The safety of oral antifungals for the treatment of onychomycosis

ABSTRACT

Introduction

Oral antifungals are used for the treatment of moderate-severe onychomycosis. Terbinafine and itraconazole are approved for onychomycosis treatment in North America; additionally, fluconazole is indicated for onychomycosis in Europe. Other oral antifungals such as ketoconazole and griseofulvin are no longer used for the treatment of onychomycosis due to safety concerns and relatively lower efficacy.

Search strategy

On 7 March 2023, we conducted a comprehensive search in PubMed and Google Scholar, while also manually examining selected article bibliographies and package inserts.

Areas covered

Terbinafine, itraconazole, and fluconazole have several interactions with cytochrome-p450, and either alone, or when co-administered with other drugs these interactions can facilitate a multitude of adverse events. This article identifies possible hepatic, renal, cutaneous, cardiovascular, neurological, hemopoietic, and obstetric adverse events. We have also compared the rates of hepatotoxicity, clinically apparent liver injury, and alanine transaminase elevations between oral antifungals, and recommendations for hepatic monitoring.

Expert opinion

We recommend laboratory testing of liver function tests prior to the administration of any oral antifungals, especially when clinically indicated. In the event of a first treatment failure, the diagnosis of onychomycosis must be confirmed, and consideration given to antifungal susceptibility testing. Antifungal stewardship will help reduce the incidence of antifungal resistance.

KEYWORDS:

• Onychomycosis
• antifungals
• terbinafine
• itraconazole
• fluconazole
• hepatotoxicity
• safety

Article highlights

• Interactions with cytochrome-p450 drive adverse reactions to oral antifungals

• Hepatotoxicity must be considered prior to treatment with all oral antifungals

• Cardiotoxicity must be considered prior to treatment with itraconazole

• Maternal toxicity is more likely when treating with fluconazole >400 mg/day

• Antifungal susceptibility testing should be more widespread to prevent resistance

• Development of antifungals that do not target the cell membrane is encouraged

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contribution statement

Conception of the manuscript was done by AKG. The work was drafted by SHN and MT, and substantively revised by AKG and MT

Additional information

Funding

This paper was not funded.