Pill Identifier App

Terbinafine (Systemic)


VA CLASSIFICATION
Primary: AM700

Commonly used brand name(s): Lamisil.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antifungal (systemic)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

General considerations
Terbinafine has in vitro activity against yeasts and a wide range of dermatophyte, filamentous, dimorphic, and dematiaceous fungi. {01} {02} {05} It is fungicidal against dermatophytes, such as Trichophyton species, Microsporum species, and Epidermophyton floccosum , as well as against Aspergillus species, Scopulariopsis brevicaulis , Blastomyces dermatitidis , Cryptococcus neoformans , Sporothrix schenckii , Histoplasma capsulatum , Candida parapsilosis , and Pityrosporum yeasts. {02} Terbinafine has also been shown to be active in vitro against the protozoal organisms Trypanosoma cruzi and Leishmania mexicana mexicana . {02} However, clinical efficacy has not been demonstrated in the treatment of infections caused by B. dermatitidis , H. capsulatum , S. schenckii , C. neoformans , T. cruzi , and L. mexicana mexicana . {02} Also, terbinafine is only fungistatic against Candida albicans . {02} {17} Clinical studies have found terbinafine to be only moderately effective against skin infections caused by Candida species, with a mycological cure of only 65% after 2 to 4 weeks of treatment. {02}

Accepted

Onychomycosis (treatment)—Terbinafine is indicated in the treatment of onychomycosis (fungal infection of the nails) caused by dermatophyte fungi {01} {02} {19} {21} {22} {29}.

[Tinea capitis (treatment)]1—Limited data suggest that terbinafine may be used in the treatment of tinea capitis (ringworm of the scalp). {23} {24} {25}

[Tinea corporis (treatment)]—Terbinafine is indicated in the treatment of tinea corporis (ringworm of the body). {01} {02} {18}

[Tinea cruris (treatment)]—Terbinafine is indicated in the treatment of tinea cruris (ringworm of the groin; jock itch). {01} {02}

[Tinea pedis (treatment)]—Terbinafine is indicated in the treatment of interdigital or plantar tinea pedis (ringworm of the foot; athlete's foot). {01} {02} {20}

Unaccepted
Terbinafine is not effective in the treatment of pityriasis versicolor {01} {04} because concentrations of oral terbinafine reached in the stratum corneum are not high enough to treat this condition adequately. {04}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Allylamine class {02} {07}.
Molecular weight—
    Terbinafine hydrochloride: 327.9 {01}

Mechanism of action/Effect:

Terbinafine interferes with fungal ergosterol biosynthesis by inhibiting squalene epoxidase in the fungal cell membrane. This leads to a deficiency of ergosterol and an intracellular accumulation of squalene, thus disrupting fungal membrane function and cell wall synthesis, and resulting in fungal cell death. {01} {02} {16}


Other actions/effects:

Unlike azole antifungal agents, terbinafine does not inhibit cytochrome P450 activity {01} {02} {16} and is only weakly bound to hepatic cytochrome P450 {01} {02}, resulting in a low propensity for interference with cytochrome P450 enzymes involved in drug metabolism and synthesis of steroid hormones and prostaglandins. {02} Terbinafine also has no effect on 14 alpha-demethylation. {01}

Terbinafine's mechanism of action against protozoal organisms is thought to involve inhibition of sterol synthesis. {02}

Absorption:

Readily absorbed from gastrointestinal tract. Bioavailability is 70 to 80% and is not affected by the presence of food. {01} {02}

Distribution:

Terbinafine is lipophilic and extensively distributed. {02} It rapidly diffuses from the vascular system, passes through the dermis and epidermis, and concentrates in the lipophilic stratum corneum. It is also distributed via the sebum to hair follicles and sebum-rich skin {02}, resulting in high concentrations in hair follicles, hair, sebum-rich skin, and the nail plate within the first few weeks of therapy. {01} {02} It is also highly distributed to adipose tissue. {05} After 12 days of treatment, concentrations in the stratum corneum exceed those in plasma by a factor of 75 and concentrations in the epidermis and dermis exceed those in plasma by a factor of 25. {26} Blood cells contain approximately 8% of administered terbinafine. {17} Terbinafine is not detected in sweat. {02}

Vol D at steady state is approximately 948 L. {02} {05} {14}

Protein binding:

Very high (> 99%) {01} {14}, with binding evenly distributed among all plasma fractions. {02} {14}

Biotransformation:

Terbinafine undergoes first pass metabolism. {17} It is extensively metabolized in the liver by N-demethylation of the central nitrogen atom, alkyl side-chain oxidation (alkyl oxidation), and arene oxide formation followed by hydrolysis to the corresponding dihydrodiol. {05} {14} Metabolism involves only a small fraction (< 5%) of total hepatic cytochrome P450 capacity. {02} Fifteen metabolites have been identified, but none are active. {05}

Half-life:


Absorption:

Approximately 0.8 hour. {01}



Distribution:

Approximately 4.6 hours. {01}



Elimination:

Plasma: 11 to 17 hours. {01} {02} {17}

Sebum: 3 to 5 days. {02} {17}

Stratum corneum: 3 to 5 days. {02} {17}



Terminal {05}:

Sebum: 18 days.

Plasma: 22 days, due to accumulation in adipose tissue and gradual release after discontinuation of treatment.

Stratum corneum: 22 days.

Hair and nails: 24 days.

Dermis and epidermis: 28 days.


Time to peak concentration:

Plasma—Approximately 2 hours. {01} {02} {05} Steady state is reached in 10 to 14 days. {02}

Stratum corneum—Maximum concentrations in the stratum corneum were found on Day 12 of treatment. {01} However, terbinafine was detected in lower levels of the stratum corneum 24 hours after a single oral dose, and fungicidal concentrations were found across the whole of the stratum corneum within 7 days. {04}

Nails—Detected in distal nail clippings as early as 3 weeks after the beginning of therapy. {04} Fungicidal levels in nails were maintained for several weeks after discontinuation of therapy. {04}

Peak serum concentration:

Serum—0.8 to 1.5 mg per L (2.4 to 4.6 micromoles per L). {01} {02} {05}

Nails—250 to 550 nanograms per mg, detected in toenails 3 to 18 weeks after starting therapy, with no progressive increase thereafter during the 48 weeks of therapy. {27}

Elimination:
    Renal—Approximately 80% of an administered dose is excreted in the urine as metabolites. {01} {02} {17}
    Fecal—Approximately 20% is eliminated in feces. {02} {17}


Precautions to Consider

Carcinogenicity

An increase in liver tumors was observed in male rats at the highest dose level (69 mg per kg of body weight [mg/kg] per day) during a 123-week carcinogenicity study. Other changes included increased enzyme activity, peroxisome proliferation, and altered triglyceride metabolism. These changes were not seen in mice or monkeys. {01}

Mutagenicity

In vitro and in vivo mutagenicity testing of terbinafine revealed no specific mutagenic or genotoxic properties. In vitro tests of cell transformation to malignancy were negative. {01}

Pregnancy/Reproduction
Fertility—
Fertility studies in animals suggest no adverse effects. {01}

Pregnancy—
Adequate and well-controlled studies in humans have not been done. {01}

Fetal toxicity studies in animals suggest no adverse effects. {01}

FDA Pregnancy Category B. {29}

Breast-feeding

Terbinafine is distributed into breast milk. {01} In 2 women, totals of 0.2 and 0.7 mg of terbinafine were detected in the breast milk after a single oral 500-mg dose in the ablactation period. {02}

Pediatrics

No information is available on the relationship of age to the effects of terbinafine in pediatric patients. Safety and efficacy have not been established. {01} However, terbinafine has been used to treat tinea capitis in a small number of children 3 to 16 years of age and was generally well tolerated. {23}


Geriatrics


No information is available on the relationship of age to the effects of terbinafine in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require an adjustment of dosage in patients receiving terbinafine. {01} {02}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol or {01}
» Hepatotoxic medications, other (see Appendix II ) {01} {03}    (severe hepatitis has been reported rarely with terbinafine; concurrent use of other hepatotoxic medications may increase the risk of hepatotoxicity )


