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Antifungal drug-drug interactions

3D image of lilac-coloured fungal pathogens

ARE DRUG-DRUG INTERACTIONS A CONCERN? CHOOSE THE RIGHT ANTIFUNGAL

Patients at high risk for invasive fungal infections (IFIs), such as those in intensive care units (ICU), those undergoing transplantation, and those with haematological malignancies or HIV/AIDS commonly receive multiple therapies.1-6 However, co-administration of some medications with certain antifungal agents can result in drug-drug interactions (DDIs), which may adversely affect treatment response.7,8
What are the important DDIs to consider and who is most at risk?

WHO IS AT RISK OF ANTIFUNGAL DDIs?

Antifungal agents are known to interact with many drugs. Over 2,600 potential DDIs are included in the antifungal drug interaction database, of which more than 540 could be severe.5 If undetected, DDIs can lead to patient harm or to potentially fatal adverse events.4

Patients at high risk of an IFI and who are on multiple therapies for their underlying disease, may be more likely to be at risk of DDIs, for example:4-6

  • Patients admitted to the ICU: Underlying conditions, certain procedures and medications all increase the risk of IFIs for patients in the ICU.3,9 These patients may also be more likely to experience a DDI due to the large number of medications they may be on, complexity of the prescribed pharmacotherapy, disease severity, and impact of potential organ failure.10
  • Patients with haematological malignancies: Patients undergoing treatment for haematological malignancies are often extensively immunosuppressed, increasing their risk of developing IFIs.2, 11-13 Concomitant use of antifungals, such as azoles, and targeted haemato-oncology therapies can result in a number of clinically relevant DDIs.14-17 Caution is advised for the concurrent use of antineoplastic agents with liposomal amphotericin B.18
  • Patients with HIV/AIDS: A depletion in CD4+ T cell count, typicially seen in HIV/AIDs patients, can increase the risk of IFIs.19,20 Antiretrovirals are used as a treatment regimen in these patients. However, antiretrovirals can interact with some azoles, resulting in a number of DDIs.21
  • Patients undergoing transplantations: Some nephrotoxic medications administered to prevent graft rejection in transplantation patients may interact with some antifungal agents such as liposomal amphotericin B when used concurrently. This may increase the risk of drug-induced renal toxicity in patients.18*

Due to the complexity of concurrent medication regimens in such patients, knowledge of antifungal DDIs and their underlying mechanisms is vital to ensure the selection of effective and well tolerated therapy.6

Two masked doctors reviewing chart

What significant mechanisms underlie antifungal DDIs?

The CYP3A4 enzyme metabolises a wide range of drugs in the liver.22,23 Inhibitors of CYP3A4, such as several azoles, are one of the major causes of DDIs when co-administered with drugs that are metabolised by the enzyme (CYP3A4 substrates).14,24
Co-administration of such drugs can lead to a high plasma concentration of the CYP3A4 substrate, and hence a potentially problematic increase in toxicity.14-16

In such cases, dosage adjustments or increased monitoring for toxicity may be required, in some instances, for patients receiving combinations of relevant therapies, and in some cases co-administration of specific therapies is contraindicated.22,23,25**

HOW DOES DDI RISK DIFFER AMONGST KEY ANTIFUNGAL DRUG CLASSES?

Azoles

Due to their inhibitory action on the CYP3A4 enzyme, some azoles exhibit a wide range of DDIs such as:14,15

  • Immunosuppressant therapies following allogenic haematopoietic stem cell transplantation (Allo-HSCT) or solid organ transplants
  • Haemato-oncology therapies including vinca alkaloids and tyrosine kinase inhibitors

Some azoles have also been associated with with prolongation of the QTc interval, which can increase the risk of cardiac events and potentially fatal arrythmia.14,15 Co-administration with other therapies known to prolong the QTc interval and are substrate of CYP3A4 are therefore contraindicated, for example, the FMS-like tyrosine kinase 3 (FLT3) inhibitors.24, 26-28

Other drugs, including some antiretrovirals, can also affect the metabolism of the azole itself, impacting the efficacy/toxicity profile of the antifungal.14,15 As such, the benefit/risk profile should be assessed before co-administration with azoles.15,29

While administration of azole antifungals may be a required treatment protocol, it is important to consider the potential DDIs in IFI patients on concomitant medications. Patients' medications may need to be substituted to limit DDIs with azoles and therapeutic drug monitoring may be required.23

Polyenes

Polyenes include conventional and liposomal amphotericin B (i.e. AmBisome®). Amphotericin B is not metabolised by hepatic CYP450 enzymes, and therefore have a lower potential for DDIs.18**

Monitoring outcomes such as renal, hepatic, and electrolyte functioning is however recommended to avoid toxicity.18

