Continuing Education Activity

Terbinafine is an antifungal medication that works through the inhibition of squalene epoxidase. It has activity against most dermatophytes, and it has approval for use as an oral therapy for the treatment of onychomycosis. Although most side effects are mild and self-limited, such as headache and gastrointestinal symptoms, taste disturbances (dysgeusia) can range from mild to severe, resulting in weight loss, and have rarely been reported permanent. This activity describes the indications, mode of action, and side effects of terbinafine and highlights the role of the interprofessional team in ensuring proper usage.

Objectives:

• Identify the mechanism of action of terbinafine.
• Describe the adverse effects of terbinafine.
• Explain the appropriate monitoring for patients receiving antifungal therapy with terbinafine.
• Review interprofessional team strategies for improving care coordination and communication to advance terbinafine and improve outcomes.

Indications

Terbinafine has FDA approval to treat onychomycosis that is suspected or proven to be caused by dermatophyte organisms. Indications for oral therapy include the following[1]:

• Proximal subungual onychomycosis
• Distal lateral subungual onychomycosis affecting over 50% of the nail plate with nail matrix involvement and plate thickness greater than two millimeters
• Greater than or equal to three nails involved

Oral terbinafine has been demonstrated to be the most effective treatment for the mycological cure of toenail dermatophyte infections.[2]

Treatment of onychomycosis in the pediatric population with systemic medications is off-label, and it is not U.S. Food and Drug Administration (FDA) approved. Although there are no proposed USA guidelines, terbinafine has been recommended by the British Association of Dermatologists as a first-line treatment.[1]

The treatment of tinea capitis is an additional non-FDA use of terbinafine. Notably, although both griseofulvin and terbinafine are effective treatment options for pediatric tinea capitis, terbinafine has demonstrated superiority in the treatment of infections caused by Trichophyton spp., while griseofulvin was more effective at treating hair shaft infections caused by Microsporum spp. As Trichophyton spp. are the most common cause of tinea capitis in North America, terbinafine is often the treatment for this condition.[3]

Mechanism of Action

Most antifungal medications work through the inhibition of fungal membrane production and ergosterol synthesis. Terbinafine is an allylamine that works early in the pathway as a non-competitive inhibitor of the enzyme squalene epoxidase and subsequent conversion of squalene to squalene epoxide.[1]

Although not directly fungicidal, the intracellular accumulation of squalene results in fungal cell death.[4]

Administration

Terbinafine is formulated as a 250 mg tablet to be taken by mouth. The routine dosing for dermatophyte infections is one tablet, by mouth, daily. The duration of therapy varies, with treatment lasting for six weeks for fingernail onychomycosis and up to 12 weeks for toenail onychomycosis. Absorption and bioavailability are similar, regardless of food intake. The clearance of terbinafine occurs through both the liver and kidneys. Terbinafine has an inhibitory effect on the hepatic CYP450 2D6 (CYP2D6) enzyme, and monitoring for drug interactions is necessary.

Other dosing schedules that have not received approval from the FDA include pulse-dose treatment with terbinafine. This treatment schedule can be performed in multiple ways but can consist of one 250 mg tablet per day for four weeks, with four weeks of no therapy, and the resumption of one 250 mg tablet per day for another four weeks. The efficacy of this treatment schedule has been demonstrated to be similar to continuous dosing.[1]

Adverse Effects

The most common adverse events associated with terbinafine tend to be mild and self-limited. These include headaches, gastrointestinal symptoms, and rash. Additional uncommon but mild adverse events include visual disturbances, dysgeusia, and mild transaminitis. In rare instances, dysgeusia can be severe or permanent.[2] However, there are reports of fulminant liver failure.[1] Although cutaneous findings are usually non-specific, rarely Stevens-Johnson syndrome, toxic epidermal necrolysis, and cutaneous or systemic lupus erythematosus may develop.[1][5]

