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1 December 1997

Possible Drug Interactions in Oral Treatment of Onychomycosis

Department of Dermatology, University of Minnesota, Minneapolis, USA
J. Am. Podiatr. Med. Assoc.1997, 87(12), 571-574;https://doi.org/10.7547/87507315-87-12-571
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Abstract

A variety of medications may interact with oral antifungal agents used to treat onychomycosis. This article summarizes some possible consequences of concurrent administration of various therapeutic agents with the oral antifungals fluconazole, griseofulvin, itraconazole, ketoconazole, and terbinafine.
Oral antifungal medications used to treat onychomycosis are generally safe, with very low rates of serious adverse events. However, when an oral antifungal medication is given concurrently with another therapeutic agent, an adverse drug interaction may occur. Some possible consequences of concurrent use of various therapeutic agents with oral antifungal agents prescribed for the treatment of onychomycosis are summarized in this article. The oral antifungals discussed are fluconazole (Diflucan®) (As of this writing, fluconazole has not yet been approved by the US Food and Drug Administration for the treatment of onychomycosis.), griseofulvin (Fulvicin®, Grifulvin®, Gris-PEG®), itraconazole (Sporanox®), ketoconazole (Nizoral®), and terbinafine (Lamisil®).
The pharmacologic mechanisms underlying drug interactions are pharmacokinetic and/or pharmacodynamic.[1,2,3] Pharmacokinetic drug interactions affect the concentration, or the patient’s blood levels, of a medication. The factors that determine the blood level of a drug at any given time include its absorption, distribution, metabolism, and elimination. Pharmacodynamic drug interactions affect a patient through competition for similar receptors or physiologic systems, resulting in either additive, synergistic, or antagonistic activity. For example, because many of the oral antifungals are metabolized by the liver and excreted renally, concurrent medications that may impair hepatic or renal function should be monitored closely.
The major types of drug interactions involving the oral antifungal agents used to treat onychomycosis are the result of pharmacokinetic factors that either limit gastrointestinal absorption or affect drug metabolism through their effect on the cytochrome P-450 catabolic enzymes [1,2,3,4,5,6]. For example, griseofulvin, itraconazole, and ketoconazole are best given with a meal because their respective gastrointestinal absorptions are increased by the presence of food [7,8,9]. Furthermore, the absorptions of itraconazole and ketoconazole increase in an acidic gastric pH.
The cytochrome P-450 enzymes catalyze the intramolecular biotransformation of substrate drugs into more easily handled compounds that can be further processed for clearance and removal [1,2,10]. Griseofulvin is a cytochrome P-450 enzyme inducer. Therefore, the metabolic clearance of certain concurrent substrate drugs may be accelerated by the presence of griseofulvin, leading to possible therapeutic failure. The imidazole antifungal agents represented by fluconazole, itraconazole, and ketoconazole are, to various degrees, human cytochrome P-450 3A inhibitors; fluconazole is also a cytochrome P-450 2C9 inhibitor. Therefore, depending on the pharmacokinetic factors of the particular imidazole as well as its blood concentration, the metabolism of cytochrome P-450 3A substrate drugs may be impaired, resulting in potentially toxic concentrations of the drugs. In addition, the imidazoles are themselves cytochrome P-450 3A substrates and may suffer metabolic acceleration by inducers, resulting in decreased imidazole levels and possible loss of antifungal effectiveness.
Table 1 lists various medications whose concurrent use with oral antifungal drugs may lead to adverse interactions. The reader should refer to the manufacturer’s specific product literature for additional data or the most current prescribing recommendations. The imidazole antifungals have greater potential for clinically significant drug interactions than the other oral antifungal agents. Therefore, it is prudent to use caution with this class of drugs.
Table 1. Drugs Listed by Generic Name, with Brand Name Example(s), That May Interact with Oral Antifungal Agents.

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