Selected drug interactions in cardiology

Authors: Prokeš M.;  Suchopár J.
Authors‘ workplace: DrugAgency a. s.
Published in: Kardiol Rev Int Med 2020, 22(3): 108-117


Rational pharmacotherapy means the choice of a drug not only in terms of its effectiveness, but also in terms of possible risks, which include drug interactions. The aim of this article is to provide the current state of knowledge about the drug interactions of digoxin, amiodarone and statins, not so that doctors stop prescribing these drugs, but so that the doctor can take certain measures (dose adjustment, patient monitoring, laboratory tests and/or patient instructions) to reduce potential risks.


amiodarone – statins – Drug interactions – cardiology – pharmacology – digoxin


1. Shitara Y, Sugiyama Y. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme function. Pharmacol Ther 2006; 112 (1): 71–105. doi: 10.1016/j.pharmthera.2006.03.003.

2. Wang Q, Zheng M, Leil T. Investigating transporter-mediated drug-drug intgeractions using a physiologically based pharmacokinetic model of rosuvastatin. CPT Pharmacometrics Syst Pharmacol 2017; 6 (4): 228–238. doi: 10.1002/psp4.12168.

3. Englund G, Hallberg P, Artursson P et al. Association between the number of coadministered P-glycoprotein inhibitors and serum digoxin levels in patients on therapeutic drug monitoring. BMC Med 2004; 2: 8. doi: 10.1186/1741-7015-2-8.

4. Rengelshausen J, Göggelmann C, Burhenne J et al. Contribution of increased oral bio­availability and reduced nonglomerular renal clearance of digoxin to the digoxin-clarihtromycin interaction. Br J Clin Pharmacol 2003; 56 (1): 32–38. doi: 10.1046/j.1365-2125.2003.01824.x.

5. Tanaka H, Matsumoto K, Ueno K et al. Effect of clarithromycin on steady-state digoxin concentrations. Ann Pharmacother 2003; 37 (2): 178–181. doi: 10.1177/106002800303700202.

6. Juurlink DN, Mamdani M, Kopp A et al. Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA 2003; 289 (13): 1652–1658. doi: 10.1001/jama.289.13.1652.

7. Gomes T, Mamdani M, Juurlink DN. Macrolide-induced digoxin toxicity: a population-based study. Clin Pharmacol Ther 2009; 86 (4): 383–386. doi: 10.1038/clpt.2009.127.

8. Quinn KL, Macdonald EM, Gomes T et al. Macrolides, digoxin toxicity and the risk of sudden death: a population-based study. Drug Saf 2017; 40 (9): 835–840. doi: 10.1007/s40264-017-0539-9.

9. Nademanee K, Kannan R, Hendrickson J et al. Amiodarone-digoxin interaction: Clinical signifikance, time course of development, potential pharmacokinetic mechanisms and therapeutic implications. J Am Coll Cardiol 1984; 4 (1): 111–116. doi: 10.1016/s0735-1097 (84) 80327-7.

10. Study INT5189. In: U.S. Food and Drug Administration; Center for Drug Evaluation and Research. NDA 22-425 Clinical Pharmacology and Biopharmaceutics Review: 230–236.

11. Hohnloser SH, Halperin JL, Camm AJ et al. Interaction between digoxin and dronedarone in the PALLAS trial. Circ Arrhythm Electrophysiol 2014; 7 (6): 1019–1025. doi: 10.1161/CIRCEP.114.002046.

12. Belz GG, Doering W, Munkes R et al. Interaction between digoxin and calcium antagonists and antiarrhythmic drugs. Clin Pharmacol Ther 1983; 33 (4): 410–417. doi: 10.1038/clpt.1983.55.

13. Salerno DM, Granrud G, Sharkey P et al. A controlled trial of propafenone for treatment of frequent and repetitive ventricular premature complexes. Am J Cardiol 1984; 53 (1): 77–83. doi: 10.1016/0002-9149 (84) 90687-8.

14. Pedersen KE, Dorf-Pedersen A, Hvidt S et al. The long-term effect of verapamil on plasma digoxin concentration and renal digoxin clearance in healthy subjects. Eur J Clin Pharmacol 1982; 22 (2): 123–127. doi: 10.1007/BF00542456.

15. SPC v ČR. Isoptin (verapamil), Mylan, 2020/4. Dostupné na: //

16. Baris N, Kalkan S, Güneri S et al. Infuence of carvedilol on serum digoxin levels in heart failure: is there any gender difference? Eur J Clin Pharmacol 2006; 62 (7): 535–538. doi: 10.1007/s00228-006-0138-7.