Contraindications

Contraindications to the use of terbinafine include:

• Chronic or active liver disease
• History of an allergic reaction to oral terbinafine

As terbinafine inhibits the hepatic CYP2D6 enzyme, drug interactions can occur.[1][6] The list of potentially interacting drugs includes, but is not limited to, cimetidine, fluconazole, cyclosporine, rifampin, caffeine, paroxetine, codeine, metoprolol, simvastatin, nifedipine, digoxin, phenytoin, and many others.[2][6]

Terbinafine, although a pregnancy safety category B medication, is not recommended for use during pregnancy. Similarly, as terbinafine is known to be excreted in breast milk, its use should be limited to after breastfeeding; this is due to the usually indolent nature of nail dermatophyte infections, lack of embryotoxicity data with terbinafine, and the litigious culture of the United States.[1] Although not FDA-approved, topical terbinafine has been recommended for the treatment of dermatophyte infections during pregnancy, and it is available over the counter in the United States of America.[7]

Monitoring

There is no standardized laboratory monitoring established for terbinafine. In light of reports of both mild and severe liver injuries, clinicians often perform liver enzyme testing. The FDA recommends measuring serum transaminases before drug initiation. Although no established monitoring guidelines exist, the average time to drug-induced liver injury is nearly 30 days and usually within three months. Therefore, monitoring for idiosyncratic liver injury during this period may be reasonable.[1] Blood dyscrasias may also rarely occur, and complete blood counts serve to monitor for this adverse drug effect.[1]

Toxicity

Taste disturbances, nausea, vomiting, abdominal cramping, and headache may occur in patients taking terbinafine. Despite these untoward effects, the continuation of the medication is often dependent on the severity of symptoms and the patient's discomfort threshold. Discontinuation may be appropriate to resolve most symptoms. Although multiple symptoms may present in patients taking therapeutic or supratherapeutic doses of terbinafine, the most concerning and consistent severe adverse effects occur in the liver.

Hepatotoxicity may be asymptomatic and only detectable by lab evaluation and evidence of transaminitis. Liver enzymes over two times the normal value requires immediate discontinuation. Supportive care, including liver transplantation (in severe cases), may be necessary.[1][8]

Enhancing Healthcare Team Outcomes

In addition to the physician's identification, diagnosis, and treatment of onychomycosis, as well as monitoring for adverse drug effects, the interprofessional team should be involved in multiple ways. As terbinafine undergoes hepatic metabolism, conversations with the pharmacist about concomitant alcohol consumption would be prudent, although the relationship between alcohol and other hepatotoxic substances and the idiosyncratic nature of terbinafine-induced liver disease is not entirely clear. The pharmacist should also verify dosing and perform therapeutic medication management, especially in light of terbinafine's interaction profile, and report any concerns to the prescribing physician.[9] The nurse will usually encounter the patient first and can note the success or failure of therapy and report any adverse drug reactions that may present. Interprofessional care coordination and open communication between providers are crucial to successful treatment with terbinafine. [Level 5]

More importantly, the patient should be worked up to ensure that the diagnosis is correct when the patient presents with refractory symptoms. Both the nurse practitioner, primary care provider, and pharmacist should refrain from extending the duration of treatment until there is diagnostic confirmation. Finally, these clinicians should assess the liver function if the patient is on prolonged therapy, and the results require communication with the entire team. Both the pharmacist and nurse should regularly question the patient about the development of drug side effects and report back to the clinical team leader if untoward problems develop. Only with this type of interprofessional collaboration will terbinafine therapy be optimal, with minimal adverse drug reactions and drug interactions. [Level 5]

The level of evidence demonstrating terbinafine efficacy compared to placebo and alternative systemic anti-fungal agents is Level-I with confirmation from multiple randomized controlled trials.[10]

Level of evidence for terbinafine and liver injury: Likelihood score: B (highly likely cause of clinically apparent liver injury).