Caffeine {02}    (terbinafine was found to decrease the clearance of caffeine by 20%)


Cyclosporine    (Terbinafine increases the clearance of cyclosporine by 15%)

{31}
» Enzyme inducers, hepatic, cytochrome P450 (see Appendix II )    (because terbinafine is hepatically metabolized, medications, such as rifampin, that induce the cytochrome P450 system may increase the clearance of terbinafine {01} {02} {17})


» Enzyme inhibitors, hepatic, cytochrome P450    (because terbinafine is hepatically metabolized, medications, such as cimetidine, that inhibit the cytochrome P450 system may decrease the clearance of terbinafine {01} {02} {17})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Absolute lymphocyte counts (ALC)    (values may be transiently decreased.)

{31}
Alanine aminotransferase (ALT [SGPT]) and
Aspartate aminotransferase (AST [SGOT])    (values may rarely be transiently increased {08})


Complete blood count (CBC)    (isolated cases of severe neutropenia have been reported. if neutrophil count is less than or equal to 1,000 cells/mm3then terbinafine should be discontinued and supportive management started.)

{31}
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Alcoholism, active or in remission or
» Hepatic function impairment or
Liver disease, chronic or acitve    (rare cases of liver failure, some leading to death or liver transplant have occurred; hepatoxicity has occured in patients with and without pre-esxisting liver disease; pretreatment serum transaminase tests (ALT and AST) are advised before starting treatment.{31})


» Hypersensitivity to terbinafine
» Renal function impairment    (the clearance of terbinafine was decreased by approximately 50% in patients with renal impairment [creatinine clearance £ 50 mL per min (0.83 mL per sec)]; the use of terbinafine is not recommended{31})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Clinical assessment {17}    (a follow-up clinical assessment is recommended after terbinafine therapy has ended, to determine whether relapse has occurred; the timing of this assessment depends on the condition being treated; for tinea corporis, tinea cruris, and tinea pedis, it is recommended that the assessment be performed at 6 to 8 weeks following cessation of treatment, for onychomycosis of the fingernails, it is recommended that the assessment be at 4 to 6 months, and for onychomycosis of the toenails, it is recommended that the assessment be at 6 to 9 months following cessation of treatment)


Hepatic function determinations {01}    (liver function tests (ALT and AST) are recommended before therapy, and periodically during terbinafine treatment, in all patients, especially in those with hepatic function impairment, alcoholic patients, or patients taking hepatotoxic medications concurrently)

{31}


Side/Adverse Effects

Note: Loss of taste has been reported rarely during terbinafine treatment, with the onset occurring 5 to 8 weeks after the start of therapy. {11} {12} {13} This effect is reversible upon discontinuation of terbinafine {04} {08} {11} {12} {13}, but recovery may take 2 to 6 weeks. {11} {12} There also has been one case of tongue discoloration associated with terbinafine. {13}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Hypersensitivity (skin rash or itching){01}

Incidence rare
    
Hepatitis or hepatic failure (dark urine; fatigue; loss of appetite; pale stools; yellow eyes or skin){01}{03}{08}{10}{31}{32}
    
neutropenia (fever, chills, or sore throat){06}
    
pancytopenia (fever, chills, or sore throat; pale skin; unusual bleeding or bruising; unusual tiredness or weakness){06}
    
Stevens-Johnson syndrome ( aching joints and muscles; redness, blistering, peeling, or loosening of skin; unusual tiredness or weakness){01}{09}{15}
    
toxic epidermal necrolysis (difficulty in swallowing; redness, blistering, peeling, or loosening of skin){01}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Gastrointestinal disturbances (diarrhea; loss of appetite; nausea and vomiting; stomach pain, mild){01}{02}{04}

Incidence less frequent
    
Change of taste or loss of taste {01} {04} {11} {12} {13}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Terbinafine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to terbinafine





Breast-feeding—Terbinafine is distributed into breast milk
Other medications, especially alcohol, cytochrome P450 enzyme inducers and inhibitors, and other hepatotoxic medications
Other medical problems, especially alcoholism, hepatic function impairment, and renal function impairment