Echinocandins

Echinocandins include caspofungin, anidulafungin and micafungin. They are poor substrates for the CYP450 system,30,31 and have a low risk of DDIs8,31. However, in vivo interactions cannot be ruled out. Some drugs may increase or decrease the exposure to other concomitant drugs. Thus, monitoring for toxicity and or dose reduction may be necessary. Please refer to the individual products' SmPCs for potential DDIs.8,31

Doctors gathered around patient in hospital bed

Managing the risk of antifungal DDIs

DDIs can alter the safety and efficacy profiles of the interacting drugs.6,8 Therefore, the risk of DDIs should be adequately assessed through the use of individual drug SmPCs (Summary of Product Characteristics) and relevant case reports, as well as involvement of a multidisciplinary team, close patient monitoring and therapeutic drug monitoring.29

The goals of antifungal DDI management are to ensure patient safety, minimise complications, and optimise the treatment outcome.

Step-by-step guide to assessing DDIs

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Understand

Understand the pharmacological mechanisms that cause DDIs

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Identify

Identify the DDI using various sources of information (e.g. SmPCs and case reports)

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Quantify

Quantify the effect of DDIs using therapeutic drug monitoring

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Classify

Severity should be classified as: no action needed, monitor therapy, consider modification, or avoid combination

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Assess patient-related factors

Factors such as disease status, comorbidities, and co-medication may influence the magnitude of the effect and significance of a DDI

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Manage DDIs

ICU specialists can manage DDIs in multiple ways including dose adjustment or change of antifungal treatment

Close up photo of doctor looking at ipad

Get further information to help you keep track of DDIs in your IFI patients.

Footnotes

*This is not an exhaustive list of DDIs associated with the use of liposomal amphotericin B. Please refer to the SmPC for a complete list of potential DDIs.18
**No specific interaction studies have been performed with liposomal amphotericin B. Potential DDIs may occur with the use of concurrent nephrotoxic medications, corticosteroids, corticotropin, diuretics, digitalis, other antifungals, antineoplastic agents, skeletal muscle relaxants and leukocyte transfusions. (Please refer to the SmPC for full information on the potential DDIs).18

References

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  2. Pagano L et al. Future Sci OA. 2018;4(6):FSO307.
  3. Bongomin F et al. J Fungi (Basel). 2017;3(4):57.
  4. Koeck JA et al. Antibiotics (Basel). 2021;10(11):1330.
  5. Niazi-Ali S et al. Ther Adv Infect Dis. 2021;8:20499361211010605.
  6. Bartell A et al. Curr Fungal Infect Rep. 2010;4:103–110.
  7. Chatelon J et al. Adv Ther. 2019;36:3308-3320.
  8. Bellmann R and Smuszkiewicz P. Infection. 2017;45(6):737-779.
  9. Gangneux JP et al. J Mycol Méd. 2020;30:100971.
  10. Baniasadi S et al. Ann Intensive Care. 2015;5:44.
  11. Kim J-Y. J Microbiol. 2016;54(3):145—148.
  12. Pagano L et al. Blood Rev. 2017;31(2):17–29.
  13. Fracchiolla NS et al. PLoS One. 2019;14(5):e0216715.
  14. Electronic medicines compendium (EMC). "Vfend (voriconazole) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/product/8408/smpc. Last accessed: April 2022.
  15. Electronic medicines compendium (EMC). "Noxafil (posaconazole) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/product/176/smpc. Accessed April 2022.
  16. Madsen ML et al. Cancer Chemother Pharmacol. 2019;84:471-485.
  17. Busca A, Pagano L. Expert Rev Anti Infect Ther. 2018;16:531-542.
  18. AmBisome® Summary of Product Characteristics (UK).
  19. Limper AH et al. Lancet Infect Dis. 2017;17(11):e334-e343.
  20. Iqbal HS et al. Journal of Bacteriology & Mycology. 2016;2(6):162-164.
  21. Armstrong-James D et al. Trends Microbiol. 2014;22(3):120-127.
  22. Brüggemann RJM et al. Clin Infect Dis. 2009;48:1441-1458.
  23. Jordan CL et al. Pediatric Pulmonology. 2016;51(S44):S61-S70.
  24. Youngs J et al. J Fungi. 2020;6(4):385.
  25. Girmenia C et al. Expert Opin Investig Drugs. 2009;18(9):1279-1295.
  26. Lindsay J et al. Curr Opin Infect Dis. 2019;32(6):538-545.
  27. European Medicines Agency (EMA). Rydapt (midostaurin) Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/rydapt-epar-product-information_en.pdf. Accessed April 2022.
  28. Electronic medicines compendium (EMC). "Rydapt (midostaurin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/product/9134. Accessed April 2022.
  29. Lempers et al. Curr Opin Pharmacol. 2015;24:38-44.
  30. Nett JE and Andes DR. Infect Dis Clin North Am. 2016;30(1):51-83.
  31. Kauffman et al. Semin Respir Crit Care Med. 2008;29(2):211-219.

Date of preparation: April 2022. Job code: IHQ-AMB-0426.