17. Ratnapalan S, Griffiths K, Costei AM et al. Digoxin carvedilol interactions in children. J Pediatr 2003; 142 (5): 572–574. doi: 10.1067/mpd.2003.160.

18. SPC v ČR. Atram (karvedilol), Zentiva, 2018/6. Dostupné na: http: //

19. Partanen J, Jalava KM, Neuvonen PJ. Intraconazole increasses serum digoxin concentration. Pharmacol Toxicol 1996; 79 (5): 274–276. doi: 10.1111/j.1600-0773.1996.tb00273.x.

20. Jalava KM, Partanen J, Neuvonen PJ. Intraconazole decreases renal clearance of digoxin. Ther Drug Monit 1997; 19 (6): 609–613. doi: 10.1097/00007691-199712000-00001.

21. Steiness E. Renal tubular secretion of digoxin. Circulation 1874; 50 (1): 103–107. doi: 10.1161/01.cir.50.1.103.

22. Waldorf S, Andersen JD, Heeboll-Nielsen N et al. Spironolactone-induced changes in digoxin kinetics. Clin Pharmacol Ther 1978; 24 (2): 162–167. doi: 10.1002/cpt1978242162.

23. Dorian P, Strauss M, Cardella C et al. Digoxin-cyclosporine interaction: severe digitalis toxicity after cyclosporine treatment. Clin Invest Med 1988; 11 (2): 108–112.

24. Woosley RL, Heise CW, Romero KA. QTdrugs List, (1. 3. 2020), AZCERT, Inc., 1822 Innovation Park Dr., Oro Valley, AZ 85755, USA. Available at:

25. Boutitie F, Boissel JP, Connolly SJ et al. Amiodarone interaction with beta-blockers: analysis of the merged EMIAT (European myocardial infarct amiodarone trial) and CAMIAT (Canadian amiodarone myocardial infarction trial) databases. The Emiat and Camiat Investigators. Ciculation 1999; 99 (17): 2268–2275. doi: 10.1161/01.cir.99.17.2268.

26. SPC ČR. Cordarone® (amiodaron), sanofi-aventis, 2019/8. Dostupné na: http: //

27. Bultas J. Antiarytmika. In: Suchopár J et al. Compendium Léčiva používaná v podmínkách ČR, 2018: 1125–1132.

28. Sanoski CA, Bauman JL. Clinical observations with the amiodarone/warfarin interaction: dosing relationships with long-term therapy. Chest 2002; 121 (1): 19–23. doi: 10.1378/chest.121.1.19.

29. Holm J, Lindh JD, Andersson ML et al. The effect of amiodarone on warfarin anticoagulation: a register-based nationwide cohort study involving the Swedish population. J Thromb Haemost 2017; 15 (3): 446–453. doi: 10.1111/jth.13614.

30. Santos PC, Soares RA, Strunz CM et al. Simultaneous use of amiodarone influences warfarin maintenance dose but is not associated with adverse events. J Manag Care Spec Pharm 2014; 20 (4): 376–381. doi: 10.18553/jmcp.2014.20.4.376.

31. Lu Y, Won KA, Nelson BJ et al. Characteristics of the amiodarone-warfarin interaction during long-term follow-up. Am J Health Syst Pharm 2008; 65 (10): 947–952. doi: 10.2146/ajhp060415.

32. Lam J, Gomes T, Juurlink DN et al. Hospitalization for hemorrhage among warfarin recipients prescribed amiodarone. Am J Cardiol 2013; 112 (3): 420–423. doi: 10.1016/j.amjcard.2013.03.051.

33. Suchý D, Poklopová Z. Lékové interakce warfarinu s kardiovaskulárními léky. Klin Farmakol Farm 2005; 19: 40–42.

34. Chang SH, Chou IJ, Yeh YH et al. Association between use of non-vitamin K oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation. JAMA 2017; 318 (13): 1250–1259. doi: 10.1001/jama.2017.13883.

35. Mendell J, Zahir H, Matsushima N et al. Drug-drug interaction studies of cardiovascular drugs involving P-glycoprotein, an efflux transporter, on the pharmacokinetics of edoxaban, an oral factor Xa inhibitor. Am J Cardiovasc Drugs 2013; 13 (5): 331–342. doi: 10.1007/s40256-013-0029-0.

36. SPC ČR. Pradaxa® (dabigatran), Behringer Ingelheim 2020/1. Dostupné na: https: //

37. Hanigan S, Das J, Pogue K et al. The real world use of combined P-glycoprotein and moderate CYP3A4 inhibitors with rivaroxaban or apixaban increases bleeding. J Thromb Thrombolysis 2020; 49 (4): 636–643. doi: 10.1007/s11239-020-02037-3.

