Terbinafine

Article Author:
Luke Maxfield
Article Author:
Charles Preuss
Article Editor:
Rene Bermudez
Updated:
6/13/2020 2:24:07 PM
PubMed Link:
Terbinafine

Indications

Terbinafine has approval for the treatment of 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 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 the 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 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 been approved by 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. This efficacy of this treatment schedule has 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. Dysgeusia rarely 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.[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] Topical terbinafine, although not FDA approved, 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 yet exist, the average time to drug-induced liver injury is near 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. Continuation of the medication despite these untoward effects 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 the consistent severe adverse effect is on 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 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, as well as report any adverse drug reactions that may present.

More importantly, when the patient presents with refractory symptoms, the patient should be worked up to ensure that the diagnosis is correct. 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 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 as well as drug interactions. [Level 5]

The level of evidence demonstrating terbinafine efficacy as 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). 


References

[1] Lipner SR,Scher RK, Onychomycosis: Treatment and prevention of recurrence. Journal of the American Academy of Dermatology. 2019 Apr;     [PubMed PMID: 29959962]
[2] Zane LT,Chanda S,Coronado D,Del Rosso J, Antifungal agents for onychomycosis: new treatment strategies to improve safety. Dermatology online journal. 2016 Mar 16;     [PubMed PMID: 27136621]
[3] Gupta AK,Mays RR,Versteeg SG,Piraccini BM,Shear NH,Piguet V,Tosti A,Friedlander SF, Tinea capitis in children: a systematic review of management. Journal of the European Academy of Dermatology and Venereology : JEADV. 2018 Dec;     [PubMed PMID: 29797669]
[4] Ryder NS, Terbinafine: mode of action and properties of the squalene epoxidase inhibition. The British journal of dermatology. 1992 Feb;     [PubMed PMID: 1543672]
[5] Kalińska-Bienias A,Kowalewski C,Woźniak K, Terbinafine-induced subacute cutaneous lupus erythematosus in two patients with systemic lupus erythematosus successfully treated with topical corticosteroids. Postepy dermatologii i alergologii. 2013 Aug;     [PubMed PMID: 24278085]
[6] Gupta AK,Versteeg SG,Shear NH, Common drug-drug interactions in antifungal treatments for superficial fungal infections. Expert opinion on drug metabolism     [PubMed PMID: 29633864]
[7] Patel VM,Schwartz RA,Lambert WC, Topical antiviral and antifungal medications in pregnancy: a review of safety profiles. Journal of the European Academy of Dermatology and Venereology : JEADV. 2017 Sep;     [PubMed PMID: 28449377]
[8] Perveze Z,Johnson MW,Rubin RA,Sellers M,Zayas C,Jones JL,Cross R,Thomas K,Butler B,Shrestha R, Terbinafine-induced hepatic failure requiring liver transplantation. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2007 Jan;     [PubMed PMID: 17192859]
[9] Mikami A,Hori S,Ohtani H,Sawada Y, Analysis of the Mechanism of Prolonged Persistence of Drug Interaction between Terbinafine and Amitriptyline or Nortriptyline. Biological & pharmaceutical bulletin. 2017     [PubMed PMID: 28674244]
[10] Gupta AK,Daigle D,Foley KA, Network Meta-Analysis of Onychomycosis Treatments. Skin appendage disorders. 2015 Sep;     [PubMed PMID: 27170937]