Basic Information
ID DDInter133 and DDInter393
Interaction Some macrolide antibiotics inhibit CYP450 3A4 and may elevate the plasma concentrations of HMG-CoA reductase inhibitors that are metabolized by the isoenzyme. Macrolides that may significantly inhibit CYP450 3A4 include troleandomycin, erythromycin, and clarithromycin.
Management The benefits of using HMG-CoA reductase inhibitors that are metabolized by CYP450 3A4 in combination with medications that can inhibit the isoenzyme such as clarithromycin and erythromycin should be carefully weighed against the potentially increased risk of myopathy including rhabdomyolysis. A lower dosage of the HMG-CoA reductase inhibitor should be considered if concomitant use is required. Atorvastatin labeling recommends that the dosage not exceed 20 mg/day when used in combination with clarithromycin. Fluvastatin, pitavastatin, and rosuvastatin may be 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] Kantola T, Kivisto KT, Neuvonen PJ "Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations." Clin Pharmacol Ther 64 (1998): 177-82 [2] Ayanian JZ, Fuchs CS, Stone RM "Lovastatin and rhabdomyolysis." Ann Intern Med 109 (1988): 682-3 [3] "Product Information. Zocor (simvastatin)." Merck & Co, Inc, West Point, PA. [4] Williams D, Feely J "Pharmacokinetic-Pharmacodynamic Drug Interactions with HMG-CoA Reductase Inhibitors." Clin Pharmacokinet 41 (2002): 343-70 [5] 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 [6] 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 [7] Amsden GW, Kuye O, Wei GC "A study of the interaction potential of azithromycin and clarithromycin with atorvastatin in healthy volunteers." J Clin Pharmacol 42 (2002): 444-9 [8] Siedlik PH, Olson SC, Yang BB, Stern RH "Erythromycin coadministration increases plasma atorvastatin concentrations." J Clin Pharmacol 39 (1999): 501-4 [9] Ayanian JZ, Fuchs CS, Stone RM "Lovastatin and rhabdomyolysis." Ann Intern Med 109 (1988): 682-3 [10] Chouhan UM, Chakrabarti S, Millward LJ "Simvastatin interaction with clarithromycin and amiodarone causing myositis." Ann Pharmacother 39 (2005): 1760-1 [11] "Product Information. Baycol (cerivastatin)." Bayer, West Haven, CT. [12] Westphal JF "Macrolide - induced clinically relevant drug interactions with cytochrome P-450 (CYP) 3A4: an update focused on clarithromycin, azithromycin, and dirithromycin." Br J Clin Pharmacol 50 (2000): 285-95 [13] Garnett WR "Interactions with hydroxymethylglutaryl-coenzyme A reductase inhibitors." Am J Health Syst Pharm 52 (1995): 1639-45 [14] Grunden JW, Fisher KA "Lovastatin-induced rhabdomyolysis possibly associated with clarithromycin and azithromycin." Ann Pharmacother 31 (1997): 859-63 [15] "Product Information. Lipitor (atorvastatin)." Parke-Davis, Morris Plains, NJ. [16] 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 [17] "Product Information. Mevacor (lovastatin)." Merck & Co, Inc, West Point, PA. [18] 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 [19] Omar MA, Wilson JP "FDA adverse event reports on statin-associated rhabdomyolysis." Ann Pharmacother 36 (2002): 288-95 [20] Lee AJ, Maddix DS "Rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin." Ann Pharmacother 35 (2001): 26-31 [21] Spach DH, Bauwens JE, Clark CD, Burke WG "Rhabdomyolysis associated with lovastatin and erythromycin use." West J Med 154 (1991): 213-5 [22] 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 [23] Sipe BE, Jones RJ, Bokhart GH "Rhabdomyolysis Causing AV Blockade Due to Possible Atorvastatin, Esomeprazole, and Clarithromycin Interaction." Ann Pharmacother 37 (2003): 808-11 [24] Cooper JM, Jones AL "Neuroleptic malignant syndrome or a statin drug reaction? A case report." Clin Neuropharmacol 32 (2009): 348-9 [25] Welling PG, Huang H, Hewitt PF, Lyons LL "Bioavailability of erythromycin stearate: influence of food and fluid volume." J Pharm Sci 67 (1978): 764-6 [26] Welling PG "Influence of food and diet on gastrointestinal drug absorption: a review." J Pharmacokinet Biopharm 5 (1977): 291-334 [27] Randinitis EJ, Sedman AJ, Welling PG, Kinkel AW "Effect of a high-fat meal on the bioavailability of a polymer-coated erythromycin particle tablet formulation." J Clin Pharmacol 29 (1989): 79-84 [28] Coyne TC, Shum S, Chun AH, Jeansonne L, Shirkey HC "Bioavailability of erythromycin ethylsuccinate in pediatric patients." J Clin Pharmacol 18 (1978): 194-202 [29] Malmborg AS "Effect of food on absorption of erythromycin. A study of two derivatives, the stearate and the base." J Antimicrob Chemother 5 (1979): 591-9 [30] Welling PG, Elliott RL, Pitterle ME, et al "Plasma levels following single and repeated doses of erythromycin estolate and erythromycin stearate." J Pharm Sci 68 (1979): 150-5 [31] Kanazawa S, Ohkubo T, Sugawara K "The effects of grapefruit juice on the pharmacokinetics of erythromycin." Eur J Clin Pharmacol 56 (2001): 799-803 [32] Richter WO, Jacob BG, Schwandt P "Interaction between fibre and lovastatin." Lancet 338 (1991): 706 [33] "Product Information. Lipitor (atorvastatin)." Parke-Davis, Morris Plains, NJ. [34] 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 [35] McMillan K "Considerations in the formulary selection of hydroxymethylglutaryl coenzyme a reductase inhibitors." Am J Health Syst Pharm 53 (1996): 2206-14 [36] Bailey DG, Malcolm J, Arnold O, Spence JD "Grapefruit juice-drug interactions." Br J Clin Pharmacol 46 (1998): 101-10 [37] 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 [38] 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
Alternative for Atorvastatin C10B
Bempedoic acid Perindopril

C10A
Fenofibric acid Clofibrate Cholestyramine Gemfibrozil Fluvastatin Alirocumab
Bempedoic acid Colestipol Evolocumab
More
Alternative for Clarithromycin A02B
Levofloxacin Dexlansoprazole Bismuth subcitrate potassium

J01F
Dirithromycin Lincomycin
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.