Ezetimibe interactions

Caco-2 cells and ezetimibe, a potent inhibitor of chloresterol absorption in humans, it was reported that (1) carotenoid transport was inhibited by ezetimibe up to 50% and the extent of that inhibition diminished with increasing polarity of the carotenoid molecule, (2) the inhibitory effects of ezetimibe and the antibody against SR-BI on P-carotene transport were additive, and (3) ezetimibe may interact physically with cholesterol transporters as previously suggested - and also down-regulate the gene expression of three surface receptors, SR-BI, NPCILI, and ABCAl. 

A statin combined with a resin results in similar reductions in LDL cholesterol as those seen with ezetimibe. However, the magnitude of triglyceride reduction is less with a resin compared to ezetimibe, and this should be considered in patients with higher baseline triglyceride levels. In addition, gastrointestinal adverse events and potential drug interactions limit the utility of this combination. 

Drug/Food interactions Ezetimibe may be administered with or without food. 

Ezetimibe/Simvastatin (Vytorin) [Antilipemic/HMG CoA Reductose Inhibitor] Uses H rp cholest olemia Action X Absorption of cholesterol phytost ol w/ HMG-CoA reductase inhibitor Dose 10/10-10/80 mg/d PO w/ cyclosporine or danazol 10/10 mg/d max w/ amio-darone or verapamil 10/20 mg/d max -1- w/ sev e renal insuff Caution [X, -] w/ CYP3A4 inhibitors (Table VI-8), gemfibrozil, niacin >lg/d, danazol, amiodarone, verapamil Contra PRG/lactation livCT Dz, t LFTs Disp Tabs SE HA, GI upset, myalgia, myopathy (muscle pain, weakness, or tendOTiess w/ CK 10 x ULN, rhab-domyolysis), Hep, Infxn Interactions t Risk of myopathy W7 clarithromycin, erythromycin, itraconazole, ketoconazole EMS None OD Sxs unknown symptomatic and supportive... 

In a randomized, open, three-way crossover, multiple-dose study in 12 healthy adult men there was no clinically significant interaction of ezetimibe with gemfibrozil (7). 

Kosoglou T, Statkevich P, Fruchart JC, Pember LJ, Reyderman L, Cutler DL, Guillaume M, Maxwell SE, Veltri EP. Pharmacodynamic and pharmacokinetic interaction between fenofibrate and ezetimibe. Curr Med Res Opin 2004 20(8) 1197-207. 

Reyderman L, Kosoglou T, Statkevich P, Pember L, Boutros T, Maxwell SE, Affrime M, Batra V. Assessment of a multiple-dose drug interaction between ezetimibe, a novel selective cholesterol absorption inhibitor and gemfibrozil. International J Clin Pharmacol Ther 2004 42(9) 512-8. 

As far as research collaboration is concerned, the Schering-Plough manufacturing process for its cholesterol absorption inhibitor, Ezetimibe (Zetia), exemplifies the collaboration case. The close interaction between Research and Development, aided by the delay caused by the realization that the first API structure (XVI) had to be modified to overcome metabolism issues, provided the intellectual resource and the time for a fuller understanding of the chemistry needed to create the chiral (3-lactam ring. 

Clinically important, potentially hazardous interactions with amiloride, aminoglycosides, amphotericin B, ampicillin, anisindione, anticoagulants, armodafinil, atorvastatin, azathioprine, azithromycin, bacampicillin, basiliximab, bezafibrate, bosentan, bupropion, carbenicillin, caspofungin, cholestyramine, clarithromycin, cloxacillin, co-trimoxazole, corticosteroids, cyclophosphamide, daclizumab, danazol, dicloxacillin, dicumarol, digoxin, diltiazem, disulfiram, echinacea, erythromycin, ethotoin, etoposide, ezetimibe, flunisolide, fluoxymesterone, fluvastatin, foscarnet, fosphenytoin, gemfibrozil, hemophilus B vaccine, HMG-CoA reductase inhibitors, imatinib, imipenem/cilastatin, influenza vaccines, ketoconazole, lanreotide, lopinavir, lovastatin, mephenytoin, methicillin, methoxsalen, methylphenidate, methylprednisolone, methyltestosterone, mezlocillin, mizolastine, mycophenolate, nafcillin, nisoldipine, NSAIDs, orlistat, oxacillin, penicillins, phellodendron, phenytoin, pravastatin, prednisolone, prednisone, pristinamycin, ranolazine, red rice yeast, rifabutin, rifampin, rifapentine, ritonavir, rosuvastatin, simvastatin, sirolimus, spironolactone, St John s wort, sulfacetamide, sulfadiazine, sulfamethoxazole, sulfisoxazole, sulfonamides, tacrolimus, telithromycin, tenoxicam, testosterone, ticarcillin, tolvaptan, trabectedin, triamterene, troleandomycin, ursodeoxycholic acid, vaccines, vecuronium, warfarin, zofenopril... 

Clinically important, potentially hazardous interactions with dicumarol, ezetimibe, lovastatin, nicotinic acid, statins, warfarin... 

Clinically important, potentially hazardous interactions with atorvastatin, bexarotene, cyclosporine, dicumarol, ezetimibe, fluvastatin, interferon alfa, lovastatin, nicotinic acid, pioglitazone, pravastatin, repaglinide, rosuvastatin, roxithromycin, simvastatin, statins, warfarin... 