38. Senesael AL, Larock AS, Douxfils J et al. Rivaroxaban plasma levels in patients admitted for bleed­ing events: insights from a prospective study. Thromb J 2018; 16: 28. doi: 10.1186/s12959-018-0183-3.

39. Stölberg C, Bastovansky A, Finsterer J. Fatal intracerebral bleeding under rivaroxaban. Int J Cardiol 2015; 201: 110–112. doi: 10.1016/j.ijcard.2015.06.081.

40. Oladiran O, Segal J, Nwosu I et al. A rare case of spontaneous cardiac tamponade idnuced by concomitant use of rivaroxaban and amiodarone. Case Rep Cardiol 2018; 1650716. doi: 10.1155/2018/1650716.

41. SPC ČR. Xarelto® (rivaroxaban), Bayeer 2020/1. Dostupné na: https: //

41. Flaker G, Lopez RD, Hylek E et al. Amiodarone, anticoagulation and clinical events in patients with atrial fibrillation. Insights from the ARISTOTLE trial. J Am Coll Cardiol 2014; 64 (15): 1541–1550. doi: 10.1016/j.jacc.2014.07.967.

42. Gulilat M, Keller D, Linton B et al. Drug interactions and pharmacogenetic factors contribute to variation in apixaban concentration in atrial fibrillation patients in routine care. J Trhomb Thrombolysis 2020; 49 (2): 294–303. doi: 10.1007/s11239-019-01962-2.

43. SPC ČR. Eliquis® (apixaban), Bristol-Myers Squib/Pfizer, 2020/3. Dostupné na: https: //

44. Steffel J, Guigliano RP, Braunwald E et al. Edoxaban vs. warfarin in patients with atrial fibrillation on amiodarone: a subgroup analysis of the ENGAGE AF-TIMI 48 Trial. Eur Heart J 2015; 36 (33): 2239–2245. doi: 10.1093/eurheartj/ehv201.

45. SPC ČR. Lixiana® (edoxaban), Daiichi Sankyo, 2020/3. Dostupné na: https: //

46. Jacobson TA. Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin and atorvastatin when coadministered with cytochrome P450 inhibitors. Am J Cardiol 2004; 94 (9): 1140–1146. doi: 10.1016/j.amjcard.2004.07.080.

47. Patel AM, Shariff S, Bailey DG et al. Statin toxicity from macrolide antibio­tic coprescription: a population-based cohort study. Ann Intern Med 2013; 158 (12): 860–876. doi: 10.7326/0003-4819-158-12-201306180-00004.

48. Li DQ, Kim R, McArthur E. Risk of adverse events among older adults following co-prescription of clarithromycin and statins not metabolized by cytochrome P450 3A4. CMAJ 2015; 187 (3): 174–180. doi: 10.1503/cmaj.140950.

49. SPC ČR. Simvastatin Mylan (simvastatin), Mylan, 2020/2n. Dostupné na: http: //

50. SPC ČR. Sortis (atorvastatin), Pfizer, 2019/9. Dostupné na: http: //

51. SPC ČR. Crestor (rosuvastatin), AstraZeneca AB, 2019/4. Dostupné na: http: //

52. SPC ČR. Lescol XL (fluvastatin), Novartis, 2018/12. Dostupné na: http: //

53. Khandwala MH. Lipid lowering inefficiacy of high-dose statin therapy due to concurrent use of phenytoin. South Med J 2006; 99 (12): 1385–1387. doi: 10.1097/01.smj.0000251470.39036.ea.

54. Candrilli SD, Manjunath R, Davis KL et al. The association between antiepileptic drugs and HMG-CoA reductase inhibitor co-medication and cholesterol management in patients with epilepsy. Epilepsy Res 2010; 91 (2–3): 260–266. doi: 10.1016/j.eplepsyres.2010.07.021.

55. Mäkinen J, Rainesalo S, Raitanen J et al. Discontinuation of carbamazepine due to concerns of long-term consequences of enzyme induction. Epilepsia Open 2018; 3 (3): 340–347. doi: 10.1002/epi4.12227.

56. Al-Sarraf A, Li M, Frohlich J. Statin resistant dyslipidemia in a patient treated with amiodarone. BMJ Case Rep 2011; bcr0820114620. doi: 10.1136/bcr.08.2011.4620.

57. Hudig F, Bakker O, Wiersinga WM. Amiodarone decreases gene expression of low-density lipoprotein receptor at both the mRNA and the protein level. Metabolism 1998; 47 (9): 1052–1057. doi: 10.1016/s0026-0495 (98) 90277-3.

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