Skip to main content
Log in

Drug Interactions Involving Antifungal Drugs: Time Course and Clinical Significance

  • Published:
Current Fungal Infection Reports Aims and scope Submit manuscript

Abstract

The antifungal armamentarium has expanded greatly over the past two decades. This expansion, along with the pharmacologically complex therapeutic regimens used in treating many patients with systemic fungal disease, enhances the risk of clinically significant drug–drug interactions. This review examines the drug–drug interaction potential of antifungal agents by pharmacologic class and attempts to provide perspective on the time course and clinical significance of these events.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Valeriote F, Medoff G, Tolen S, Dieckman J: Amphotericin B potentiation of the cytotoxicity of anticancer agents against both normal hematopoietic and leukemia cells in mice. J Natl Cancer Inst 1984, 73:475–482.

    CAS  PubMed  Google Scholar 

  2. Valeriote F, Medoff G, Dieckman J: Potentiation of cytotoxicity of anticancer agents by several different polyene antibiotics. J Natl Cancer Inst 1984, 72:435–439.

    CAS  PubMed  Google Scholar 

  3. Ozols RF, Hogan WM, Grotzinger KR, et al.: Effects of amphotericin B on Adriamycin and melphalan cytotoxicity in human and murine ovarian carcinoma and in L1210 leukemia. Cancer Res 1983, 43:959–964.

    CAS  PubMed  Google Scholar 

  4. Valeriote F, Medoff G, Dieckman J: Potentiation of anticancer agent cytotoxicity against sensitive and resistant AKR leukemia by amphotericin B1. Cancer Res 1979, 39:2041–2045.

    CAS  PubMed  Google Scholar 

  5. Saad AH, DePestel DD, Carver PL: Factors influencing the magnitude and clinical significance of drug interactions between azole antifungals and select immunosuppressants. Pharmacotherapy 2006, 25:1730–1744.

    Article  Google Scholar 

  6. Sugar AM, Saunders C, Idelson BA, Bernard DB: Interaction of fluconazole and cyclosporine. Ann Intern Med 1989, 110:844.

    CAS  PubMed  Google Scholar 

  7. Diflucan [prescribing information]. New York, NY: Pfizer; 2008.

  8. Blum RA, Wilton JH, Hilligoss DM, et al.: Effect of fluconazole on the disposition of phenytoin. Clin Pharmacol Ther 1991, 49:420–425.

    CAS  PubMed  Google Scholar 

  9. Tarumi Y, Perira, J, Watanabe S: Methadone and fluconazole: respiratory depression by drug interaction. J Pain Symptom Manage 2002, 23:286–298.

    Article  Google Scholar 

  10. Cobb MN, Desai J, Brown LS, et al.: The effect of fluconazole on the clinical pharmacokinetics of methadone. Clin Pharmacol Ther 1998, 63:655–662.

    Article  CAS  PubMed  Google Scholar 

  11. Panomvana Na, Ayudhya D, Thanompuangseree N, Tansubphaswadikul S: Effect of rifampin on the pharmacokinetics of fluconazole in patients with AIDS. Clin Pharmacokinet 2004, 43:725–732.

    Article  Google Scholar 

  12. Shaukat A, Benekli M, Vladutiu GD, et al.: Simvastatin-fluconazole causing rhabdomyolysis. Ann Pharmacother 2003, 56:24–29.

    Google Scholar 

  13. Kantola T, Backman JT, Niemi M, et al.: Effect of fluconazole on plasma fluvastatin and pravastatin concentrations. Eur J Clin Pharmacol 2005, 56:225–229.

    Article  Google Scholar 

  14. Romero AJ, Le Pogamp P, Nilsson LG, Wood N: Effect of voriconazole on the pharmacokinetics of cyclosporine in renal transplant patients. Clin Pharmacol Ther 2005, 71:226–234.

    Article  Google Scholar 

  15. VFEND, IV (voriconazole) for injection, VFEND, tablets (voriconazole), VFEND (voriconazole) for oral suspension [prescribing information]. New York, NY: Pfizer; 2008.

