Terbinafine


Article Author:
Luke Maxfield
Charles Preuss


Article Editor:
Rene Bermudez


Editors In Chief:
David Wood
Andrew Wilt
Hajira Basit


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
8/12/2019 10:36:17 AM

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 3 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 of with systemic medications is off-label, and it is not the U.S. Food and Drug Administration (FDA) approved. Although there are no proposed US 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 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. 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, fulminant liver failure has been reported to occur.[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 do occur.[1][6] This list 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 additions 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. 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 recalcitrant 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 to 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 V]

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.[9]

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


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Terbinafine - Questions

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A 54-years-old patient with a history of type II diabetes and congestive heart failure with arrhythmia. The patient is taking metformin, amiodarone, captopril, and spironolactone already for the aforementioned premorbid conditions. The patient acquired cutaneous sporotrichosis for which he was being managed using itraconazole for the past few months. His symptoms are not improving. Which of the following would be the best recommendation for his treatment?



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In which class is terbinafine correctly be placed?



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A 65-year-old man with a past medical history of diabetes mellitus presents for evaluation of his nails. The patient reports that over the last five years they have been progressively becoming thicker. The patient's pulse is 110/min, blood pressure 115/70 mmHg, respirations 12/min, and temperature 36.7 C (98 F). The physical examination reveals thickened, dystrophic, and yellow nails. If systemic treatment is utilized, what is the most appropriate choice?



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A 44-year-old woman presents for evaluation of her nails. The patient reports that over the past six years they have been progressively becoming thicker. The patient's pulse is 110/min, blood pressure 120/70 mmHg, respirations 13/min, and temperature 36.7°C (98°F). The physical examination reveals thickened, dystrophic, and yellow nails that are separating from the nail bed. Which of the following adverse events is associated with the first-line systemic treatment for her condition?



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A 29-year-old woman with no past medical history presents for an evaluation of the big toenail of the right foot. The patient reports that over the last year it has progressively become thicker and yellow. The patient's pulse is 80/min, blood pressure 115/70 mmHg, respirations 12/min, and temperature 36.7°C (98°F). The physical examination reveals a thickened, dystrophic, and a yellow toenail which is separating from the nail bed. What is the enzyme inhibited by the most appropriate first-line therapy?

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    Contributed by Myron Bodman DPM
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A 65-year-old man with no previous medical history presents for evaluation of his toes. The patient reports that over the last month his nails have become thickened and yellow. The patient's pulse is 88/min, blood pressure 115/70 mmHg, respirations 12/min, and temperature 36.7 C (98 F). The physical examination reveals a thickened, dystrophic, yellow nails with subungal debris. If systemic treatment is used, what laboratory monitoring test would be most useful for this patient?



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An 8-year-old boy, in the United States, with no previous medical history, presents with his mother for an evaluation of his scalp. The mother reports that over the last month his scalp has become scaley and inflamed. The mother has tried over the counter shampoos and coconut oil without improvement. The patient's pulse is 94/min, blood pressure 115/70 mmHg, respirations 12/min, and temperature 36.7°C (98°F). The physical examination reveals scaley erythematous plaques on the scalp with patchy alopecia. Broken hair shafts that appear as black dots are also present. What is the most effective medication for this condition?

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    Contributed by Ahmad Al Aboud, MD
Attributed To: Contributed by Ahmad Al Aboud, MD



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Terbinafine - References

References

Lipner SR,Scher RK, Onychomycosis: Treatment and prevention of recurrence. Journal of the American Academy of Dermatology. 2019 Apr;     [PubMed]
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]
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]
Ryder NS, Terbinafine: mode of action and properties of the squalene epoxidase inhibition. The British journal of dermatology. 1992 Feb;     [PubMed]
Gupta AK,Versteeg SG,Shear NH, Common drug-drug interactions in antifungal treatments for superficial fungal infections. Expert opinion on drug metabolism     [PubMed]
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]
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]
Gupta AK,Daigle D,Foley KA, Network Meta-Analysis of Onychomycosis Treatments. Skin appendage disorders. 2015 Sep;     [PubMed]
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]

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