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TERBINAFINE AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Terbinafine, an allylamine derivative, is an antifungal agent that acts by inhibiting fungal sterol synthesis through inhibition of squalene epoxidase, a key enzyme necessary for the development of the fungal cell wall sterol. Butenafine, a benzylamine antifungal, has actions similar to those of allylamine terbinafine, and is used topically to treat superficial dermatophyte infections.

Specific Substances

    A) TERBINAFINE
    1) SF-86-327
    2) Molecular Formula: C21-H26-Cl-N
    3) CAS 91161-71-6 (terbinafine)
    4) CAS 78628-80-5 (terbinafine hydrochloride)
    5) (E)-6,6-dimethyhelpt-2-en-4-ynl (methyl)-1-Naphthyl methyl) amine hydrochloride
    BUTENAFINE
    1) Butenafine hydrochloride
    2) Butenafina
    3) CAS 101828-21-1 (butenafine)
    4) CAS 101827-46-7 (butenafine hydrochloride
    5) Molecular formula: C23-H27-N,HCl

    1.2.1) MOLECULAR FORMULA
    1) BUTENAFINE HYDROCHLORIDE: C23H27N.HCl
    2) TERBINAFINE HYDROCHLORIDE: C21H26C1N.HCl

Available Forms Sources

    A) USES
    1) TERBINAFINE
    a) Terbinafine oral granules are used for the treatment of tinea capitis in patients 4 years of age and older (Prod Info LAMISIL(R) oral granules, 2007).
    b) Terbinafine tablets are used for the treatment of onychomycosis of the toenail or fingernail due to dermatophytes (tinea unguium) (Prod Info Lamisil(R) tablets, terbinafine, 1997).
    c) Terbinafine cream (1%) and solution (1%) are administered topically for the treatment of tinea (pityriasis) versicolor due to Malassezia furfur, and tinea pedis, tinea cruris, or tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes, or Epidermophyton floccosum (Prod Info Lamisil(R) cream 1%, terbinafine, 1997; Prod Info Lamisil(R) solution 1%, terbinafine, 1997).
    2) BUTENAFINE
    a) Butenafine hydrochloride cream, 1% is indicated for the topical treatment of the tinea (pityriasis) versicolor that is due to M. furfur (formerly known as P. orbiculare) (Prod Info MENTAX(R) topical cream, 2006).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Terbinafine is used for the treatment of onychomycosis of toenail or fingernail secondary to dermatophytes (tinea unguium).
    B) PHARMACOLOGY: Terbinafine is an allylamine antifungal. It inhibits biosynthesis of ergosterol via inhibition of squalene epoxidase enzyme resulting in fungal cell death.
    C) EPIDEMIOLOGY: Exposure can occur.
    D) WITH THERAPEUTIC USE
    1) COMMON: Various dermatologic adverse reactions, including pustular and psoriasis-like eruptions, erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome have commonly occurred with oral terbinafine therapy. Hypersensitivity reactions and cutaneous and systemic lupus erythematosus have also been reported. Headache, nausea, vomiting, diarrhea, dyspepsia, liver enzyme abnormalities, pruritus, flatulence and abdominal pain can develop following oral therapy.
    2) INFREQUENT: Ocular disturbances, taste impairment and smell disturbance (sometimes prolonged and may be permanent), leukopenia, renal impairment and hepatotoxicity are infrequent occurrences following therapy.
    3) RARE: Hematologic effects including, neutropenia, agranulocytosis, and thrombocytopenia have occurred rarely following chronic oral terbinafine therapy. Cases of liver failure leading to liver transplant or death have occurred with oral therapy. In most cases, individuals had underlying hepatic events and systemic conditions. Hypersensitivity reactions and cutaneous lupus erythematosus have been reported following terbinafine therapy.
    E) WITH POISONING/EXPOSURE
    1) Limited data. Anticipate toxic effects similar to adverse events reported, predominantly dermatologic manifestations and gastrointestinal irritation, with therapeutic use. Doses up to 5 g (20 times the therapeutic daily dose) have been associated with nausea, vomiting, abdominal pain, rash, headache, dizziness, and frequent urination.
    0.2.20) REPRODUCTIVE
    A) Butenafine is classified as FDA pregnancy category C and terbinafine is classified as FDA pregnancy category B. In animal studies, no teratogenicity or adverse fetal effects were noted with the administration of butenafine or terbinafine in rats or rabbits. Terbinafine is present in human breast milk in a ratio of 7:1 following oral administration.

