Ezetimibe with simvastatin

Recent studies implicate the role of Toll-like receptors (TLRs) in the pathogenesis of atherosclerosis. In a study with 60 hypercholesterolemic patients, TLR2 and TLR4 membrane expression were upregulated compared with controls [8]. A high simvastatin dose or the combination of a low-dose simvastatin with ezetimibe reduced membrane expression of TLR2 and TLR4 in monocytes from hypercholesterolemic patients. In addition, LPS-induced IL-6 and IL-ip production were also suppressed. 

Ezetimibe interferes with the absorption of cholesterol from the brush border of the intestine, a novel mechanism that makes it a good choice for adjunctive therapy. It is approved as both monotherapy and for use with a statin. The dose is 10 mg once daily, given with or without food. When used alone, it results in an approximate 18% reduction in LDL cholesterol. When added to a statin, ezetimibe lowers LDL by about an additional 12% to 20%. A combination product (Vytorin) containing ezetimibe 10 mg and simvastatin 10, 20, 40, or 80 mg is available. Ezetimibe is well tolerated approximately 4% of patients experience GI upset. Because cardiovascular outcomes with ezetimibe have not been evaluated, it should be reserved for patients unable to tolerate statin therapy or those who do not achieve satisfactory lipid lowering with a statin alone. 

Concomitant amiodarone or verapamil In patients taking amiodarone or verapamil concomitantly with ezetimibe/simvastatin, do not exceed 10 mg ezetimibe/20 mg simvastatin daily. 

Feldman T, Koren M, Insull W, et al. Treatment of high-risk patients with ezetimibe plus simvastatin co-administration versus simvastatin alone to attain National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol goals. Am.J. Cardiol, 2004, 93, 1481-1486. 

Ezetimibe has caused elevations in transaminases when used with simvastatin, with which it is usually combined. 

Ezetimibe is only partly metabolised by the liver and should be safe to use alone. However, ezetimibe has caused elevations in transaminases when used with simvastatin, with which it is usually combined. Simvastatin would not be recommended (see Statins, above). 

Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008 Sep 25 359(13) 1343-56. 

Simvastatin Vytorln (with ezetimibe), Zocor Hypolipaemic 43605... 

In a three-arm study, patients were given simvastatin 80 mg daily, simvastatin 80 mg daily with ezetimibe 10 mg daily, or simvastatin 40 mg daily with ezetimibe 10 mg daily. No difference in adverse events was noted between each of the 3 groups and there were no significant elevations in creatine kinase. No cases of myopathy or rhabdomyolysis occurred, and the combination was well-tolerated. In another study, ezetimibe 0.25 mg, 1 mg or 10 mg daily had no effect on the pharmacokinetics of simvastatin 10 mg daily, when both were given for 14 days. In addition, 10 and 20-mg doses of simvastatin were well-tolerated in combination with ezetimibe. ... 

Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, and 44 other authors. SHARP Investigators. The effect of lowering LDL cholesterol with simvastatin and ezetimibe in patients with chronic kidney disease, a randomised placebo-controlled trial. Lancet 2011 377 2181-92. 

Liver Hepatotoxic events occasionally have been reported when ezetimibe is used in conjunction with a statin, as in the case of a 70-year-old woman who developed fulminant hepatic failure, necessitating liver transplantation 10 weeks after switching from simvastatin to simvastatin 4- ezetimibe[25]. A study with 32 subjects with nonalcoholic fatty liver disease pathology showed that ezetimibe improved hepatic fibrosis but increased hepatic long-chain fatty acids and HbA c [26]. 

Pancreas Case reports and pharmacoepidemiological studies have provided evidence that statins may cause pancreatitis. However, data from the SHARP study, a placebo-controlled study of the effects of a combination of simvastatin and ezetimibe on cardiovascular events in patients with chronic kidney disease, showed a reduction in the number of cases of pancreatitis [75] [40 -]. Recent prospective cohort study with 1062 subjects of whom 92 were taking statins found severe pancreatitis was more common in the statin nonuser than statin user. Pancreatitis-related mortality was higher in the statin nonuser, and among patients who developed severe acute pancreatitis, statin users showed lower Ranson s and APACHE II scores and lower maximal CRP, suggesting that prior statin treatment reduced morbidity and mortality in acute pancreatitis [76]. 

Moutzouri E, TeUis CC, Rousouli K, Liberopoulos EN, Milionis HJ, Ehsaf MS, et al. Effect of simvastatin or its combination with ezetimibe on toll-like receptor expression and lipopolysaccharide - induced cytokine production in monocytes of h)percholesterolemic patients. Atherosclerosis 2012 225 381-7. 

Dose The recommended usual starting dose is 10 mg ezetimibe/20 mg simvastatin daily. Initiation of therapy with 10 mg ezetimibe/10 mg simvastatin daily may be considered for patients requiring less aggressive LDL-C reductions. Patients who require a larger reduction in LDL-C (more than 55%) may be started at 10 mg ezetimibe/40 mg simvastatin daily. After initiation or titration of ezetimibe/simvastatin, lipid levels may be analyzed after 2 or more weeks and dosage adjusted, if needed. 

Homozygous familial hypercholesterolemia The recommended dosage for patients with homozygous familial hypercholesterolemia is 10 mg ezetimibe/40 mg simvastatin daily or 10 mg ezetimibe/80 mg simvastatin daily in the evening. Use ezetimibe/simvastatin as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) in these patients or if such treatments are unavailable. 