Proper use of this medication
May be taken with or without food

» Compliance with full course of therapy

» Importance of not missing doses and taking at evenly spaced times

» Proper dosing
Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress during therapy

Checking with physician if no improvement within a few weeks (or months for onychomycosis)

Caution in drinking alcoholic beverages during terbinafine therapy

Reporting any signs of hepatic failure to physician immediately


Side/adverse effects
Signs of potential side effects, especially hypersensitivity, hepatitis, neutropenia, pancytopenia, Stevens-Johnson syndrome, and toxic epidermal necrolysis


General Dosing Information
Terbinafine may be taken with or without food.{01}

To prevent relapse, therapy should be continued until the infecting organism is completely eradicated as determined by clinical or laboratory examination. Representative treatment periods are: onychomycosis, 6 weeks to 3 months; tinea corporis and tinea cruris, 2 to 4 weeks; and tinea pedis, 2 to 6 weeks.{01}

Hepatotoxicity may occur in patients with and without preexisting liver disease and patients should be warned to report any symptoms immediately (persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain or jaundice, dark urine or pale stools). Terbinafine should be temporarily discontinued and the patient's liver function should be immediately evaluated.{31}{32}

Terbinafine is not recommended in patients with impaired renal function (creatinine clearance £ 50 mL per min [0.83 mL per sec]).{31}


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

TERBINAFINE HYDROCHLORIDE TABLETS

Note: The dosing and strengths available are expressed in terms of terbinafine base. {29}


Usual adult and adolescent dose
Antifungal
Onychomycosis: Oral, 250 mg (base) once a day, for six weeks (for fingernail infections) {29} to twelve weeks (for toenail infections) {29}. {29} {30} Some toenail infections may require longer therapy, depending on the extent of the infection. {01} {02}
[Tinea capitis]1: Oral, 250 mg (base) once a day, for four to six weeks. {23} {24} {25}
[Tinea corporis]: Oral, 250 mg (base) once a day, for two to four weeks. {30}
[Tinea cruris]: Oral, 250 mg (base) once a day, for two to four weeks. {30}
[Tinea pedis (interdigital or plantar)]: Oral, 250 mg (base) once a day, for two to six weeks. {30}


Usual pediatric dose
Dosage has not been established. {01} However, in one study the following doses were used in the treatment of tinea capitis in children 3 to 16 years of age {23}
Children 12.5 to 18.5 kg of body weight: Oral, 62.5 mg (base) once a day.
Children 18.5 to 25 kg of body weight: Oral, 125 mg (base) once a day.
Children more than 25 kg of body weight: Oral, 250 mg (base) once a day.


Strength(s) usually available
U.S.—


250 mg (base) (Rx) [Lamisil{29}]

Canada—


250 mg (base) (Rx) [Lamisil{30}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Continue medicine for full time of treatment.



