Reevaluating the Need for Laboratory Testing in the Treatment of Onychomycosis: Safety and Cost-effectiveness Considerations

In this issue of JAMA Dermatology, Mikailov et al1 challenge our propensity to automatically order costly confirmatory diagnostic testing before initiating systemic therapywith terbinafinehydrochloride for onychomycosis. There are 2 issues of importance here: safety and cost-effectiveness. The issue of cost-effectiveness is relatively straightforward now that the price of generic terbinafine for an entire treatment course has fallen from $547 to $10. Mikailov et al1 have shown that it is more cost-effective to treat every presumptive case of onychomycosis with oral terbinafine rather than prove that the abnormality of the toenail is in fact due to onychomycosis. If the nail does not respond to terbinafine treatment, it is possible that the etiology of the onychomycosis is a saprophyteor yeast. Terbinafine is effective againstdermatophytes, with minimal efficacy toward these other organisms. In these instances,atrialoforal fluconazole would be the appropriate option. In addition to treating dermatophytes, fluconazole also possesses antifungal activity against a wide rangeof saprophytesandyeasts.Studieshaveshownthatwhen used in apulse fashion (not approvedby theUSFoodandDrug Administration), fluconazole can result in clinical success rates of86%to89%andcure ratesof28%to36%.2One typical pulse therapy regimen is 200mgof fluconazole onceweekly for 3 to 9months,oruntil thenail growsout. (Fluconazole200-mgtablets are less expensive than the 150-mgtablets,whichareavailable only in single-dose packets.) When fluconazole is administered in this pulse regimen, liver function testing is not necessary. Patients are reassured about the safety of this treatment when told that this regimen is similar to giving women single doses of fluconazole for recurrent yeast infections. What is stated, but not stressed, by Mikailov et al1 is the significant difference in price between oral terbinafine and newer topical treatments such as efinaconazole. Owing to the highcost of efinaconazole, theauthors correctlypoint out that confirmatorydiagnostic testingbefore initiatingtreatmentdoes result in overall cost savings. The unasked question is “Why choose efinaconazole, whose cure rates are 15%3 (at a cost of $2307), when the response rate to terbinafine is significantly higher at a cost of $10?” Theanswer lies in themisconception (bybothpatientsand physicians) thatoral terbinafine is adangerousdrug.TheClinical andResearch InformationonDrug-InducedLiver InjuryDatabase (a subgroupof theNational Library ofMedicine) states that clinically apparent liver injury from terbinafine treatment occurs in 1 case per 50 000 to 120 000 treatments.4 Review of the actual case reports on this site shows thatmost of these patients’ symptoms completely resolve after cessation of terbinafine treatment. A reviewof liver transplantations in the United States from 1990 to 2002 showed that only 0.2% of these transplantswereperformed for idiosyncratic drug reactions, and none of these patients had been exposed to terbinafine.5 Asymptomatic elevations of liver enzyme levels havebeenseen in0.2%to0.5%ofpatients takingterbinafine,6,7 with no known clinical significance. Further review of the published case reports of liver injury associated with terbinafine have shown that symptoms typically occur 4 to 6 weeks after initiation of therapy. The mechanism of action of the liver injury is unknown but is speculated to be idiosyncratic,4 much like the mechanism of liver damage from the combination of trimethoprim and sulfamethoxazole. Although trimethoprim-sulfamethoxazole ranks among the top causesofdrug-induced idiosyncratic fulminant hepatitis, howoftendoprimary care physicians order liver function tests before treating a patient for a urinary tract infection? The fact is that liver injury from terbinafine is extremely rare.Nonetheless, for those leeryof liver injury issueswith terbinafine, pulse therapy represents anexcellent alternative.Although not approved by the US Food and Drug Administration,pulse therapywithoral terbinafinehasbecomeacommon treatment for onychomycosis in clinical practice. Only 3 cases of liver injury from short-term (less than 2 weeks’ exposure) terbinafine exposure were reported in the Clinical and Research Information on Drug-Induced Liver Injury Database.4 One of the most commonly used pulse regimens was reported by Zaias andRebell,8 inwhich 250mg of terbinafine is administered once daily for 7 days and repeated every other monthorevery thirdmonthuntil thenail ishealthy.Otherpublished dosage schedules include 500 mg of terbinafine daily for 1 week, repeated monthly for a total of 3 pulses.9 Pulse therapy isalsopopularwithpatients.Theanalogypatients tend to understand is: “It is like drinking alcohol. You probably are not going to develop liver damage if you overindulge with alcohol every few months, but heavy drinking every day for prolonged periods will hurt your liver.” In addition, since the mechanism of liver injury is postulated to be idiosyncratic and usually occurs after 4 to 6weeks Related article page 276 Opinion