  16. Venkataramanan R, Zang S, Gayowski T, Singh N: Voriconazole inhibition of the metabolism of tacrolimus in a liver transplant and in human liver microsomes. Antimicrob Agents Chemother 2002, 46:3091–3093.

    Article  CAS  PubMed  Google Scholar 

  17. Purkins L, Wood N, Ghahramani P, et al.: Co-administration of voriconazole and phenytoin: pharmacokinetic interaction, safety, and toleration. Br J Clin Pharmacol 2003, 56:35–44.

    Google Scholar 

  18. Saari TI, Laine K, Neuvonen M, et al.: Effect of voriconazole and fluconazole on the pharmacokinetics of intravenous fentanyl. Eur J Clin Pharmacol 2008, 64:25–30.

    Article  CAS  PubMed  Google Scholar 

  19. Purkins L, Wood N, Kleinermans D, Nichols D: Voriconazole potentiates warfarin-induced prothrombin time prolongation. Br J Clin Pharmacol 2003, 56:24–29.

    Article  CAS  PubMed  Google Scholar 

  20. •• Nivoix Y, Ubeaud-Sequier G, Engel P, et al.: Drug–drug interaction of triazole antifungal agents in multimorbid patients and implications for patient care. Curr Drug Metab 2009, 10:395–409. This article summarizes azole drug interactions in patients with complicated medical histories. It assesses azole drug interactions in conditions such as HIV, cancer, and transplantation, and can help practitioners assess appropriate drug regimens for complicated patients.

    Article  CAS  PubMed  Google Scholar 

  21. Noxafil (posaconazole) suspension [package insert]. Kenilworth, NJ: Schering-Plough; 2008.

  22. Krishna G, Parsons A, Kantesaria B, Mant T: Evaluation of the pharmacokinetics of posaconazole and rifabutin following co-administration to healthy men. Curr Med Res Opin 2007, 23:545–552.

    Article  CAS  PubMed  Google Scholar 

  23. Krishna G, Sansone-Parsons A, Kantesaria B: Drug interaction assessment following concomitant administration of posaconazole and phenytoin in healthy men. Curr Med Res Opin 2007, 23:1415–1422.

    Article  CAS  PubMed  Google Scholar 

  24. Krishna G, Moton A, Ma L, et al.: Effects of oral posaconazole on the pharmacokinetic properties of oral and intravenous midazolam: a phase I, randomized, open-label, crossover study in healthy volunteers. Clin Ther 2009, 31:286–298.

    Article  CAS  PubMed  Google Scholar 

  25. Sansone-Parsons A, Krishna G, Martinho M, et al.: Effect of oral posaconazole on pharmacokinetics of cyclosporine and tacrolimus. Pharmacotherapy 2007, 27:825–834.

    Article  CAS  PubMed  Google Scholar 

  26. Krishna G, Moton A, Ma L, et al.: Effects of oral posaconazole on the pharmacokinetics of atazanavir alone and with ritonavir or with efavirenz in healthy adult volunteers. J Acquir Immune Defic Syndr 2009, 51:437–444.

    Article  CAS  PubMed  Google Scholar 

  27. Sporanox (itraconazole) capsules [package insert]. Titusville, NJ: Janssen; 2008.

  28. Kaukonen KM, Olkkola KT, Neuvonen PJ: Itraconazole increases plasma concentrations of quinidine. Clin Pharmacol Ther 1997, 62:510–517.

    Article  CAS  PubMed  Google Scholar 

  29. Jalava KM, Partanen J, Neuvonen PJ: Itraconazole decreases renal clearance of digoxin. Ther Drug Monit 1997, 19:609–613.

    Article  CAS  PubMed  Google Scholar 

  30. Marr KA, Leisenring W, Crippa F, et al.: Cyclophosphamide metabolism is affected by azole antifungals. Blood 2004, 103:1557–1559.

