LDL-C targets were shown in a randomized, double-blind, placebo-controlled study comparing simvastatin-ezetimibe (30 men, 26 women) and simvastatin monotherapy (32 men, 24 women) [10].A post-hoc analysis of two randomized, double-blind trials comparing atorvastatin-ezetimibe and atorvastatin monotherapy showed  somewhat more pronounced reductions in lipid levels in patients treated with the combination compared with atorvastatin only (around-29% vs. -11%), and results were similar in men and women [12].

Monotherapy

The efficacy of ezetimibe 10 mg/day in patients with primary (non-familiar) hypercholesterolemia (434 men, 458 women) was analyzed in a randomized, double-blind, placebo-controlled study and showed LDL levels to be similarly reduced in men and women [13].Ezetimibe as monotherapy (10 men, 14 women) or in combination with a statin or fenofibrate (10 men, 16 women) were compared in hypercholesterolic Japanese patients. In multivariate analysis, both treatments reduced lipid levels in a similar way in both sexes [14].In children 6-10 years old with hypercholesterolemia, ezetimibe monotherapy reduced LDL-C levels to a similar extent in girls and boys, as shown in a randomized, double-blind, placebo-controlled study (59 boys, 79 girls). [15].

Adverse effects

In a meta-analysis comparing statin + ezetimibe and statin monotherapy (see Effects), women reported more adverse events, such as gastrointestinal-related and allergic reactions for all included treatments. No significant sex differences in myopathy were reported [7].

Reproductive health issues

Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).

Other information

Treatment with simvastatin-ezetimibe has been associated with cancer [16]. A follow-up of patients participating in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial (820 men, 539 women) investigated the incidence of cancer and total mortality during 21 months after the end of trial. However, this study showed no association between simvastatin-ezetimibe treatment and an increased risk of new cancers or mortality, and there were no differences in hazard ratios between men and women [17].

Försäljning på recept

Fler män än kvinnor hämtade ut läkemedel innehållande ezetimib (ATC-kod C10AX09) på recept i Sverige år 2015, totalt 17 597 män och 13 108 kvinnor. Det motsvarar 3,6 respektive 2,7 patienter per tusen invånare. Andelen som hämtat ut läkemedel var högst i åldersgruppen 70-74 år hos båda könen. I genomsnitt var läkemedel innehållande ezetimib 1,8 gånger vanligare hos män.

Fler män än kvinnor hämtade ut läkemedel innehållande kombination av simvastatin och ezetimib (ATC-kod C10BA02) på recept i Sverige år 2015, totalt 695 män och 352 kvinnor [18].

Uppdaterat: 2019-02-26

Litteratursökningsdatum: 2016-10-17

Referenser

  1. Kosoglou T, Statkevich P, Johnson-Levonas AO, Paolini JF, Bergman AJ, Alton KB. Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin Pharmacokinet 2005;44(5):467-94 PubMed
  2. Chu NN, Chen WL, Xu HR, Li XN. Pharmacokinetics and safety of ezetimibe/simvastatin combination tablet: an open-label, single-dose study in healthy Chinese subjects. Clin Drug Investig. 2012;32:791-8. PubMed
  3. Zetia (ezetimibe). DailyMed [www]. US National Library of Medicine. [updated 2016-02-26, cited 2016-10-17]. länk
  4. Zetia (ezetimibe). Summary of Product Characteristics. Medical Products Agency Sweden (MPA); 2003.
  5. Food and Drug Administration (FDA). Clinical Pharmacology and Biopharmaceutics Review - ZETIA (ezetimibe). Food and Drug Administration [www]. [updated 2002-10-25, cited 2016-10-17]. länk
  6. Thomas F Lüscher, A John Camm, Gerald Maurer, Patrick W Serruys. The ESC Textbook of Cardiovascular Medicine (3 ed). Oxford University Press; 2016.
  7. Abramson BL, Benlian P, Hanson ME, Lin J, Shah A, Tershakovec AM. Response by sex to statin plus ezetimibe or statin monotherapy: a pooled analysis of 22,231 hyperlipidemic patients. Lipids Health Dis. 2011;10:146. PubMed
  8. Shigematsu E, Yamakawa T, Taguri M, Morita S, Tokui M, Miyamoto K et al. Efficacy of ezetimibe is associated with gender and baseline lipid levels in patients with type 2 diabetes. J Atheroscler Thromb. 2012;19:846-53. PubMed
  9. Ose L, Shah A, Davies MJ, Rotonda J, Maccubbin D, Tribble D et al. Consistency of lipid-altering effects of ezetimibe/simvastatin across gender, race, age, baseline low density lipoprotein cholesterol levels, and coronary heart disease status: results of a pooled retrospective analysis. Curr Med Res Opin. 2006;22:823-35. PubMed
  10. Averna M, Zaninelli A, Le Grazie C, Gensini GF. Ezetimibe/simvastatin 10/20 mg versus simvastatin 40 mg in coronary heart disease patients. J Clin Lipidol. 2010;4:272-8. PubMed
  11. Sager PT, Capece R, Lipka L, Strony J, Yang B, Suresh R et al. Effects of ezetimibe coadministered with simvastatin on C-reactive protein in a large cohort of hypercholesterolemic patients. Atherosclerosis. 2005;179:361-7. PubMed
  12. Bays HE, Conard SE, Leiter LA, Bird SR, Lowe RS, Tershakovec AM. Influence of age, gender, and race on the efficacy of adding ezetimibe to atorvastatin vs atorvastatin up-titration in patients at moderately high or high risk for coronary heart disease. Int J Cardiol. 2011;153:141-7. PubMed
  13. Dujovne CA, Ettinger MP, McNeer JF, Lipka LJ, LeBeaut AP, Suresh R et al. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol. 2002;90:1092-7. PubMed
  14. Kishimoto M, Sugiyama T, Osame K, Takarabe D, Okamoto M, Noda M. Efficacy of ezetimibe as monotherapy or combination therapy in hypercholesterolemic patients with and without diabetes. J Med Invest. 2011;58:86-94. PubMed
  15. Kusters DM, Caceres M, Coll M, Cuffie C, Gagné C, Jacobson MS et al. Efficacy and safety of ezetimibe monotherapy in children with heterozygous familial or nonfamilial hypercholesterolemia. J Pediatr. 2015;166:1377-84e1-3. PubMed
  16. Rossebø AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359:1343-56. PubMed
  17. Green A, Ramey DR, Emneus M, Iachina M, Stavem K, Bolin K et al. Incidence of cancer and mortality in patients from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial. Am J Cardiol. 2014;114:1518-22. PubMed
  18. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2015 [cited 2016-11-08.] Socialstyrelsens statistikdatabas

Författare: Linnéa Karlsson Lind

Faktagranskat av: Mia von Euler

Godkänt av: Karin Schenck-Gustafsson