Laboratory Monitoring

    A) Serum levels are not clinically useful for these agents.
    B) Monitor fluids and electrolyte status following significant vomiting and/or diarrhea.
    C) Monitor CBC with differential. Leukopenia and thrombocytopenia have been reported following chronic oral terbinafine therapy. Severe neutropenia has developed in some individuals following the therapeutic use of oral terbinafine
    D) Obtain liver enzymes in symptomatic patients or as indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe vomiting and/or diarrhea.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor CBC with differential and vital signs for evidence of infection in a symptomatic patient or following chronic exposure. Severe neutropenia has developed in some cases; the effects were reversible upon discontinuation of terbinafine, with or without supportive care. Monitor for bleeding as indicated; blood transfusions and/or platelets may be necessary. In patients with an acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Obtain baseline liver enzymes in patients following a significant or chronic exposure.
    C) DECONTAMINATION
    1) PREHOSPITAL: Toxicity after an acute ingestion is not anticipated; activated charcoal is unlikely to be necessary following a minor ingestion. It is not known if gastric decontamination will be useful in treating acute terbinafine ingestions.
    2) HOSPITAL: Toxicity after an acute ingestion is unlikely, and is often only expected with chronic use. Consider activated charcoal only if coingestants with significant toxicity are involved.
    D) AIRWAY MANAGEMENT
    1) Airway support is unlikely to be necessary following a minor or moderate ingestion. Ensure adequate ventilation and perform endotracheal intubation early in patients with a terbinafine overdose (eg, severe allergic reactions, severe bleeding, hemodynamic instability).
    E) ANTIDOTE
    1) None.
    F) MYELOSUPPRESSION
    1) Administer colony stimulating factors in patients who develop severe neutropenia or neutropenic sepsis that does not improve with the discontinuation of terbinafine. During postmarketing experience, pancytopenia, thrombocytopenia and anemia have also been reported with oral therapy. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    G) ENHANCED ELIMINATION
    1) Due to the high degree (greater than 99%) of protein binding of terbinafine, it is unlikely that hemodialysis will be effective.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients who are asymptomatic or have minimal gastrointestinal symptoms following exposure to terbinafine and are otherwise improving may be managed at home.
    2) OBSERVATION CRITERIA: Patients who develop significant symptoms (ie, hypersensitivity, allergic reactions) or evidence of laboratory abnormalities (ie, increased liver enzymes, hematologic effects) need to have ongoing monitoring until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Only patients with systemic toxicity (ie, serious skin reactions, hepatotoxicity and hematologic effects) may require admission.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PHARMACOKINETICS
    1) ORAL: Terbinafine is greater than 99% bound to plasma proteins. Terbinafine is greater than 70% absorbed following oral ingestion and the bioavailability is approximately 40%. Approximately 70% of terbinafine granules are eliminated in the urine and 20% is excreted in the feces. Volume of distribution at steady-state is approximately 947 L. Peak plasma concentrations of 1 mcg/mL within 2 hours after a single 250 mg dose. It has a terminal half-life of 200 to 400 hours and may be representative of the slow elimination of terbinafine from tissues such as skin and adipose. TOPICAL: Absorption is variable with the plasma concentration ranging from approximately 11 to 21 ng/mL and is dependent upon the total amount of terbinafine applied to the skin.

Range Of Toxicity

    A) TOXICITY: Limited data. Doses up to 5 g (20 times the therapeutic daily adult dose) have been associated with mild toxicity (ie, nausea, vomiting, abdominal pain, dizziness, rash, frequent urination and headache).
    B) THERAPEUTIC DOSE: TINEA CAPITIS: ORAL GRANULES: ADULT: Weighing greater than 35 kg: 250 mg/day for 6 weeks. PEDIATRIC: For children weighing between 25 and 35 kg: 187.5 mg/day for 6 weeks and weighing less than 25 kg: 125 mg/day for 6 weeks.

Clinical Effects

Summary Of Exposure

    A) USES: Terbinafine is used for the treatment of onychomycosis of toenail or fingernail secondary to dermatophytes (tinea unguium).
    B) PHARMACOLOGY: Terbinafine is an allylamine antifungal. It inhibits biosynthesis of ergosterol via inhibition of squalene epoxidase enzyme resulting in fungal cell death.
    C) EPIDEMIOLOGY: Exposure can occur.
    D) WITH THERAPEUTIC USE
    1) COMMON: Various dermatologic adverse reactions, including pustular and psoriasis-like eruptions, erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome have commonly occurred with oral terbinafine therapy. Hypersensitivity reactions and cutaneous and systemic lupus erythematosus have also been reported. Headache, nausea, vomiting, diarrhea, dyspepsia, liver enzyme abnormalities, pruritus, flatulence and abdominal pain can develop following oral therapy.
    2) INFREQUENT: Ocular disturbances, taste impairment and smell disturbance (sometimes prolonged and may be permanent), leukopenia, renal impairment and hepatotoxicity are infrequent occurrences following therapy.
    3) RARE: Hematologic effects including, neutropenia, agranulocytosis, and thrombocytopenia have occurred rarely following chronic oral terbinafine therapy. Cases of liver failure leading to liver transplant or death have occurred with oral therapy. In most cases, individuals had underlying hepatic events and systemic conditions. Hypersensitivity reactions and cutaneous lupus erythematosus have been reported following terbinafine therapy.
    E) WITH POISONING/EXPOSURE
    1) Limited data. Anticipate toxic effects similar to adverse events reported, predominantly dermatologic manifestations and gastrointestinal irritation, with therapeutic use. Doses up to 5 g (20 times the therapeutic daily dose) have been associated with nausea, vomiting, abdominal pain, rash, headache, dizziness, and frequent urination.