    Article  CAS  PubMed  Google Scholar 

  31. Varhe A, Olkkola KT, Neuvonen PJ: Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 1994, 56:601–607.

    CAS  PubMed  Google Scholar 

  32. Ahonen J, Olkkola KT, Neuvonen PJ: Effects of itraconazole and terbinafine on the pharmacokinetics and pharmacodynamics of midazolam in healthy volunteers. Br J Clin Pharmacol 1995, 40:270–272.

    CAS  PubMed  Google Scholar 

  33. •• Bruggemann R, Alffenaar JW, Blijlevens NM, et al.: Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents. Clin Infect Dis 2009, 48:1441–1458. This article provides the most current and complete review of azole drug interactions available. To assist practitioners in assessing the relevance of the interaction, the authors include a detailed table that ranks drug interactions by potential clinical significance.

    Article  PubMed  CAS  Google Scholar 

  34. Backman JT, Kivisto KT, Olkkola KT, Neuvonen PJ: The area under the plasma concentration-time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin. Eur J Clin Pharmacol 1998, 54:53–58.

    Article  CAS  PubMed  Google Scholar 

  35. Neuvonen PJ, Jalava KM: Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1996, 60:54–61.

    Article  CAS  PubMed  Google Scholar 

  36. 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.

    Article  CAS  PubMed  Google Scholar 

  37. Kantola T, Kivisto KT, Neuvonen PJ: Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998, 64:58–65.

    Article  CAS  PubMed  Google Scholar 

  38. Clinical Pharmacology. Drug Interaction Report. http://clinicalpharmacology-ip.com/Forms/Reports/intereport.aspx. Accessed January 15, 2010.

  39. Sugar AM: Use of amphotericin B with azole antifungal drugs: What are we doing? Antimicrob Agents Chemother 1995, 39:1907–1912.

    CAS  PubMed  Google Scholar 

  40. Rex JH, Pappas PG, Karchmer AW, et al.: A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects. Clin Infect Dis 2003, 36:1221–1228.

    Article  CAS  PubMed  Google Scholar 

  41. Denning DW: Echinocandins: a new class of antifungal. J Antimicrob Chemother 2002, 49(6):889–891.

    Article  CAS  PubMed  Google Scholar 

  42. •• Sucher A, Chahine E, Balcer H: Echinocandins: the newest class of antifungals. Ann Pharmacother 2009, 43:1647–1657. This paper provides a current review of the echinocandin class. Drug interactions of the class are briefly discussed and placed in perspective.

    Article  PubMed  CAS  Google Scholar 

  43. Cancidas [package insert]. Whitehouse Station, NJ: Merck; 2010.

  44. Herbert M, Smith H, Marbury T: Pharmacokinetics of micafungin in healthy volunteers, volunteers with moderate liver disease, and volunteers with renal dysfunction. J Clin Pharmacol 2005, 45:1145–1152.

    Article  CAS  Google Scholar 

  45. Mycamine [package insert]. Deerfield, IL: Astellas Pharma US; 2005.

  46. Morris MI, Villmann M: Echinocandins in the management of invasive fungal infections, part 1. Am J Health Syst Pharm 2006, 63(18):1697–1703.

    Article  Google Scholar 

  47. Dowell J, Stogniew M, Krause D, et al.: Assessment of the safety and pharmacokinetics of anidulafungin when administered with cyclosporine. J Clin Pharmacol 2005, 45:227–233.

    Article  CAS  PubMed  Google Scholar 

  48. Eraxis [package insert]. New York, NY: Pfizer; 2006.

  49. Cada D, Levien T, Baker D: Anidulafungin. Hosp Pharm 2006, 41:669–680.

    Article  Google Scholar 

  50. Wood N, Tan K, Purkins L, et al.: Effect of omeprazole on the steady-state pharmacokinetics of voriconazole. Br J Clin Pharmacol 2003, 56(Suppl 1):56–61.

    Article  CAS  PubMed  Google Scholar 

Download references

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael Postelnick.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bartell, A., Phatak, A., Horn, K. et al. Drug Interactions Involving Antifungal Drugs: Time Course and Clinical Significance. Curr Fungal Infect Rep 4, 103–110 (2010). https://doi.org/10.1007/s12281-010-0014-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12281-010-0014-x

Keywords

Navigation