Revised: 06/27/2001



References
  1. Lamisil package insert (Sandoz—Canada), Rev 4/93, Rec 2/94.
  1. Balfour JA, Faulds D. Terbinafine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial mycoses. Drugs 1992; 43(2): 259-84.
  1. van't Wout JA, Herrmann WA, de Vries RA, Stricker BHCh. Terbinafine-associated hepatic injury. J Hepatol 1994; 21: 115-7.
  1. Finlay AY. Global overview of Lamisil. Br J Dermatol 1994; 130 (suppl 43): 1-3.
  1. Zehender H, Cabiac MD, Denouël J, et al. Elimination kinetics of terbinafine from human plasma and tissues following multiple-dose administration, and comparison with 3 main metabolites. Drug Invest 1994; 8(4): 203-10.
  1. Kovacs MJ, Alshammari S, Guenther L, Bourcier M. Neutropenia and pancytopenia associated with oral terbinafine. J Am Acad Dermatol 1994; 31(5): 806.
  1. Meinhof W. Kinetics and spectrum of activity of oral antifungals: the therapeutic implications. J Am Acad Dermatol 1993; 29(1): S37-S41.
  1. Hay RJ. Risk/benefit ratio of modern antifungal therapy: focus on hepatic reactions. J Am Acad Dermatol 1993; 29(1): S50-S54.
  1. Rzany B, Mockenhaupt J, Gehring W, Schöpf E. Stevens-Johnson syndrome after terbinafine therapy. J Am Acad Dermatol 1994; 30(3): 509.
  1. Lowe G, Green C, Jennings P. Hepatitis associated with terbinafine treatment. BMJ 1993; 306(6872): 248.
  1. Beutler M, Hartmann K, Kuhn M, Gartmann J. Taste disorders and terbinafine. BMJ 1993; 307(6895): 26.
  1. Juhlin L. Loss of taste and terbinafine. Lancet 1992; 339: 1483.
  1. Ottervanger JP, Stricker BHCh. Loss of taste and terbinafine. Lancet 1992; 340: 728.
  1. Schäfer-Korting M. Pharmacokinetic optimization of oral antifungal therapy. Clin Pharmacokinet 1993; 25(4): 329-41.
  1. McGregor JM, Rustin MHA. Terbinafine and erythema multiforme. Br J Dermatol 1994; 131(4): 587-8.
  1. Ryder NS. Terbinafine: mode of action and properties of the squalene epoxidase inhibition. Br J Dermatol 1992; 126(suppl 39): 2-7.
  1. Gupta AK, Saunder DN, Shear NH. Antifungal agents: an overview. Part II. J Am Acad Dermatol 1994; 30(6): 911-33.
  1. Tüzün Y, Kotogyan A, Oguz O. Terbinafine: efficacy and safety in the treatment of dermatophytosis. Int J Dermatol 1992; 31: 720-1.
  1. Goodfield MJD, Andrew L, Evans EGV. Short term treatment of dermatophyte onychomycosis with terbinafine. BMJ 1992; 304: 1151-4.
  1. De Keyser P, De Backer M, Massart DL, Westelinck KJ. Two-week oral treatment of tinea pedis, comparing terbinafine (250 mg/day) with itraconazole (100 mg/day): a double-blind, multicentre study. Br J Dermatol 1994; 130(suppl 43): 22-5.
  1. van der Schroeff JG, Cirkel PKS, Crijns MB, et al. A randomized treatment duration-finding study of terbinafine in onychomycosis. Br J Dermatol 1992; 126(suppl 39): 36-9.
  1. Baudraz-Rosselet F, Rakosi T, Wili PB, Kenzelmann R. Treatment of onychomycosis with terbinafine. Br J Dermatol 1992; 126(suppl 39): 40-6.
  1. Haroon TS, Hussain I, Mahmood A, Nagi AH, Ahmad I, Zahid M. An open clinical pilot study of the efficacy and safety of oral terbinafine in dry non-inflammatory tinea capitis. Br J Dermatol 1992; 126(suppl 39): 47-50.
  1. Degreef HJ, DeDoncker PRG. Current therapy of dermatophytosis. J Am Acad Dermatol 1994; 31: S25-S30.
  1. Frieden IJ, Howard R. Tinea capitis: epidemiology, diagnosis, treatment, and control. J Am Acad Dermatol 1994; 31: S42-S46.
  1. Elewski BE. Mechanisms of action of systemic antifungal agents. J Am Acad Dermatol 1993; 28(5 part 1): S28-S34.
  1. Finlay AY. Pharmacokinetics of terbinafine in the nail. Br J Dermatol 1992; 126(suppl 39): 28-32.
  1. Nolting S, Brautigam M, Weidinger G. Terbinafine in onychomycosis with involvement by non-dermatophytic fungi. Br J Dermatol 1994; 130(suppl 43): 16-21.
  1. Lamisil package insert (Novartis—US), Rev 10/97, Rec 9/98.
  1. Lamisil (Novartis). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p. 857-8.
  1. Product Information: Lamisil®, terbinafine. Novartis Pharmaceuticals Corporation, East Hanover, New Jersey. (PI revised 4/2001) PI reviewed 5/2001
  1. FDA Talk Paper: FDA Issues Health Advisory regarding the safety of Sporanox® Products and Lamisil® Tablets to Treat Fungal Nail Infection. Issued 05/09/2001 (reviewed 5/2001)
Hide
(web2)