Heent

    3.4.3) EYES
    A) UVEITIS
    1) WITH THERAPEUTIC USE
    a) Anterior uveitis developed in a 40-year-old man with late-stage AIDS 12 days after beginning terbinafine therapy to treat oral candidiasis. Terbinafine therapy was stopped and the patient's ocular symptoms began to decrease. Upon restarting treatment with terbinafine, the patient's symptoms rapidly worsened. The uveitis gradually resolved following treatment with ocular steroid drops and discontinuation of terbinafine (Price et al, 1997).
    B) COLOR VISION CHANGES
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 39-year-old woman experienced vision disturbances, including a greenish hue to non-green objects, lights brighter than usual, and sparkly lights, 3 weeks after beginning treatment with terbinafine. The visual disturbances resolved within 1 week after discontinuing terbinafine therapy (Gupta et al, 1996).
    3.4.6) THROAT
    A) TASTE IMPAIRMENT
    1) WITH THERAPEUTIC USE
    a) Partial or complete loss of taste has been associated with long-term terbinafine therapy and was generally reversible upon discontinuation of terbinafine (Juhlin, 1992; Beutler et al, 1993; Stricker et al, 1996), although severe, persistent taste loss (greater than 1 year) and in some cases permanent taste disturbances have been reported despite withdrawal of terbinafine (Prod Info LAMISIL(R) oral tablets, 2013; Ottervanger & Stricker, 1992; Bong et al, 1998; Duxbury et al, 2000).
    1) RISK FACTORS: Low body mass index, a history of taste loss, and increased age may increase the risk for the development of taste loss secondary to terbinafine therapy (Stricker et al, 1996).
    B) PAROTID SWELLING
    1) WITH THERAPEUTIC USE
    a) Parotid swelling has been reported in association with therapeutic terbinafine administration and was reversible upon withdrawal of the medication (Torrens & McWhinney, 1998).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has been reported with terbinafine therapy (Prod Info LAMISIL(R) oral tablets, 2013).
    2) WITH POISONING/EXPOSURE
    a) Headache may occur in overdose (Prod Info LAMISIL(R) oral tablets, 2013).
    B) FATIGUE
    1) WITH THERAPEUTIC USE
    a) CASE REPORTS: Two patients experienced severe fatigue several days after beginning terbinafine therapy, 250 mg daily. The patients also experienced loss of concentration and lack of initiative. The symptoms gradually resolved without discontinuation of the medication (Tsankov & Kamarashev, 1995).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting have been reported following oral terbinafine therapy (Prod Info LAMISIL(R) oral tablets, 2013; Filho et al, 1998).
    2) WITH POISONING/EXPOSURE
    a) Nausea and vomiting may occur in overdose (Prod Info LAMISIL(R) oral tablets, 2013; Filho et al, 1998).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea has been reported in patients taking oral terbinafine therapeutically (Prod Info LAMISIL(R) oral tablets, 2013).
    b) Mild diarrhea occurred in one patient following oral terbinafine therapy (Filho et al, 1998).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain and dyspepsia occurred with therapeutic administration of terbinafine (Prod Info LAMISIL(R) oral tablets, 2013).
    2) WITH POISONING/EXPOSURE
    a) Abdominal pain has occurred following overdose (Prod Info LAMISIL(R) oral tablets, 2013).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) CHOLESTATIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Cholestatic hepatitis has been reported in several patients following long- term oral administration of terbinafine. Symptoms included nausea, upper abdominal pain, pruritus, jaundice, dark urine, and pale stools. Laboratory analyses showed elevated liver enzyme and bilirubin levels and liver biopsies revealed hepatocellular and cunicular cholestasis (van't Wout et al, 1994) (Dwyer et al, 1997) (Lazaros et al, 1996) (Gupta et al, 1998; Fernandes et al, 1998). The hepatitis gradually resolved following withdrawal of terbinafine therapy.
    b) CASE REPORT: A 75-year-old woman ingested 250 mg of terbinafine daily for 3 weeks and developed weight loss, jaundice, and pruritus a few days after discontinuation of therapy. Laboratory analysis revealed elevated liver enzyme and bilirubin levels. Approximately 10 weeks after terbinafine discontinuation, the patient's jaundice disappeared and her bilirubin and liver enzyme levels returned to normal, with the exception of serum GGT which remained elevated 17 months after terbinafine cessation. A liver biopsy, performed 6 months after withdrawal of terbinafine therapy, showed a mild centrilobular cunicular cholestasis (Mallat et al, 1997).
    B) HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) Liver failure has occurred following the therapeutic use of terbinafine in some individuals with or without a history of preexisting liver disease. In some cases, liver failure led to liver transplant or death (Prod Info LAMISIL(R) oral tablets, 2013).
    b) CASE REPORT: A 48-year-old woman developed fulminant hepatic failure within 4 weeks after beginning oral terbinafine therapy, 250 mg daily. The patient underwent liver transplantation after developing encephalopathy requiring ventilation (Agarwal et al, 1999). The explanted liver showed submassive necrosis with complete disappearance of hepatocytes.

