Basic Information
ID DDInter1098 and DDInter424
Interaction Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of simvastatin and lovastatin and their active acid metabolites, all of which are primarily metabolized by the isoenzyme.
Management Due to the potential for severe interaction, concomitant use of simvastatin or lovastatin with potent CYP450 3A4 inhibitors is considered contraindicated. Red yeast rice, which contains lovastatin, should also be avoided. Fluvastatin, pravastatin, pitavastatin, and rosuvastatin are probably safer alternatives, since they are not metabolized by CYP450 3A4. All patients receiving statin therapy should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.
References [1] "Product Information. Zocor (simvastatin)." Merck & Co, Inc, West Point, PA. [2] Bottorf MB "Possible interaction between nefazodone and pravastatin." Ann Pharmacother 34 (2000): 538 [3] Itakura H, Vaughn D, Haller DG, O'Dwyer PJ "Rhabdomyolysis from cytochrome p-450 interaction of ketoconazole and simvastatin in prostate cancer." J Urol 169 (2003): 613 [4] Watkins JL, Atkinson BJ, Pagliaro LC "Rhabdomyolysis in a prostate cancer patient taking ketoconazole and simvastatin: case report and review of the literature." Ann Pharmacother 45 (2011): e9 [5] Williams D, Feely J "Pharmacokinetic-Pharmacodynamic Drug Interactions with HMG-CoA Reductase Inhibitors." Clin Pharmacokinet 41 (2002): 343-70 [6] Ayanian JZ, Fuchs CS, Stone RM "Lovastatin and rhabdomyolysis." Ann Intern Med 109 (1988): 682-3 [7] Kantola T, Kivisto KT, Neuvonen PJ "Effect of itraconazole on cerivastatin pharmacokinetics." Eur J Clin Pharmacol 54 (1999): 851-5 [8] Neuvonen PJ, Backman JT, Niemi M "Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin." Clin Pharmacokinet 47 (2008): 463-74 [9] Corpier CL, Jones PH, Suki WN, et al. "Rhabdomyolysis and renal injury with lovastatin use. Report of two cases in cardiac transplant recipients." JAMA 260 (1988): 239-41 [10] Neuvonen PJ, Jalava KM "Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid." Clin Pharmacol Ther 60 (1996): 54-61 [11] "Product Information. Advicor (lovastatin-niacin)." Kos Pharmaceuticals, Miami, FL. [12] Kantola T, Kivisto KT, Neuvonen PJ "Effect of itraconazole on the pharmacokinetics of atorvastatin." Clin Pharmacol Ther 64 (1998): 58-65 [13] Huynh T, Cordato D, Yang F, et al. "HMG coA reductase-inhibitor-related myopathy and the influence of drug interactions." Intern Med J 32(9-10) (2002): 486-90 [14] Gilad R, Lampl Y "Rhabdomyolysis induced by simvastatin and ketoconazole treatment." Clin Neuropharmacol 22 (1999): 295-7 [15] Gruer PJK, Vega JM, Mercuri MF, Dobrinska MR, Tobert JA "Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin." Am J Cardiol 84 (1999): 811-5 [16] Jacobson TA "Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors." Am J Cardiol 94 (2004): 1140-6 [17] Lees RS, Lees AM "Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole." N Engl J Med 333 (1995): 664-5 [18] Jacobson RH, Wang P, Glueck CJ "Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone." JAMA 277 (1997): 296 [19] Grunden JW, Fisher KA "Lovastatin-induced rhabdomyolysis possibly associated with clarithromycin and azithromycin." Ann Pharmacother 31 (1997): 859-63 [20] Sipe BE, Jones RJ, Bokhart GH "Rhabdomyolysis Causing AV Blockade Due to Possible Atorvastatin, Esomeprazole, and Clarithromycin Interaction." Ann Pharmacother 37 (2003): 808-11 [21] Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R, Bernini F "New insights into the pharmacodynamic and pharmacokinetic properties of statins." Pharmacol Ther 84 (1999): 413-28 [22] Alderman CP "Possible interaction between nefazodone and pravastatin." Ann Pharmacother 34 (2000): 538-9 [23] Alderman CP "Possible interaction between nefazodone and pravastatin." Ann Pharmacother 33 (1999): 871 [24] Hare CB, Vu MP, Grunfeld C, Lampiris HW "Simvastatin-nelfinavir interaction implicated in rhabdomyolysis and death." Clin Infect Dis 35 (2002): E111-2 [25] Chouhan UM, Chakrabarti S, Millward LJ "Simvastatin interaction with clarithromycin and amiodarone causing myositis." Ann Pharmacother 39 (2005): 1760-1 [26] Karnik NS, Maldonado JR "Antidepressant and statin interactions: a review and case report of simvastatin and nefazodone-induced rhabdomyolysis and transaminitis." Psychosomatics 46 (2005): 565-8 [27] Stein CA, Goel S, Ghavamian R "Hepatitis and rhabdomyolysis in a patient with hormone refractory prostate cancer on ketoconazole and concurrent lovastatin therapy." Invest New Drugs 25 (2007): 277-8 [28] Skrabal MZ, Stading JA, Monaghan MS "Rhabdomyolysis associated with simvastatin-nefazodone therapy." South