Basic Information
ID DDInter1098 and DDInter561
Interaction Coadministration with diltiazem has been shown to significantly increase the plasma concentrations of lovastatin acid, the active metabolite of lovastatin. The mechanism of interaction is not fully understood, but may involve diltiazem inhibition of the CYP450 3A4 isoenzyme and/or P-glycoprotein efflux transporter, of which both lovastatin and lovastatin acid are substrates. High levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death.
Management Lovastatin dosage should not exceed 20 mg daily when used in combination with diltiazem. The benefits of this combination should be carefully weighed against the potentially increased risk of myopathy including rhabdomyolysis. Fluvastatin, pravastatin, and rosuvastatin are probably safer alternatives in patients receiving diltiazem, 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] Ayanian JZ, Fuchs CS, Stone RM "Lovastatin and rhabdomyolysis." Ann Intern Med 109 (1988): 682-3 [2] Masica AL, Azie NE, Brater DC, Hall SD, Jones DR "Intravenous diltiazem and CYP3A-mediated metabolism." Br J Clin Pharmacol 50 (2000): 273-6 [3] Garnett WR "Interactions with hydroxymethylglutaryl-coenzyme A reductase inhibitors." Am J Health Syst Pharm 52 (1995): 1639-45 [4] Holtzman CW, Wiggins BS, Spinler SA "Role of P-glycoprotein in statin drug interactions." Pharmacotherapy 26 (2006): 1601-7 [5] Agbin NE, Brater DC, Hall SD "Interaction of diltiazem with lovastatin and pravastatin." Clin Pharmacol Ther 61 (1997): 201 [6] Azie NE, Brater DC, Becker PA, Jones DR, Hall SD "The interaction of diltiazem with lovastatin and pravastatin." Clin Pharmacol Ther 64 (1998): 369-77 [7] Paoletti R, Corsini A, Bellosta S "Pharmacological interactions of statins." Atheroscler Suppl 3 (2002): 35-40 [8] "Product Information. Mevacor (lovastatin)." Merck & Co, Inc, West Point, PA. [9] Ayanian JZ, Fuchs CS, Stone RM "Lovastatin and rhabdomyolysis." Ann Intern Med 109 (1988): 682-3 [10] Williams D, Feely J "Pharmacokinetic-Pharmacodynamic Drug Interactions with HMG-CoA Reductase Inhibitors." Clin Pharmacokinet 41 (2002): 343-70 [11] Worz CR, Bottorff M "The role of cytochrome P450-mediated drug-drug interactions in determining the safety of statins." Expert Opin Pharmacother 2 (2001): 1119-27 [12] "Product Information. Dilacor XR (diltiazem)." Aventis Pharmaceuticals, Bridgewater, NJ. [13] Dresser GK, Spence JD, Bailey DG "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition." Clin Pharmacokinet 38 (2000): 41-57 [14] 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 [15] Richter WO, Jacob BG, Schwandt P "Interaction between fibre and lovastatin." Lancet 338 (1991): 706 [16] 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 [17] Kantola T, Kivisto KT, Neuvonen PJ "Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid." Clin Pharmacol Ther 63 (1998): 397-402 [18] "Product Information. Mevacor (lovastatin)." Merck & Co, Inc, West Point, PA. [19] Bailey DG, Malcolm J, Arnold O, Spence JD "Grapefruit juice-drug interactions." Br J Clin Pharmacol 46 (1998): 101-10 [20] 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 [21] Thompson PD, Clarkson P, Karas RH "Statin-associated myopathy." JAMA 289 (2003): 1681-90 [22] "Product Information. Zocor (simvastatin)." Merck & Co, Inc, West Point, PA. [23] Sigusch H, Henschel L, Kraul H, Merkel U, Hoffmann A "Lack of effect of grapefruit juice on diltiazem bioavailability in normal subjects." Pharmazie 49 (1994): 675-9 [24] Christensen H, Asberg A, Holmboe AB, Berg KJ "Coadministration of grapefruit juice increases systemic exposure of diltiazem in healthy volunteers." Eur J Clin Pharmacol 58 (2002): 515-520 [25] Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0 [26] Bailey DG, Arnold JMO, Spence JD "Grapefruit juice and drugs - how significant is the interaction." Clin Pharmacokinet 26 (1994): 91-8 [27] Bailey DG, Malcolm J, Arnold O, Spence JD "Grapefruit juice-drug interactions." Br J Clin Pharmacol 46 (1998): 101-10
Alternative for Lovastatin C10A
Fenofibric acid Mipomersen Pitavastatin Evinacumab Evolocumab Probucol
Dextrothyroxine Cholestyramine Clofibrate Colestipol Bempedoic acid
More
Alternative for Diltiazem C08D

C05A
Tetracaine Zinc sulfate Zinc acetate Fluocinolone acetonide Fluocinonide Zinc chloride
Procaine Betamethasone Fluorometholone Zinc gluconate
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.