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL RENAL FUNCTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 33-year-old man began terbinafine therapy, 250 mg daily, for treatment of chronic tinea pedis and 5 days later a laboratory analysis showed an elevated serum creatinine level. The patient experienced lethargy and collapsed 10 weeks after beginning terbinafine therapy. A repeat laboratory analysis again showed a progressively increasing serum creatinine level. The serum creatinine level gradually returned to normal approximately 1 week after discontinuing terbinafine therapy (Lee et al, 1996).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) Severe neutropenia has occurred with therapy. If the neutrophil count is less than or equal to 1000 cells/mm(3) therapy should be stopped. Cases were reversible upon discontinuation of therapy, with or without supportive care (Prod Info LAMISIL(R) oral tablets, 2013). In other studies, neutropenia resolved following terbinafine discontinuation and treatment with granulocyte colony-stimulating factor (G-CSF) (Kovacs et al, 1994; Gupta et al, 1998; Shapiro et al, 1999).
    B) LYMPHOCYTE
    1) WITH THERAPEUTIC USE
    a) Transient decreases in absolute lymphocyte counts have occurred in controlled clinical trials (Prod Info LAMISIL(R) oral tablets, 2013).
    C) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 55-year-old woman developed fever, vomiting, and diarrhea approximately 4 weeks after beginning terbinafine therapy, 250 mg daily, to treat onychomycosis of the toenail. A complete blood count revealed a WBC count of 1600 cells/microliter with 0% granulocytes and 0% banded neutrophils. After receiving recombinant granulocyte colony-stimulating factor, 5 mcg/kg daily for 5 days, the patient's agranulocytosis gradually resolved, with a final WBC count of 12,300 cells/microliter and an absolute granulocyte count of 6200 cells/microliter (Ornstein & Ely, 1998).
    D) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) During postmarketing experience, pancytopenia, thrombocytopenia and anemia have been reported with therapy (Prod Info LAMISIL(R) oral tablets, 2013).
    b) CASE REPORT: A 25-year-old woman, with a past medical history of leukopenia, developed epistaxis approximately 4 months after beginning oral terbinafine therapy, 250 mg daily. A complete blood count showed a platelet count of 63 x 10(9)/L, indicating thrombocytopenia. The platelet count returned to normal (314 x 10(9)/L) with no further bleeding episodes approximately 8 days after discontinuing terbinafine therapy (Grunwald & Amichai, 1998).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) PUSTULE
    1) WITH THERAPEUTIC USE
    a) There have been postmarketing reports of serious skin and/or hypersensitivity reactions including erythema multiforme, toxic epidermal necrolysis, exfoliative dermatitis, bullous dermatitis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) and Stevens-Johnson Syndrome with terbinafine use (Prod Info LAMISIL(R) oral tablets, 2013).
    b) Acute generalized exanthematous pustulosis, characterized by fever and the development of erythematous nonfollicular, confluent pustules primarily affecting the trunk and the proximal and distal extremities, was reported in several patients following long-term (greater than 2 weeks) of oral terbinafine therapy, 250 mg daily. The skin eruptions generally resolved within 3 weeks after treatment with corticosteroids and discontinuation of terbinafine therapy (Dupin et al, 1996; Kempinaire et al, 1997; Condon et al, 1998; Bennett et al, 1999).
    c) CASE REPORT: A 64-year-old woman developed acute generalized exanthematous pustulosis (AGEP) on her trunk and upper and lower extremities approximately 3 days after completing a 28-day course of oral terbinafine therapy to treat onychomycosis of the toenails. The patient noted a sore throat 2 days prior to onset of rash, but she did not have a fever. A punch biopsy revealed nonfollicular subcorneal and intra-epithelial pustules containing neutrophils, which was consistent with the diagnosis of AGEP. There was complete resolution of the pustulosis approximately 6 weeks later, following treatment with topical and oral corticosteroids (Hall & Tate, 2000).
    B) GENERALIZED PUSTULAR PSORIASIS
    1) WITH THERAPEUTIC USE
    a) Several cases of pustular psoriasis were reported, with the majority occurring within 2 weeks of initiating oral terbinafine therapy. The psoriasis gradually resolved after terbinafine discontinuation and administration of oral and topical corticosteroids (Gupta et al, 1997; Papa & Miller, 1998; Wilson & Evans, 1998; Gupta et al, 1998; Pauluzzi & Boccucci, 1999).
    b) CASE REPORT: A 56-year-old woman began oral terbinafine therapy, 250 mg daily, and 5 days later developed erythema anulare centrifugum-like psoriatic eruptions and single lesions on her trunk and extremities. The skin eruptions resolved within 2 weeks after discontinuing terbinafine therapy and beginning prednisone therapy, 60 mg daily for 5 days (Wach et al, 1995).
    C) ERYTHEMA MULTIFORME
    1) WITH THERAPEUTIC USE
    a) There have been postmarketing reports of serious skin and/or hypersensitivity reactions including erythema multiforme, toxic epidermal necrolysis, exfoliative dermatitis, bullous dermatitis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) and Stevens-Johnson Syndrome with terbinafine use (Prod Info LAMISIL(R) oral tablets, 2013).
    b) Erythema multiforme, characterized by macules, papules, and large confluent, erythematous areas with superficial desquamation, was reported in several patients within 4 weeks after beginning oral terbinafine therapy, 250 mg daily, for treatment of onychomycosis. The rash resolved within 3 weeks after discontinuing terbinafine and beginning treatment with oral prednisone (Todd et al, 1995; McGregor & Rustin, 1994; Carstens et al, 1994; Gupta et al, 1998).
    D) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) There have been postmarketing reports of serious skin and/or hypersensitivity reactions including erythema multiforme, toxic epidermal necrolysis, exfoliative dermatitis, bullous dermatitis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) and Stevens-Johnson Syndrome with terbinafine use (Prod Info LAMISIL(R) oral tablets, 2013).
    b) CASE REPORT: A 26-year-old woman with cerebral palsy developed a widespread blistering rash with progressive desquamation over her trunk and limbs approximately 2 weeks after beginning terbinafine therapy, 250 mg daily, for treatment of tinea corporis. The patient was also on long-term anti- epileptic therapy. Dermal histologic examination revealed extensive necrosis of the keratinocytes and bullous degeneration of the cells. Despite supportive therapy, the patient's condition deteriorated and she died approximately 2 days later (White & Bowen-Jones, 1996).
    c) CASE REPORT: Toxic epidermal necrolysis (TEN) has been reported in a 49-year-old woman approximately 10 days after beginning therapeutic administration of oral terbinafine. The patient developed pruritus, edema, large flaccid bullae of the legs, and generalized confluent maculopapular erythema with severe peeling. A histologic exam of the lower legs confirmed the diagnosis of TEN. The skin eruptions gradually resolved with oral and topical corticosteroid therapy (Carstens et al, 1994).
    E) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) There have been postmarketing reports of serious skin and/or hypersensitivity reactions including erythema multiforme, toxic epidermal necrolysis, exfoliative dermatitis, bullous dermatitis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) and Stevens-Johnson Syndrome with terbinafine use (Prod Info LAMISIL(R) oral tablets, 2013).
    b) CASE REPORT: A 61-year-old woman began treatment with oral terbinafine, 250 mg daily for 8 days, and developed a fever, oral mucosa erosions, and a macular rash on her trunk 2 days after discontinuing terbinafine therapy. Within one day, the rash became generalized with erosions and blisters and a biopsy revealed a perivascular lymphocytic infiltrate. A diagnosis of Stevens-Johnson syndrome was made and the patient was treated with oral and topical corticosteroids, resulting in the resolution of the lesions within 2 weeks (Rzany et al, 1994).
    F) DRUG-INDUCED LUPUS ERYTHEMATOSUS
    1) WITH THERAPEUTIC USE
    a) Terbinafine ingestion, 250 mg daily for 6 weeks, has been associated with the development of cutaneous lupus erythematosus. In each case, a widespread erythematous scaly rash was observed and autoantibody screens showed the presence of antinuclear antibodies with speckled patterns. Skin biopsies revealed hyperkeratosis, basal vacuolation, follicular plugging, and perivascular lymphocytic infiltrate, confirming the diagnosis of cutaneous lupus erythematosus (Brooke et al, 1998; Holmes & Kemmett, 1998; Murphy & Barnes, 1998). The rash resolved following terbinafine discontinuation and administration of antihistamines, hydroxychloroquine, and oral and topical corticosteroids.

