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Long-term effects of ezetimibe-plus-statin therapy on low-density lipoprotein cholesterol levels as compared with double-dose statin therapy in patients with coronary artery disease. Atherosclerosis , — Patrick, J. Disposition of the selective cholesterol absorption inhibitor ezetimibe in healthy male subjects.
Drug Metab. Pfizer Inc. Rosuvastatin, fluvastatin, and pravastatin are not significantly affected by this interaction. Of all macrolides, azithromycin can be used with statins. Erythromycin increased the Cmax of simvastatin in its lactone form by 3.
Erythromycin increased Cmax and AUC of atorvastatin by The effect is attributed to decreased metabolism of statins, inhibition of intestinal P-gp, and decreased bile secretion. In general, case reports of rhabdomyolysis are available due to the interaction between simvastatin and clarithromycin, between lovastatin and erythromycin, and between clarithromycin and azithromycin [ 35 ]. Some patients may require the combination of several lipid lowering agents, the statin-fibrate association being the most common.
However, the greater hypolipidemic effect is accompanied by an increased risk of myopathy, especially with gemfibrozil, due to its inhibitory effect on glucuronidation of statins, increasing the concentrations of the latter. Therefore, there is a report of cases of rhabdomyolysis and kidney disease, due to the combination of gemfibrozil with simvastatin, atorvastatin, and lovastatin.
In addition, gemfibrozil increases the AUC of rosuvastatin by 1. Metabolism is only a minor pathway for pitavastatin via CYP2C9, which is unaffected by gemfibrozil. Fluvastatin transport in hepatocytes via the OATP transporters is potently inhibited by gemfibrozil [ 38 ]. However, in at least 1 study of 17 subjects, no significant difference was observed in the AUC and Cmax in a comparison of the gemfibrozil-fluvastatin combination and gemfibrozil alone.
Related to this interaction, it is important to note that fenofibrate is considered more suitable than gemfibrozil, which is supported in studies showing the absence of interaction of fenofibrate with pravastatin, simvastatin, and atorvastatin.
However, fenofibrate may increase rosuvastatin plasma levels and there is a case report of renal failure in a patient taking this combination. The combination of gemfibrozil with lovastatin, pravastatin, and simvastatin is potentially harmful and should be avoided.
Although gemfibrozil interacts with atorvastatin, pitavastatin, and rosuvastatin, the result is only a minor increase in statin concentrations, and the combination may be considered if clinically indicated.
Fluvastatin may be used in combination with gemfibrozil without any specific dose limitations, and this particular statin does not interact with gemfibrozil. Ezetimibe is well tolerated and does not interact with fluvastatin, lovastatin, rosuvastatin, or simvastatin. However, cases of myopathy have been reported in patients due to the combination ezetimibe and atorvastatin. Although coadministration of statins and antidepressants is likely, given the association between depression and many chronic diseases, the prevalence of clinically relevant interactions between them is not well-documented.
With the exception of atorvastatin and fluvastatin, which inhibit the activity of CYP3A4 and CYP2C9, respectively, most statins do not appear to be inhibitors or inducers of the main drug metabolizing enzymes. On the other hand, some antidepressants act as inhibitors of several CYPs and, therefore, may impair the elimination of statins metabolized through these isoforms. Based on this knowledge, it can be anticipated that concomitant use of nefazodone or fluvoxamine, potent or moderate CYP3A4 inhibitors, respectively, with atorvastatin, lovastatin, or simvastatin should increase the plasma concentrations of these statins.
Statin metabolism may be susceptible to OATP inhibition by imipramine, nortriptyline, and amitriptyline, with a possible increase in drug concentration. Atorvastatin, a CYP3A4 inhibitor, can act on the metabolism of tricyclic antidepressants excluding nortriptyline. Also, an interaction between imipramine a P-gp substrate and statins P-gp inhibitors could be hypothesized.
Fluvoxamine is the only moderate CYP3A4 inhibitor, and may be associated with an increased risk of interactions if administered with atorvastatin, lovastatin, and simvastatin. While the potential interaction between fluoxetine and statins has not been investigated in humans, experimental evidence in animal models found that the combination of simvastatin with fluoxetine may enhance anxiolytic and antidepressant properties.
Both fluvoxamine and fluoxetine act as moderate inhibitors of CYP2C9 activity and, in theory, can increase plasma concentrations of fluvastatin, which is metabolized primarily through this isoform. However, the magnitude of this interaction would probably be below the threshold of clinical importance.
Due to the theoretical risk of a metabolic interaction, lower doses of atorvastatin, lovastatin, and simvastatin may be indicated in patients treated with fluvoxamine. On the other hand, it is unlikely that the pharmacokinetics of pitavastatin and rosuvastatin, minimally metabolized by CYP2C9, may be significantly affected by the coadministration of fluvoxamine and fluoxetine.