Clinically important, potentially hazardous interactions with alfentanil, alfuzosin, alprazolam, amiodarone, amprenavir, aprepitant, astemizole, atazanavir, bepridil, buprenorphine, bupropion, carbamazepine, chlordiazepoxide, ciclesonide, clozapine, conivaptan, cyclosporine, cyproterone, dasatinib, diazepam, dihydroergotamine, ergot alkaloids, estazolam, eszopidone, etravirine, ezetimibe, fentanyl, fesoterodine, flecainide, flurazepam, fluticasone, halazepam, ivabradine, ixabepilone, ketoconazole, lapatinib, levothyroxine, meperidine, meptazinol, methysergide, midazolam, nifedipine, nilotinib, oral contraceptives, phenytoin, pimozide, piroxicam, propafenone, propoxyphene, quazepam, quinidine, ranolazine, rifabutin, rifampin, rifapentine, rimonabant, rivaroxaban, saquinavir, sildenafil, silodosin, simvastatin, solifenacin, St John s wort, tadalafil, temsirolimus, trabectedin, triazolam, vardenafil, voriconazole, zolpidem... 

Table 30.8. Drug Interactions for Ezetimibe Result of Interaction...

Kosoglou T, Statkevich P, Johnson-Levonas AO, et al. Ezetimibe a review of its metabolism, pharmacokinetics, and drug interactions. Clin Pharmacokinet 2005 44 467-494. 

No clinically significant interaction occurred between ezetimibe and warfarin in one study. However, raised INRs have been seen in patients taking warfarin after they were also given ezetimibe. 

No significant pharmacokinetic interaction appears to occur between ezetimibe and an ethinylestradiol/noigestrel-containing oral contraceptive. 

Ezctimibe is a cholesterol absorption inhibitor, and, as the name suggests, it and the major metabolite, ezetimibe glucuronide, impair the intestinal absorption of cholesterol, both from the diet and biliary cholesterol. The absorption of other fats is not affected. Ezetimibe has not been found to have significant effects on cytochrome P450, suggesting it is unlikely to interact by this mechanism. 

Bergman AJ, Burke J, Larson P, Johnson-Levonas AO, Reyderman L, Statkevich P, Maxwell SE, Kosc ou T, Murpl G, Gottesdiener K, Robson R, P Uni JF. Interaction of single-dose ezetimibe and steady-state cyclospcrine in renal transplant patients. J Clin Pharmacol (2006) 46,328-36. 

In a study of 40 healthy hypercholesterolaemic subjects, colesly-ramine 4 g twice daily decreased the mean AUC of ezetimibe by about 80% and decreased the mean AUC of total ezetimibe (ezetimibe plus metaboUtes) by about 55%. Colestyramine may therefore be expected to decrease the lipid-loweiing effects of ezetimibe. Note that ezetimibe undei oes enterohepatic recirculation, so separating administration may not fully resolve this interaction. 

Information about the interaction between ezetimibe and rifampicin appears to be limited to these studies, which were primarily designed to investigate ezetimibe disposition. However, it seems likely that the effects of ezetimibe will be reduced in patients who are also given multiple doses... 

Gustavson LE, Schweitzer SM, Burt Achari R, Rieser MJ, Hdeld T, Chira T, Yannicelli HD, Kelly MT. Evaluatioii of the potential for phannacokinetic interaction between fenofibrate and ezetimibe a phase 1, open-label, mult le-dose, three-period crossover study in healthy subjects. Clin Ther (200 28,373—87. 

Ezetimibe does not appear to have adverse pharmacokinetic interactions with atorvastatin, fluvastatin, iovastatin, rosuvastatin or simvastatin. However, some evidence suggests that concurrent use may increase the risk of myopathy. 

In a randomised, erossover study 32 otherwise healthy subjects with hy-pereholesterolaemia were given either ezetimibe 10 mg daily, fluvastatin 20 mg daily or both drugs in combination for 14 days. The combination was well tolerated, no significant pharmacokinetic interaction occurred, and an enhanced lowering of LDL-cholesterol was noted, which was considered to be clinically favourable. However, a case report describes a 52-year-old man taking fluvastatin 80 mg daily who developed elevated creatinine kinase levels 8 weeks after ezetimibe 10 mg daily was added. 

In a randomised, crossover study 18 healthy suhjeets were given either ezetimibe 10 mg daily, lovastatin 20 mg daily or both drugs in combination for 7 days. The combination was well tolerated, and no significant pharmacokinetic interaction was noted. ... 

Reyderman L, Kosc lou T, Boutros T, Sieberling M, Statkevich P. Fhannacokinetic interaction between ezetimibe and lovastatin in healthy volunteers. Curr MedRes Opin (2004) 20, 1493-1500. 

Kosoglou T, Statkevich P, Yang B, Suresh R, Zhu Y, Boutros T, M nvell SE, TiessenR, Cutler DL, Pharmacodynamic interaction between ezetimibe and rosuvastatin. Curr MedRes Opm (2004) 20,1185-95. 

The interaction of pomegranate juice with rosuvastatin and ezetimibe seems to be limited to one case report, which is clouded by other possible contributory factors. Furthermore, although pomegranate juice has been shown to inhibit CYP3A4, rosuvastatin is not metabolised by this route. Although it is possible that other mechanisms may be responsible, no firm conclusions can be drawn from this case. 

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