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) There have been postmarketing reports of serious skin and/or hypersensitivity reactions including erythema multiforme, toxic epidermal necrolysis, exfoliative dermatitis, bullous dermatitis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) and Stevens-Johnson Syndrome with terbinafine use (Prod Info LAMISIL(R) oral tablets, 2013).
    b) Hypersensitivity reactions were reported in two patients following ingestion of terbinafine, 250 mg daily for 10 days and 4.5 weeks, respectively. Both patients experienced fever, elevated liver enzyme levels, lymphadenopathy, and erythematous, pruritic rash, with pustules occurring in one patient. The patients gradually recovered following withdrawal of terbinafine therapy and the administration of oral prednisone (Gupta et al, 1997; Gupta & Porges, 1998).
    B) DRUG-INDUCED LUPUS ERYTHEMATOSUS
    1) WITH THERAPEUTIC USE
    a) Terbinafine ingestion, 250 mg daily for 6 weeks, has been associated with the development of cutaneous lupus erythematosus. In each case, a widespread erythematous scaly rash was observed and autoantibody screens showed the presence of antinuclear antibodies with speckled patterns. Skin biopsies revealed hyperkeratosis, basal vacuolation, follicular plugging, and perivascular lymphocytic infiltrate, confirming the diagnosis of cutaneous lupus erythematosus (Brooke et al, 1998; Holmes & Kemmett, 1998; Murphy & Barnes, 1998). The rash resolved following terbinafine discontinuation and administration of antihistamines, hydroxychloroquine, and oral and topical corticosteroids.