Renal function impairment For patients with severe renal insufficiency, do not start ezetimibe/simvastatin unless the patient has already tolerated treatment with simvastatin at a dose of 5 mg or higher. Exercise caution when ezetimibe/simvastatin is administered to these patients, and monitor them closely. Concomitant bile acid sequestrants Give ezetimibe/simvastatin either 2 hours or more before or 4 hours or more after administration of a bile acid sequestrant. Concomitant cyclosporine Exercise caution when initiating ezetimibe/simvastatin in the setting of cyclosporine. In patients taking cyclosporine, do not start ezetimibe/simvastatin unless the patient has already tolerated treatment with simvastatin at a dose of 5 mg or higher. Do not exceed 10 mg ezetimibe/10 mg simvastatin daily. 

Ezetimibe is the first member of a group of drugs that inhibit intestinal absorption of phytosterols and cholesterol. Its primary clinical effect is reduction of LDL levels. In one trial, patients receiving ezetimibe in combination with simvastatin had marginal, but not statistically significant, increases in carotid intimal-medial thickness (IMT) compared with those... 

Ezetimibe is a selective potent inhibitor of the intestinal absorption of dietary and biliary cholesterol. A total of 432 patients were included in a pooled analysis of two phase-II studies, both lasting for 12 weeks ezetimibe was well tolerated, with an adverse events profile similar to that of placebo (1). In 668 patients who took ezetimibe with simvastatin, the adverse effects were similar to those with simvastatin alone (2). 

In 668 patients ezetimibe was given with simvastatin and adverse effects were similar to those experienced with simvastatin alone (8). 

Davidson MH, McGarry T, Bettis R, Melani L, Lipka LJ, LeBeaut AP, Suresh R, Sun S, Veltri EP. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002 40(12) 2125-34. 

Abbreviations AM, amlodipine AT, atorvastatin DS, diclofenac sodium EZ, ezetimibe FB, fenofibrate HAT, hydroxy atorvastatin IS, internal standard o-HAT, ortfio-hydroxy atorvastatin p-HAT, para-hydroxy atorvastatin HPLC-ESI-MS, high-performance liquid chromatography with electrospray tandem mass spectrometry LV, lovastatin NA, nicotinic acid NB, novobiocin FV, pravastatin RV, rosuastatin SV, simvastatin RT, roxethromycin UPLC, ultra performance liquid chromatography. 

Ballantyne CM, Blazing MA, KingTR, et al. Efficacy and safety of ezetimibe co-administration with simvastatin compared with atorvastatin in adults with hypercholesterolemia. Am.J. Cardiol., 2002, 93,1487-1494. 

Ezetimibe is usually used in combination with simvastatin. Patients should be monitored for signs of myopathy. Monitor transaminases. The extended therapeutic effect due to enterohepatic recycling may be reduced in obstructive jaundice. 

Another spectrophotometric method used the derivative method. Rajput and Raj [19] developed a first-order derivative zero-crossing method to analyze ezetimibe in combination with simvastatin. This method was further applied to determine ezetimibe in combination with lovastatin. The first derivation method also applied to determine ezetimibe in combination with rosuvastatin [20]. Besides the first-derivative method, second- and third-derivative methods were also reported for defermining ezetimibe as a single compound in its dosage form [21]. Flowever, the third-derivative method yielded the lowest limits of defecfion and quantitation relative to other methods used in this research. The maximum wavelength also remained constant regardless of fhe derivative method applied. 

In more recent development, chemometric or multivariate calibration techniques have been applied into spectrophotometric methods. As reported by Palabiyik and Onur [24], principal component regression and partial least square were used to determine ezetimibe in combination with simvastatin. This method offers advanfages such as no chemical prefreafmenf prior to analysis as well as no need to observe graphical spectra and calculations as with the derivative method. In addition, the instrumentation used is also simpler. 

The simplest UV-spectrophotometric method was developed by Rajesh and Reddy [25] to determine ezetimibe as a single compoimd. This method was based only on an absorbance measurement of ezetimibe af one wavelength. Similarly, Jain et al. [26] also employed a simple method to determine ezetimibe in combination with simvastatin. In this method, ezetimibe was observed at a wavelength where simvastatin did not give interference. While no LOD and LOQ values were reported, the linearity of the method was over the range of 5-20 pg/mL. 

For the purpose of analyzing ezetimibe in combination with simvastatin, three HPTLC methods have been developed. The first method was developed by Shivshankar et al. [33] and yielded higher Rf values for either ezetimibe or simvastatin. In the method developed by Dhaneshwar et al. [30], a combination of toluene and isopropanol was shown to produce shorter Rf times for ezetimibe and simvastatin, leading to methods of shorter duration and lower mobile phase consumption. The recent method developed by Dixit et al. [31] used combination of acetone and n-hexane as the mobile phase and resulted in shorter Rf values when compared to the other two methods for assessing ezetimibe in combination with simvastatin. This method has also been validated to distinguish the degradation products of ezetimibe. Further, during the determination of ezetimibe in combination with atorvastatin, shorter Rf values were obtained as well as better peak shape when a combination of toluene and methanol was used as the mobile phase [30]. 

In both MEKC methods reported, the mobile phase consisted of borate buffer containing surfactant and acetonitrile. It was foimd that mobile phase prepared at pH 9.75 gave better resolution compared to other conditions, and increasing pH also increased the migration time of ezetimibe. An analyte concentration of 25 mM was chosen due to its lower current, and the sharp peaks observed [41]. In addition, for the analysis of ezetimibe in combination with another drug such as simvastatin, increasing the borate concentration increased both resolution and migration times. 

Ezetimibe is a newer dmg that inhibits cholesterol absorption by the G1 tract it reduces LDLc modestly as monotherapy and is used in combination therapy with simvastatin (marketed as Vytorin) to achieve good cholesterol lowering and minimizing... 

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