Abstract
Background: Co-administration of cytochrome P450 (CYP) 3A4 inhibitors with simvastatin or atorvastatin is associated with increased risk of developing myopathy or rhabdomyolysis.
Objective: To detect co-prescriptions of CYP3A4 inhibitors with simvastatin or atorvastatin in community pharmacies and assess the risk-preventive actions taken by the prescribing physicians who were alerted about the co-prescription by the pharmacist.
Methods: This naturalistic study was performed during four separate 6-week periods in 2004 and 2005, and involved 110 Norwegian community pharmacists (25–30 in each period). Co-prescription of the selected CYP3A4 inhibitors diltiazem, verapamil, clarithromycin, erythromycin, fluconazole, itraconazole and ketoconazole with either simvastatin or atorvastatin was detected with the aid of a simple computer programme. In instances where the pharmacist alerted the prescribing physician about the co-prescription, information on possible strategies to minimize the risk associated with the interaction was also provided. Odds ratios (ORs) were estimated to describe the associations between prescription variables and frequencies of physician information and prescription change, respectively.
Results: In total, 245 co-prescriptions of CYP3A4 inhibitors with simvastatin (134 events) or atorvastatin (111) were detected. Diltiazem (86 events), verapamil (72), erythromycin (48) and clarithromycin (29) were the most commonly coprescribed CYP3A4 inhibitors. Physicians were informed in 168 out of 245 cases (68.6%). The prescription was subsequently changed in 100 out of 168 cases (59.5%). Another 50 physicians (29.8%) responded that they would consult the patient and monitor potential adverse effects, while only 18 physicians (10.7%) replied that they had already managed the interactions or considered the issue as irrelevant. The adjusted OR for the informing of the physician was 1.89 (95% CI 0.98, 3.63) in patients receiving a daily HMG-CoA reductase inhibitor (‘statin’) dose of ≥40 mg compared with patients receiving a statin dose of <40 mg/day. The adjusted OR for prescription change was 4.98 (95% CI 2.36, 10.52) if coprescription was detected prior to the initiation of concurrent use compared with if it was detected during concurrent use.
Conclusion: Nine out of ten physicians changed prescriptions or monitored potential adverse effects when informed by community pharmacists about the risk associated with co-prescription of CYP3A4 inhibitors with simvastatin or atorvastatin. This suggests that an important risk factor for myotoxicity due to these statins could be minimized through interdisciplinary co-operation.
Similar content being viewed by others
References
Bottorff MB. Statin safety and drug interactions: clinical implications. Am J Cardiol 2006; 97: 27C–31C
Evans M, Rees A. Effects of HMG-CoA reductase inhibitors on skeletal muscle: are all statins the same? Drug Saf 2002; 25: 649–63
Antons KA, Williams CD, Baker SK, et al. Clinical perspectives of statin-induced rhabdomyolysis. Am J Med 2006; 119: 400–9
Ucar M, Mjorndal T, Dahlqvist R. HMG-CoA reductase inhibitors and myotoxicity. Drug Saf 2000; 22: 441–57
Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol 2006; 97: 52C–60C
Furberg CD, Pitt B. Withdrawal of cerivastatin from the world market. Curr Control Trials Cardiovasc Med 2001; 2: 205–7
Chang JT, Staffa JA, Parks M, et al. Rhabdomyolysis with HMG-CoA reductase inhibitors and gemfibrozil combination therapy. Pharmacoepidemiol Drug Saf 2004; 13: 417–26
Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 2006; 80: 565–81
Gilad R, Lampl Y. Rhabdomyolysis induced by simvastatin and ketoconazole treatment. Clin Neuropharmacol 1999; 22: 295–7
Itakura H, Vaughn D, Haller DG, et al. Rhabdomyolysis from cytochrome p-450 interaction of ketoconazole and simvastatin in prostate cancer [letter]. J Urol 2003; 169: 613
Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998; 64: 58–65
Neuvonen PJ, Kantola T, Kivisto KT. Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther 1998; 63: 332–41
Saliba WR, Elias M. Severe myopathy induced by the coadministration of simvastatin and itraconazole [letter]. Eur J Intern Med 2005; 16: 305
Shaukat A, Benekli M, Vladutiu GD, et al. Simvastatin-fluconazole causing rhabdomyolysis. Ann Pharmacother 2003; 37: 1032–5
Kahri J, Valkonen M, Backlund T, et al. Rhabdomyolysis in a patient receiving atorvastatin and fluconazole. Eur J Clin Pharmacol 2005; 60: 905–7
Mousa O, Brater DC, Sunblad KJ, et al. The interaction of diltiazem with simvastatin. Clin Pharmacol Ther 2000; 67: 267–74
Lewin 3rd JJ, Nappi JM, Taylor MH. Rhabdomyolysis with concurrent atorvastatin and diltiazem. Ann Pharmacother 2002; 36: 1546–9
Kanathur N, Mathai MG, Byrd Jr RP, et al. Simvastatin-diltiazem drug interaction resulting in rhabdomyolysis and hepatitis. Tenn Med 2001; 94: 339–41
Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther 1998; 64: 177–82