Reproductive

    3.20.1) SUMMARY
    A) Butenafine is classified as FDA pregnancy category C and terbinafine is classified as FDA pregnancy category B. In animal studies, no teratogenicity or adverse fetal effects were noted with the administration of butenafine or terbinafine in rats or rabbits. Terbinafine is present in human breast milk in a ratio of 7:1 following oral administration.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Butenafine is classified as FDA pregnancy category C (Prod Info MENTAX(R) topical cream, 2006).
    2) Terbinafine is classified as FDA pregnancy category B (Prod Info Lamisil(R) oral granules, 2013).
    B) ANIMAL STUDIES
    1) BUTENAFINE
    a) RATS, RABBITS: In animal studies, butenafine was not teratogenic when administered to rats at subQ doses up to 25 mg/kg/day (0.5 times the maximum recommended human dose (MRHD) for tinea versicolor based on body surface area) during organogenesis. No treatment-related external, visceral, skeletal malformations or variations were observed in the offspring of rabbits administered butenafine hydrochloride at oral doses up to 400 mg/kg/day (16 times the MRHD for tinea versicolor based on body surface area) during organogenesis (Prod Info MENTAX(R) topical cream, 2006).
    2) TERBINAFINE
    a) RATS, RABBITS: No evidence of fetal harm was noted in rats and rabbits administered oral terbinafine at doses up to 300 mg/kg/day (12 to 23 times the maximum recommended human dose, respectively, based on body surface area) (Prod Info Lamisil(R) oral granules, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Following oral administration, terbinafine is present in human breast milk in a milk-to-plasma ratio of 7:1. Nursing is not recommended in women receiving terbinafine (Prod Info Lamisil(R) oral granules, 2013).
    3.20.5) FERTILITY
    A) LACK OF EFFECT
    1) BUTENAFINE
    a) In animal studies, administration of oral butenafine hydrochloride in rats at doses up to 125 mg/kg/day (2.5 times the maximum recommended human dose based on body surface area) did not result in treatment-related fertility effects (Prod Info MENTAX(R) topical cream, 2006).
    2) TERBINAFINE
    a) No evidence of impaired fertility was noted in animals administered oral terbinafine at doses up to 300 mg/kg/day (12 times the maximum recommended human dose in rats and rabbits, respectively, based on body surface area) (Prod Info Lamisil(R) oral granules, 2013).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Serum levels are not clinically useful for these agents.
    B) Monitor fluids and electrolyte status following significant vomiting and/or diarrhea.
    C) Monitor CBC with differential. Leukopenia and thrombocytopenia have been reported following chronic oral terbinafine therapy. Severe neutropenia has developed in some individuals following the therapeutic use of oral terbinafine
    D) Obtain liver enzymes in symptomatic patients or as indicated.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Serum levels are not clinically useful for these agents.
    2) Monitor liver enzyme levels in symptomatic patients. Long-term administration of oral terbinafine may cause hepatotoxicity (Prod Info Lamisil(R) oral granules, 2013).
    3) CBC should be obtained in symptomatic patients. Leukopenia and thrombocytopenia have been reported following chronic oral terbinafine therapy (Prod Info Lamisil(R) oral granules, 2013).
    4) Severe neutropenia has developed in some individuals following the therapeutic use of oral terbinafine (Prod Info Lamisil(R) oral granules, 2013).

