Interaction between
Atorvastatin
and
Gemfibrozil
Major
Others
Basic Information
| ID | DDInter133 and DDInter812 |
| Interaction | Severe myopathy and rhabdomyolysis have been reported during concomitant use of HMG-CoA reductase inhibitors and fibric acid derivatives, especially gemfibrozil. Gemfibrozil has been reported to significantly increase the plasma concentrations of some HMG-CoA reductase inhibitors and/or their active metabolites, including lovastatin, simvastatin, pravastatin, cerivastatin, and rosuvastatin (but not fluvastatin). High levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity. |
| Management | Concurrent use of fibric acid derivatives and HMG-CoA reductase inhibitors should generally be avoided unless the benefit of further alterations in lipid levels is anticipated to outweigh the potential risks. Addition of fibrates to HMG-CoA reductase inhibitor therapy typically provides little additional reduction in LDL cholesterol, but further reductions of triglycerides and increases in HDL cholesterol may be attained. Lovastatin labeling recommends that the dosage not exceed 20 mg daily when prescribed with gemfibrozil or other fibrates. All patients treated with HMG-CoA reductase inhibitors and/or fibrates 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. In addition, patients should be closely monitored for hepatotoxicity. |
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Pharmacol Ther 63 (1994): 163-76 [8] Tomlinson B, Lan IW "Combination therapy with cerivastatin and gemfibrozil causing rhabdomyolysis: Is the interaction predictable?." Am J Med 110 (2001): 669 [9] Schwandt P "Drug interactions and side effects of hypolipidemic drugs." Int J Clin Pharmacol Biopharm 17 (1979): 351-6 [10] Jacob SS, Jacob S, Williams C, Deeg MA "Simvastatin, fenofibrate, and rhabdomyolysis." Diabetes Care 28 (2005): 1258 [11] "Product Information. Zocor (simvastatin)." Merck & Co, Inc, West Point, PA. [12] Pogson GW, Kindred LH, Carper BG "Rhabdomyolysis and renal failure associated with cerivastatin-gemfibrozil combination therapy." Am J Cardiol 83 (1999): 1146 [13] Abdul-Ghaffar NU, el-Sonbaty MR "Pancreatitis and rhabdomyolysis associated with lovastatin-gemfibrozil therapy." J Clin Gastroenterol 21 (1995): 340-1 [14] Fujino H, Shimada S, Yamada I, Hirano M, Tsunenari Y, Kojima J "Studies on the interaction between fibrates and statins using human hepatic microsomes." Arzneimittelforschung 53 (2003): 701-7 [15] Williams D, Feely J "Pharmacokinetic-Pharmacodynamic Drug Interactions with HMG-CoA Reductase Inhibitors." Clin Pharmacokinet 41 (2002): 343-70 [16] 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 [17] Wang JS, Neuvonen M, Wen X, Backman JT, Neuvonen PJ "Gemfibrozil inhibits CYP2C8-mediatd cerivastatin metabolism in human liver microsomes." Drug Metab Dispos 30 (2002): 1352-6 [18] Pierce LR, Wysowski DK, Gross TP "Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy." JAMA 264 (1990): 71-5 [19] Davidson MH "Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions." Exp Opin Drug Saf 5 (2006): 145-56 [20] "Product Information. Atromid-S (clofibrate)." Wyeth-Ayerst Laboratories, Philadelphia, PA. [21] Spence JD, Munoz CE, Hendricks L, Latchinian L, Khouri HE "Pharmacokinetics of the combination of fluvastatin and gemfibrozil." Am J Cardiol 76 (1995): a80-3 [22] Prueksaritanont T, Zhao JJ, Ma B, et al. "Mechanistic Studies on Metabolic Interactions between Gemfibrozil and Statins." J Pharmacol Exp Ther 301 (2002): 1042-51 [23] Bruno-Joyce J, Dugas JM, MacCausland OE "Cerivastatin and gemfibrozil-associated rhabdomyolysis." Ann Pharmacother 35 (2001): 1016-9 [24] Kyrklund C, Backman JT, Kivisto KT, Neuvonen M, Laitila J, Neuvonen PJ "Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate." Clin Pharmacol Ther 69 (2001): 340-5 [25] "Product Information. Baycol (cerivastatin)." Bayer, West Haven, CT. [26] Roca B, Calvo B, Monferrer R "Severe rhabdomyolysis and cerivastatin-gemfibrozil combination therapy." Ann Pharmacother 36 (2002): 730-1 [27] Miller DB, Spence JD "Clinical pharmacokinetics of fibric acid derivatives (fibrates)." Clin Pharmacokinet 34 (1998): 155-62 [28] Backman JT, Kyrklund C, Kivisto KT, Wang JS, Neuvonen PJ "Plasma concentrations of active simvastatin acid are increased by gemfibrozil." Clin Pharmacol Ther 68 (2000): 122-9 [29] "Product Information. Lipitor (atorvastatin)." Parke-Davis, Morris Plains, NJ. [30] Tal A, Rajeshawari M, Isley W "Rhabdomyolysis associated with simvastatin-gemfibrozil therapy." South Med J 90 (1997): 546-7 [31] Garcia-Valdecasas-Campelo E, Gonzalez-Reimers E, Lopez-Lirola A, Rodriguez-Rodriguez E, Santolaria-Fernandez F "Acute rhabdomyolysis associated with cerivastatin therapy." Arch Intern Med 161 (2001): 893 [32] Alexandridis G, Pappas GA, Elisaf MS "Rhabdomyolysis due to combination therapy with cerivastatin and gemfibrozil." Am J Med 109 (2000): 261-2 [33] Rodriguez ML "Cerivastatin-induced rhabdomyolysis." Ann Intern Med 132 (2000): 598 [34] Unal A, Torun E, Sipahioglu MH, et al. "Fenofibrate-induced acute renal failure due to massive rhabdomyolysis after coadministration of statin in two patients." Intern Med 47 (2008): 1017-9 [35] "Product Information. Tricor (fenofibrate)." Abbott Pharmaceutical, Abbott Park, IL. [36] "Product Information. Mevacor (lovastatin)." Merck & Co, Inc, West Point, PA. [37] Ireland JH, Eggert CH, Arendt CJ, Williams AW "Rhabdomyolysis with cardiac involvement and acute renal failure in a patient taking rosuvastatin and fenofibrate." Ann Intern Med 142 (2005): 949-50 [38] Prueksaritanont T, Tang C, Qiu Y, Mu L, Subramanian R, Lin JH "Effects of fibrates on metabolism of statins in human hepatocytes." Drug Metab Dispos 30 (2002): 1280-7 [39] Schneck DW, Birmingham BK, Zalikowski JA, et al. "The effect of gemfibrozil on the pharmacokinetics of rosuvastatin." Clin Pharmacol Ther 75 (2004): 455-63 [40] Murdock DK, Murdock AK, Murdock RW, Olson KJ, Frane AM, Kersten ME, Joyce DM, Gantner SE "Long-term safety and efficacy of combination gemfibrozil and HMG-CoA reductase inhibitors for the treatment of mixed lipid disorders." Am Heart J 138 (1999): 151-5 [41] Staffa JA, Chang J, Green L "Cerivastatin and reports of fatal rhabdomyolysis." N Engl J Med 346 (2002): 539-40 [42] Kyrklund C, Backman JT, Neuvonen M, Neuvonen PJ "Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance." Clin Pharmacol Ther 73 (2003): 538-44 [43] Richter WO, Jacob BG, Schwandt P "Interaction between fibre and lovastatin." Lancet 338 (1991): 706 [44] Lilja JJ, Kivisto KT, Neuvonen PJ "Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin." Clin Pharmacol Ther 66 (1999): 118-27 [45] Boberg M, Angerbauer R, Fey P, Kanhai WK, Karl W, Kern A, Ploschke J, Radtke M "Metabolism of cerivastatin by human liver microsomes in vitro. Characterization of primary metabolic pathways and of cytochrome P45 isozymes involved." Drug Metab Dispos 25 (1997): 321-31 [46] "Product Information. Lipitor (atorvastatin)." Parke-Davis, Morris Plains, NJ. [47] McMillan K "Considerations in the formulary selection of hydroxymethylglutaryl coenzyme a reductase inhibitors." Am J Health Syst Pharm 53 (1996): 2206-14 [48] Bailey DG, Malcolm J, Arnold O, Spence JD "Grapefruit juice-drug interactions." Br J Clin Pharmacol 46 (1998): 101-10 [49] 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 |
| Alternative for Atorvastatin |
C10B
C10A |
| Alternative for Gemfibrozil |
C10A
|
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.