Becquemont L, Neuvonen M, Verstuyft C, et al. Amiodarone interacts with simvastatin but not with pravastatin disposition kinetics. Clin Pharmacol Ther 2007; 81: 679–84
Roten L, Schoenenberger RA, Krahenbuhl S, et al. Rhabdomyolysis in association with simvastatin and amiodarone. Ann Pharmacother 2004; 38: 978–81
Ricaurte B, Guirguis A, Taylor HC, et al. Simvastatin-amiodarone interaction resulting in rhabdomyolysis, azotemia, and possible hepatotoxicity. Ann Pharmacother 2006; 40: 753–7
Mah Ming JB, Gill MJ. Drug-induced rhabdomyolysis after concomitant use of clarithromycin, atorvastatin, and lopinavir/ ritonavir in a patient with HIV. AIDS Patient Care STDS 2003; 17: 207–10
Fichtenbaum CJ, Gerber JG, Rosenkranz SL, et al. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047. AIDS 2002; 16: 569–77
Hsyu PH, Schultz-Smith MD, Lillibridge JH, et al. Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and simvastatin. Antimicrob Agents Chemother 2001; 45: 3445–50
Hare CB, Vu MP, Grunfeld C, et al. Simvastatin-nelfinavir interaction implicated in rhabdomyolysis and death. Clin Infect Dis 2002; 35: e111–2
Jacobson TA. Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors. Am J Cardiol 2004; 94: 1140–6
Molden E, Andersson K. Simvastatin-associated rhabdomyolysis after co-administration of macrolide antibiotics in two patients. Pharmacotherapy 2007; 27: 603–7
Amsden GW, Kuye O, Wei GC. A study of the interaction potential of azithromycin and clarithromycin with atorvastatin in healthy volunteers. J Clin Pharmacol 2002; 42: 444–9
Sipe BE, Jones RJ, Bokhart GH. Rhabdomyolysis causing AV blockade due to possible atorvastatin, esomeprazole, and clarithromycin interaction. Ann Pharmacother 2003; 37: 808–11
Siedlik PH, Olson SC, Yang BB, et al. Erythromycin coadministration increases plasma atorvastatin concentrations. J Clin Pharmacol 1999; 39: 501–4
Rätz Bravo AE, Tchambaz L, Krahenbuhl-Melcher A, et al. Prevalence of potentially severe drug-drug interactions in ambulatory patients with dyslipidaemia receiving HMG-CoA reductase inhibitor therapy. Drug Saf 2005; 28: 263–75
Ronaldson KJ, O’Shea JM, Boyd IW. Risk factors for rhabdomyolysis with simvastatin and atorvastatin. Drug Saf 2006; 29: 1061–7
Omar MA, Wilson JP. FDA adverse event reports on statinassociated rhabdomyolysis. Ann Pharmacother 2002; 36: 288–95
Cziraky MJ, Willey VJ, McKenney JM, et al. Statin safety: an assessment using an administrative claims database. Am J Cardiol 2006; 97: 61C–8C
Lee AJ, Maddix DS. Rhabdomyolysis secondary to a drug interaction between simvastatin and clarithromycin. Ann Pharmacother 2001; 35: 26–31
Kivisto KT, Kantola T, Neuvonen PJ. Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin. Br J Clin Pharmacol 1998; 46: 49–53
Rubinstein E. Comparative safety of the different macrolides. Int J Antimicrob Agents 2001; 18 Suppl. 1: S71–6
von Rosensteil NA, Adam D. Macrolide antibacterials: drug interactions of clinical significance. Drug Saf 1995; 13: 105–22
Backman JT, Olkkola KT, Neuvonen PJ. Azithromycin does not increase plasma concentrations of oral midazolam. Int J Clin Pharmacol Ther 1995; 33: 356–9
Wrighton SA, Ring BJ. Inhibition of human CYP3A catalyzed 1′-hydroxy midazolam formation by ketoconazole, nifedipine, erythromycin, cimetidine, and nizatidine. Pharm Res 1994; 11: 921–4
Katoh M, Nakajima M, Shimada N, et al. Inhibition of human cytochrome P450 enzymes by 1,4-dihydropyridine calcium antagonists: prediction of in vivo drug-drug interactions. Eur J Clin Pharmacol 2000; 55: 843–52
Ma B, Prueksaritanont T, Lin JH. Drug interactions with calcium channel blockers: possible involvement of metaboliteintermediate complexation with CYP3A. Drug Metab Dispos 2000; 28: 125–30
Zocor (simvastatin) prescribing information [online]. Available from URL: http://www.zocor.com/zocor/shared/documents/english/pi.pdf [Accessed 2007 Jul 10]
Lipitor (atorvastatin) prescribing information [online]. Available from URL: http://www.lipitor.com/content/LipitorPI.pdf [Accessed 2007 Jul 10]
Molden E, Westergren T. Interaction risk with statin switch [in Norwegian]. Tidsskr Nor Laegeforen 2007; 127: 428–31
Molden E, Garcia BH, Braathen P, et al. Co-prescription of cytochrome P450 2D6/3A4 inhibitor-substrate pairs in clinical practice: a retrospective analysis of data from Norwegian primary pharmacies. Eur J Clin Pharmacol 2005; 61: 119–25
Acknowledgements
The authors thank Trond Raudsandmoen and Marit Andrew for valuable input during the planning of the study. We are grateful to Kathlyn J. Ronaldson for sending information about individual CYP3A4 inhibitors (see Ronaldson et al.[33]
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Molden, E., Skovlund, E. & Braathen, P. Risk Management of Simvastatin or Atorvastatin Interactions with CYP3A4 Inhibitors. Drug-Safety 31, 587–596 (2008). https://doi.org/10.2165/00002018-200831070-00004
Published:
Issue Date:
DOI: https://doi.org/10.2165/00002018-200831070-00004