SKIN May 2018 Volume 2 Issue 3 Copyright 2018 The National Society for Cutaneous Medicine 191 PEARLS FROM THE PRACTITIONER Capsule Commentaries: Selected Oral Antifungal Drug-Drug Interactions with Itraconazole and Terbinafine James Q Del Rosso, DO a,b,c a Adjunct Clinical Professor (Dermatology), Touro University Nevada, Henderson, NV b Research Director, JDR Dermatology Research Las Vegas, NV c Dermatology and Cutaneous Surgery, Thomas Dermatology, Las Vegas, NV Terbinafine and itraconazole are oral antifungal agents utilized in dermatology to treat a variety of superficial mycotic infections. Itraconazole is associated with a long list of potential drug-drug interactions, and terbinafine with a shorter list; importantly, both may induce clinically significant interactions when administered concurrently with certain drugs. 1,2 A complete review of drug-drug interactions is beyond the scope of this review, which serves as a capsule summary of three selected drug-drug interactions with itraconazole or terbinafine, with commentary suggestions on management. Statins. Three commonly used “statins”(simvastatin, atorvastatin, lovastatin) used to treat hyperlipidemia are metabolized by hepatic cytochrome P450 (CYP) 3A4. 3 Potent inhibitors of CYP 3A4, such as itraconazole, ketoconazole, posaconazole, and erythromycin can induce muscle cramping, and in some cases rhabdomyolysis, by decreasing the metabolic clearance of these “statin” agents which causes higher serum levels; multiple cases of myopathy related to such interactions have been reported. 1-4 Commentary: If antifungal therapy is needed in a patient using a statin metabolized by CYP3A4, potential options are (1) topical antifungal therapy if appropriate for the infection being treated (2) use of a non-CYP3A4-inhibiting antifungal agent such as terbinafine or (3) temporary discontinuation of the statin therapy with the approval of the prescribing clinician. 1 ABSTRACT This article provides a review of selected drug-drug interactions with itraconazole and terbinafine that are clinically relevant with potential for toxicity. These include itraconazole and certain statin agents, itraconazole and digoxin, and terbinafine and some antidepressants, with commentary suggestions on management. INTRODUCTION ITRACONAZOLE SKIN May 2018 Volume 2 Issue 3 Copyright 2018 The National Society for Cutaneous Medicine 192 Digoxin. Itraconazole has been shown to reduce the tubular renal excretion of digoxin, reported to be related to inhibition of p- glycoprotein; digoxin toxicity associated with this interaction has been reported. 5-8 One study demonstrated that itraconazole produced a 56% increase in serum digoxin levels as compared to placebo. 5 Commentary: As digoxin exhibits a narrow therapeutic- safety index, an alternative approach to antifungal therapy is suggested to avoid this interaction. Antidepressants. Terbinafine is an inhibitor of hepatic CYP 2D6, which has been shown to markedly increase serum levels of tricyclic antidepressants (eg nortriptyline, amitriptyline, imipramine) metabolized by CYP 2D6; toxicity has been reported with these interactions, presenting as ataxia, fatigue, dizziness/vertigo, appetite loss, and difficulty swallowing. 8-10 Some selective serotonin reuptake inhibitors (eg paroxetine, fluoxetine) are metabolized by CYP 2D6; terbinafine has been shown to increase peak serum levels through inhibition of paroxetine metabolism. 11 Commentary: When oral antifungal therapy is needed in a patient on an antidepressant that is metabolized by CYP 2D6, an alternative approach to antifungal therapy that is also expected to be effective and devoid of drug- drug interactions appears to be a prudent approach. Conflict of Interest Disclosures: Dr. Del Rosso is a consultant, investigator, and/or speaker for Allergan, Aqua/Almirall, Bayer, BioPharmX, Celgene, Cipher (Innocutis), Cutanea, Dermira, Ferndale, Foamix, Galderma, Genentech, Innovaderm, LeoPharma, Novan, Pfizer (Anacor), Pharmaderm, Promius, Regeneron, Sanofi/Genzyme, Sebacia, SunPharma, Taro, Unilever, Valeant (Ortho Dermatologics), and Viamet. This article was developed and written solely by the author. The author did not receive any form of compensation, either directly or indirectly, from any company or agency related to the development, authorship, or publication of this article. Funding: None Corresponding Author: James Q. Del Rosso, DO JDR Dermatology Research 9080 West Post Road Suite 100 Las Vegas, Nevada 89148 702-331-4123 jqdelrosso@yahoo.com References: 1. Katz HI, Gupta AK. Oral antifungal drug interactions: a mechanistic approach to understanding their cause. Dermatol Clin. 2003 Jul;21(3):543-563. 2. Shear N, Drake L, Gupta AK, et al. The implications and management of drug interactions with itraconazole, fluconazole and terbinafine. Dermatology. 2000;201(3):196-203. 3. Dybro AM, Damkier P, Rasmussen TB, et al. Statin-associated rhabdomyolysis triggered by drug-drug interaction with itraconazole. BMJ Case Rep. 2016 Sep 7;2016. pii: bcr2016216457. 4. Tatro DS. Drug Interactions Facts, Wolters Kluwer Health Inc, St. Louis, Missouri, USA, 2005, p 718. TERBINAFINE SKIN May 2018 Volume 2 Issue 3 Copyright 2018 The National Society for Cutaneous Medicine 193 5. Alderman CP, Allcroft PD. Digoxin- itraconazole interaction: possible mechanisms. Ann Pharmacother. 1997;31(4):438-440. 6. Angirasa AK, Koch AZ. P-glycoprotein as the mediator of itraconazole-digoxin interaction. J Am Podiatr Med Assoc. 2002;92(8):471-472. 7. Jalava KM, Partanen J, Neuvonen PJ. Itraconazole decreases renal clearance of digoxin. Ther Drug Monit. 1997 Dec;19(6):609-13. 8. Van Der Kuy PH, Van Den Heuvel HA, Kempen RW, et al. Pharmacokinetic interaction between nortriptyline and terbinafine. Ann Pharmacother. 2002;36(11):1712-1714. 9. Castberg I, Helle J, Aamo TO. Prolonged pharmacokinetic drug interaction between terbinafine and amitriptyline. Ther Drug Monit. 2005 Oct;27(5):680-2. 10. 4 Tatro DS. Drug Interactions Facts, Wolters Kluwer Health Inc, St. Louis, Missouri, USA, 2005, p 1507. 11. Yasui-Furukori N, Saito M, Inoue Y, et al. Terbinafine increases the plasma concentration of paroxetine after a single oral administration of paroxetine in healthy subjects. Eur J Clin Pharmacol. 2007;63(1):51- 56.