Med J 96 (2003): 1034-5 [29] Thompson M, Samuels S "Rhabdomyolysis with simvastatin and nefazodone." Am J Psychiatry 159 (2002): 1607 [30] Horn M "Coadministration of itraconazole with hypolipidemic agents may induce rhabdomyolysis in healthy individuals." Arch Dermatol 132 (1996): 1254 [31] Paoletti R, Corsini A, Bellosta S "Pharmacological interactions of statins." Atheroscler Suppl 3 (2002): 35-40 [32] East C, Alivizatos PA, Grundy SM, Jones PH, Farmer JA "Rhabdomyolysis in patients receiving lovastatin after cardiac transplantation." N Engl J Med 318 (1988): 47-8 [33] Wong PW, Dillard TA, Kroenke K "Multiple organ toxicity from addition of erythromycin to long-term lovastatin therapy." South Med J 91 (1998): 202-5 [34] Garnett WR "Interactions with hydroxymethylglutaryl-coenzyme A reductase inhibitors." Am J Health Syst Pharm 52 (1995): 1639-45 [35] Omar MA, Wilson JP "FDA adverse event reports on statin-associated rhabdomyolysis." Ann Pharmacother 36 (2002): 288-95 [36] Spach DH, Bauwens JE, Clark CD, Burke WG "Rhabdomyolysis associated with lovastatin and erythromycin use." West J Med 154 (1991): 213-5 [37] Schmidt GA, Hoehns JD, Purcell JL, Friedman RL, Elhawi Y "Severe rhabdomyolysis and acute renal failure secondary to concomitant use of simvastatin, amiodarone, and atazanavir." J Am Board Fam Med 20 (2007): 411-6 [38] Jody DN "Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone." JAMA 277 (1997): 296-7 [39] Piliero PJ "Interaction between ritonavir and statins." Am J Med 112 (2002): 510-1 [40] Kivisto KT, Kantola T, Neuvonen PJ "Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin." Br J Clin Pharmacol 46 (1998): 49-53 [41] Cheng CH, Miller C, Lowe C, Pearson VE "Rhabdomyolysis due to probable interaction between simvastatin and ritonavir." Am J Health Syst Pharm 59 (2002): 728-30 [42] "Product Information. Mevacor (lovastatin)." Merck & Co, Inc, West Point, PA. [43] Neuvonen PJ, Kantola T, Kivisto KT "Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole." Clin Pharmacol Ther 63 (1998): 332-41 [44] Lee AJ, Maddix DS "Rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin." Ann Pharmacother 35 (2001): 26-31 [45] Dresser GK, Spence JD, Bailey DG "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition." Clin Pharmacokinet 38 (2000): 41-57 [46] Fichtenbaum CJ, Gerber JG, Rosenkranz SL, et al. "Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047." AIDS 16 (2002): 569-577 [47] Richter WO, Jacob BG, Schwandt P "Interaction between fibre and lovastatin." Lancet 338 (1991): 706 [48] Neuvonen PJ, Backman JT, Niemi M "Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin." Clin Pharmacokinet 47 (2008): 463-74 [49] Lilja JJ, Kivisto KT, Neuvonen PJ "Grapefruit juice-simvastatin interaction: Effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors." Clin Pharmacol Ther 64 (1998): 477-83 [50] "Product Information. Mevacor (lovastatin)." Merck & Co, Inc, West Point, PA. [51] Thompson PD, Clarkson P, Karas RH "Statin-associated myopathy." JAMA 289 (2003): 1681-90 [52] "Product Information. Zocor (simvastatin)." Merck & Co, Inc, West Point, PA. [53] Kantola T, Kivisto KT, Neuvonen PJ "Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid." Clin Pharmacol Ther 63 (1998): 397-402 [54] Bailey DG, Malcolm J, Arnold O, Spence JD "Grapefruit juice-drug interactions." Br J Clin Pharmacol 46 (1998): 101-10
Alternative for Lovastatin C10A
Probucol Fenofibric acid Colestipol Mipomersen Bempedoic acid Colesevelam
Ezetimibe Dextrothyroxine Cholestyramine Fenofibrate Evinacumab
More
Alternative for Cobicistat J05A
Ombitasvir Ibalizumab Famciclovir Maraviroc Peramivir Zanamivir
Brincidofovir Lopinavir Cidofovir Adefovir dipivoxil Raltegravir
More
Potential Metabolism Interactions
Substrate-Substrate Interaction：If more than one drug is metabolized by the same CYP, it is possible that its metabolism is inhibited because of the competition between the drugs. That means, it can be useful to lower the dosage of the drugs in the drug-cocktail because they remain longer in the organism than in monotherapy.
Inhibitor-Inhibitor Interaction：Combining two or more inhibitors of one CYP, should be compensated by lowering the dosage of these drugs because the metabolism is reduced and the drugs remain longer in the organism than in monotherapy. Not adapting the dosage bears the risk of even more side effects.
Inhibitor-Substrate Interaction：Combining drugs that have inhibitory effect and are substrates of one particular CYP, should be compensated by lowering the dosage. They rest longer in the organism than in monotherapy. Not adapting the dosage bears the risk of even more side effects.