Methods

    A) CHROMATOGRAPHY
    1) High-performance liquid chromatographic (HPLC) methods have been used to determine the presence of terbinafine and its metabolites in human plasma, milk, and urine. The limits of detection and quantification, using this method, range from 50 to 300 ng/mL and 2 to 500 ng/mL, respectively, and are dependent on the biological samples used, the compound, and the specific HPLC method performed (Schatz & Haberl, 1989; Denouel et al, 1995; Zehender et al, 1994).
    2) A gas chromatographic method has been described for the determination of the terbinafine metabolite, 1-Naphthoic acid. The limit of detection, using this method, was 50 ng/mL (Schatz & Haberl, 1989).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Only patients with systemic toxicity (ie, serious skin reactions, hepatotoxicity and hematologic effects) may require admission.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients who are asymptomatic or have minimal gastrointestinal symptoms following exposure to terbinafine and are otherwise improving may be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients who develop significant symptoms (ie, hypersensitivity, allergic reactions) or evidence of laboratory abnormalities (ie, increased liver enzymes, hematologic effects) need to have ongoing monitoring until they are clearly improving and clinically stable.

Monitoring

    A) Serum levels are not clinically useful for these agents.
    B) Monitor fluids and electrolyte status following significant vomiting and/or diarrhea.
    C) Monitor CBC with differential. Leukopenia and thrombocytopenia have been reported following chronic oral terbinafine therapy. Severe neutropenia has developed in some individuals following the therapeutic use of oral terbinafine
    D) Obtain liver enzymes in symptomatic patients or as indicated.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Toxicity after an acute ingestion is not anticipated; activated charcoal is unlikely to be necessary following a minor ingestion. It is not known if gastric decontamination will be useful in treating acute terbinafine ingestions.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Most cases of toxicity reported have involved chronic ingestion of terbinafine. It is not know if gastric decontamination will be useful in treating acute terbinafine ingestions.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe vomiting and/or diarrhea.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Monitor CBC with differential and vital signs for evidence of infection in a symptomatic patient or following chronic exposure. Severe neutropenia has developed in some cases; the effects were reversible upon discontinuation of terbinafine, with or without supportive care. Monitor for bleeding as indicated; blood transfusions and/or platelets may be necessary. In patients with an acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Obtain baseline liver enzymes in patients following a significant or chronic exposure.
    B) MONITORING OF PATIENT
    1) Terbinafine serum levels are not clinically useful.
    2) Monitor fluids and electrolyte status following significant vomiting and/or diarrhea.
    3) Monitor CBC with differential and liver enzymes in symptomatic patients or as indicated. Long-term administration of terbinafine may cause hepatotoxicity and/or hematoxicity (ie, leukopenia, thrombocytopenia, neutropenia).
    C) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    D) MYELOSUPPRESSION
    1) Severe neutropenia has occurred with therapy. If the neutrophil count is less than or equal to 1000 cells/mm(3) therapy should be stopped. Cases were reversible upon discontinuation of therapy, with or without supportive care (Prod Info LAMISIL(R) oral tablets, 2013).
    2) During postmarketing experience, pancytopenia, thrombocytopenia and anemia have also been reported with oral therapy (Prod Info LAMISIL(R) oral tablets, 2013).
    3) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    4) Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or hemorrhage.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Due to the high degree (greater than 99%) of protein binding of terbinafine, it is unlikely that hemodialysis will be effective (Prod Info Lamisil(R) oral granules, 2013).

Range Of Toxicity

Summary

    A) TOXICITY: Limited data. Doses up to 5 g (20 times the therapeutic daily adult dose) have been associated with mild toxicity (ie, nausea, vomiting, abdominal pain, dizziness, rash, frequent urination and headache).
    B) THERAPEUTIC DOSE: TINEA CAPITIS: ORAL GRANULES: ADULT: Weighing greater than 35 kg: 250 mg/day for 6 weeks. PEDIATRIC: For children weighing between 25 and 35 kg: 187.5 mg/day for 6 weeks and weighing less than 25 kg: 125 mg/day for 6 weeks.