In the case of joint administration of selective inhibitors reuptake serotonins SSRIs with statins, escitalopram, citalopram, and sertraline appear to be safe with all statins.
Coadministration with statins metabolized through CYP3A4 atorvastatin, simvastatin, and lovastatin or, to a lesser extent, fluvastatin through CYP2D6, could lead to a potentially competitive inhibition. There are no studies on the coadministration of specific noradrenergic and serotonergic antidepressants NaSSA , mirtazapine coadministered with statins.
Therefore, there is a low probability of interactions. The joint use of simvastatin with erlotinib or imatinib has been related to cases of rhabdomyolysis. With the concomitant use of simvastatin and pazopanib , an increase in the incidence of ALT elevations has been documented, so simvastatin treatment should be discontinued when these alterations are observed. In addition, it cannot be ruled out that pazopanib affects the pharmacokinetics of other statins atorvastatin, fluvastatin, and rosuvastatin.
This potential for interaction and morbidity in cancer patients can be minimized by the use of pravastatin, instead of simvastatin, since this drug is excreted by the kidneys and has no significant metabolism via CYP3A4. On the other hand, with rosuvastatin, the effect was minor and was not considered clinically relevant. Cholestyramine: there is possible reduction of plasma levels of statins, by fixation to the resin in the intestinal lumen and lipid-lowering activity, although clinical practice seems to indicate otherwise.
It is recommended to administer the statin 1 hour before or 4 hours after the resin. Sildenafil: there is a report of myopathy with rosuvastatin and a case of rhabdomyolysis with simvastatin. Ciprofloxacin weak CYP3A4 inhibitor : there is a report of rhabdomyolysis with simvastatin. Efalizumab: there is a case report of rhabdomyolysis with pravastatin. Danazol: it is a moderate androgen receptor agonist and a partial progestogenic agonist. It is able to inhibit the metabolism of some statins by increasing their plasma concentrations.
Cases of myopathy and rhabdomyolysis have been described. Likewise, a case of acute pancreatitis was published in an year-old patient treated with this combination of drugs.
Although documented cases affect simvastatin and lovastatin, it is advisable to exercise caution with any statin administered in conjunction with danazol and control the occurrence of muscle symptoms. Risperidone and simvastatin: risperidone inhibits the oxidative metabolism of statin and increases its toxicity with a risk of rhabdomyolysis. In patients taking ranolazine, the use of statins, whose metabolism is highly dependent on CYP3A4 as simvastatin or lovastatin, should be limited due to the risk of rhabdomyolysis [ 3 ].
There are phytotherapeutic agents that can interact with medications. Some studies show a decrease in statin concentrations and, therefore, their effectiveness when St. The effect is not observed for pravastatin. It is recommended to avoid grapefruit juice with lovastatin and simvastatin; avoid large quantities of grapefruit just if taking atorvastatin increases in area-under-the-curve to 2. In the case of lovastatin, grapefruit juice causes a fold increase in Cmax and fold increase in AUC; on the other hand, for the acid form of lovastatin, the increase in Cmax was 4 times, and in AUC, it was 5 times.
In the case of orange juice, its administration has been linked to a significant increase of pravastatin AUC in healthy volunteers [ 2 ]. Red yeast rice is a popular over-the-counter treatment for hyperlipidemia.
Red yeast rice has varying amounts of monacolin K similar to lovastatin. The products are not standardized and no red yeast rice product should be administered to a patient taking a prescribed statin. Licorice Glycyrrhiza glabra L. Some cases of muscular alteration with increased creatin kinase and, in some cases, rhabdomyolysis have been reported in patients taking high amounts.
The risk may increase when associated with drugs that cause muscle toxicity, such as statins, so their combination should be avoided [ 41 ]. OATP1B1 affects the hepatic uptake of statins, where statins are going to be metabolized and exert their action at the intracellular level. A reduced activity of OATP1B1 may decrease their efficacy and increase their plasma concentrations, with the consequent risk of muscle toxicity. Thus, the Genome Wide Association Study GWAS studied , polymorphisms in patients treated with statins and who had presented myopathies in front of a control group with statins and who had not presented myopathies.
The application of genetic information to individualize pharmacological treatments to maximize efficacy and avoid adverse events, or pharmacogenetics, is an important component of precision medicine [ 42 ]. A review of all medications that are treated by patients treated with statins should be performed at each medical consultation and during all healthcare transitions within a health system so that drug interactions can be identified early, evaluated, and properly managed, implementing adjustments of dose, changing to another safer statin or discontinuing when necessary.
A thorough understanding of the pharmacokinetics of statins and other concomitantly administered medications is paramount to ensure patient safety.
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Address for correspondence: F. E-mail: fahfonseca terra. Received February 17, Accepted May 10,
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