terbinafine (Lamisil)

Introduction

Tradename: Lamisil. (terbinafine hydrochloride)

Indications

• onychomycosis caused by dermatophytes
• Tinea capitis, Tinea cruris, Tinea pedis, Tinea corporis, Tinea versicolor
• chromoblastomycosis
• cutaneous candidiasis

Contraindications

Pregnancy category B.

Not recommended in pregnant women.

Not recommended in nursing mothers.

pregnancy category = b

safety in lactation = -

safety in lactation = ?

Dosage

• Tinea: apply 1% cream BID.
• Onychomycosis:
  • 250 mg PO QD
    • 6 weeks (fingernails)
    • 12 weeks (toenails)
  • pulse dose: 500 mg PO QD for 1st week of month
    • 2 months for fingernails
    • 4 months for toenails

Tabs: 250 mg.

Pharmacokinetics

• well absorbed orally
• extensively metabolized by the liver
• highly protein bound
• elimination 1/2 life
  • phase 1: 11-16 hours
  • phase 2: 200-400 hours (due to slow release from skin & tissue
• clearance is decreased in hepatic & renal impairment

elimination via liver

elimination via kidney

1/2life = 11-16 hours

1/2life = 8-16 days

Monitor

• baseline & at 6 weeks of therapy
  • renal function tests
  • liver function tests
  • complete blood count (CBC) Antibiotic susceptiblity:
    • susceptible organisms:
      • E. floccosum
      • T. mentagrophytes
      • T. rubrum
    • less active against yeast than azole antifungal agents

Adverse effects

(% vs placebo)

• general
  • headache (12.9% vs. 9.5%)
  • malaise
  • fatigue
• gastrointestinal
  • diarrhea (5.6% vs 2.9%)
  • dyspepsia (4.3% vs 2.9%)
  • abdominal pain (2.4% vs 1.5%)
  • nausea/vomiting
• skin
  • rash (5.6% vs 2.2%)
  • pruritus (2.8% vs 1.5%)
  • urticaria (1.1% vs 0%)
  • hair loss
• abnormal liver function tests: (3.3% vs 1.4%)
• taste disturbance (2.8% vs 0.7%)
• musculoskeletal
  • arthralgia
  • myalgia
• rare adverse effects:
  • cholestatic hepatitis
  • serious skin reactions
    • Stevens-Johnson syndrome
    • toxic epidermal necrolysis
  • severe neutropenia
  • thrombocytopenia
  • severe allergic reactions including anaphylaxis

Overdose:

• doses of up to 5 grams have been taken without serious adverse effects
• symptoms of toxicity
  • nausea/vomiting
  • abdominal pain
  • dizziness
  • rash
  • frequent urination
  • headache
• treatment is decontinuation & supportive

* see hepatotoxicity for management of toxicity

Drug interactions

• increases the potency of sulfonylureas
• terfenadine, astemizole: metabolism inhibited resulting in prolongation of the QT interval
• cisapride: prolongation of QT interval
• cyclosporine: decreased concentration of cyclosporine (15%)
• rifampin increases metabolism of terbinafine
• cimetidine decreases metabolism of terbinafine

• drug interaction(s) of antibiotics with warfarin

Mechanism of action

• allyamine derivative that inhibits squalene epoxidase, a key enzyme involved in membrane sterol synthesis in fungi
• results in ergosterol deficiency in fungi & accumulation of squalene resulting in fungal cell death
• fungicidal
• remains active in the skin for at least a week after cessation of use
• 50% long-term success in fungal eradication

More general terms

• antifungal agent

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=1549008
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5402
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5282481