Therapeutic Dose

    7.2.1) ADULT
    A) TERBINAFINE
    1) ORAL GRANULES
    a) TINEA CAPITIS: (For patients weighing greater than 35 kg): 250 mg once daily for 6 weeks (Prod Info Lamisil(R) oral granules, 2013).
    2) TABLETS
    a) Fingernail onychomycosis: 250 mg tablet once daily for 6 weeks (Prod Info LAMISIL(R) oral tablets, 2013)
    b) Toenail onychomycosis: 250 mg tablet once daily for 6 weeks (Prod Info LAMISIL(R) oral tablets, 2013)
    3) TOPICAL
    a) SOLUTION (1%)
    1) TINEA (PITYRIASIS) VERSICOLOR: Apply once daily for 1 week (Prod Info LAMISIL(R) topical gel, 1999).
    2) TINEA CORPORIS: Apply once daily for 1 week (Prod Info LAMISIL(R) topical gel, 1999).
    3) TINEA CRURIS: Apply once daily for 1 week (Prod Info LAMISIL(R) topical gel, 1999).
    4) TINEA PEDIS: Apply twice daily for 1 week (Prod Info LAMISIL(R) topical gel, 1999).
    b) CREAM (1%)
    1) INTERDIGITAL TINEA PEDIS: Apply to affected and immediately surrounding areas twice daily for a minimum of 1 week, not to exceed 4 weeks (Prod Info Lamisil(R) cream 1%, terbinafine, 1997).
    2) TINEA CRURIS: Apply to affected and immediately surrounding areas once or twice daily for a minimum of 1 week, not to exceed 4 weeks (Prod Info Lamisil(R) cream 1%, terbinafine, 1997).
    3) TINEA CORPORIS: Apply to affected and immediately surrounding areas once or twice daily for a minimum of 1 week, not to exceed 4 weeks (Prod Info Lamisil(R) cream 1%, terbinafine, 1997).
    4) PLANTAR TINEA PEDIS: Apply to affected and immediately surrounding areas twice daily for 2 weeks (Prod Info Lamisil(R) cream 1%, terbinafine, 1997).
    B) BUTENAFINE
    1) CREAM (1%)
    a) TINEA (PITYRIASIS) VERSICOLOR: Apply 1% cream topically once daily for 2 weeks (Prod Info MENTAX(R) topical cream, 2006).
    7.2.2) PEDIATRIC
    A) TERBINAFINE
    1) ORAL GRANULES
    a) TINEA CAPITIS: Indicated in patients 4 years of age and older (Prod Info Lamisil(R) oral granules, 2013):
    1) Children weighing less than 25 kg: 125 mg/day for 6 weeks (Prod Info Lamisil(R) oral granules, 2013)
    2) Children weighing 25 to 35 kg: 187.5 mg/day for 6 weeks (Prod Info Lamisil(R) oral granules, 2013)
    3) Children weighing greater than 35 kg: 250 mg/day for 6 weeks (Prod Info Lamisil(R) oral granules, 2013)
    2) ORAL TABLETS
    a) The safety and efficacy of terbinafine tablets have not been established in pediatric patients with onychomycosis (Prod Info LAMISIL(R) oral tablets, 2013).
    B) BUTENAFINE
    1) CREAM (1%)
    a) The safety and efficacy in pediatric patients below the age of 12 years have not been established; tinea versicolor is uncommon in children less than 12 years (Prod Info MENTAX(R) topical cream, 2006).
    b) TINEA (PITYRIASIS) VERSICOLOR: Children 12 years of age or older: Apply 1% cream topically once daily for 2 weeks (Prod Info MENTAX(R) topical cream, 2006).

Maximum Tolerated Exposure

    A) SUMMARY
    1) Doses up to 5 g (20 times the therapeutic daily adult dose) have been associated with mild toxicity (ie, nausea, vomiting, abdominal pain, dizziness, rash, frequent urination and headache) (Prod Info Lamisil(R) oral granules, 2013).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Terbinafine, an allylamine derivative antifungal, inhibits biosynthesis of ergosterol, an essential component of fungal cell membrane, by inhibition of the squalene epoxidase enzyme. This results in fungal cell death, not ergosterol deficiency. This mechanism is due to increased membrane permeability mediated by the accumulation of high concentrations of squalene (Prod Info LAMISIL(R) oral granules, 2007).
    B) Dermatophytes and other fungi require partial inhibition of biosynthesis of ergosterol in order to achieve full growth inhibition, thus suggesting that cell death in susceptible fungi may be related to squalene accumulation instead of to ergosterol deficiency (Ryder, 1989).

Physicochemical

Physical Characteristics

    A) BUTENAFINE HYDROCHLORIDE is a white, odorless, crystalline powder that is slightly soluble in water and freely soluble in methanol, ethanol, and chloroform (Prod Info MENTAX(R) topical cream, 2006).
    B) TERBINAFINE HYDROCHLORIDE is a white to off-white fine crystalline powder that is slightly soluble in water, soluble in ethanol, and freely soluble in methanol and methylene chloride (Prod Info LAMISIL(R) oral granules, 2007).

Molecular Weight

    A) BUTENAFINE HYDROCHLORIDE: 353.93 (Prod Info MENTAX(R) topical cream, 2006)
    B) TERBINAFINE: 291.44 (Prod Info LAMISIL(R) topical gel, 1999)
    C) TERBINAFINE HYDROCHLORIDE: 327.9 (Prod Info LAMISIL(R) oral granules, 2007)

References

General Bibliography

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