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Terbinafine (Systemic)

Pronunciation

Pronunciation

(TER bin a feen)

Index Terms

  • Terbinafine HCl
  • Terbinafine Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Kit, Combination:

Terbinex: 250 mg & 1% [DSC]

Packet, Oral:

LamISIL: 125 mg (1 ea [DSC], 14 ea [DSC]); 187.5 mg (1 ea [DSC], 14 ea [DSC]) [contains polyethylene glycol]

Tablet, Oral:

LamISIL: 250 mg

Generic: 250 mg

Brand Names: U.S.

  • LamISIL
  • Terbinex [DSC]

Pharmacologic Category

  • Antifungal Agent, Oral

Pharmacology

Synthetic allylamine derivative which inhibits squalene epoxidase, a key enzyme in sterol biosynthesis in fungi. This results in a deficiency in ergosterol within the fungal cell wall and results in fungal cell death.

Absorption

Children and Adults: >70%

Distribution

Distributed to sebum and skin predominantly

Metabolism

Hepatic predominantly via CYP1A2, 3A4, 2C8, 2C9, and 2C19 to inactive metabolites

Excretion

Urine (80%, primarily as inactive metabolites); feces (20%) (Debruyne 2001)

Clearance: Children (14 to 68 kg): 15.6 to 26.7 L/hour

Time to Peak

Plasma: Children and Adults: Within 2 hours

Half-Life Elimination

Terminal half-life: 200 to 400 hours; very slow release of drug from skin and adipose tissues occurs; effective half-life: Children: 27 to 31 hours; Adults: ~36 hours

Protein Binding

Plasma: >99%

Special Populations: Renal Function Impairment

In CrCl ≤50 mL/minute, terbinafine clearance is decreased 50%.

Special Populations: Hepatic Function Impairment

In hepatic cirrhosis, terbinafine clearance is decreased 50%.

Use: Labeled Indications

Onychomycosis (tablets only): Treatment of onychomycosis of the toenail or fingernail caused by dermatophytes (tinea unguium).

Tinea capitis (granules only): Treatment of tinea capitis in patients 4 years and older.

Use: Unlabeled

Sporotrichosis: Treatment of sporotrichosis (lymphocutaneous and cutaneous)

Contraindications

Hypersensitivity to terbinafine or any component of the formulation; chronic or active hepatic disease

Dosing: Adult

Onychomycosis: Oral: Tablet: Fingernail: 250 mg once daily for 6 weeks; Toenail: 250 mg once daily for 12 weeks

Missed doses: If a dose is missed, take as soon as remembered, unless it is less than 4 hours before the next dose is due.

Tinea capitis (patients >35 kg): Oral: Granules: 250 mg once daily for 6 weeks

Tinea corporis, tinea cruris (off-label use): Oral: 250 mg daily in 1 to 2 divided doses for 2 to 6 weeks (Del Palacio Hernanz 1990; Gupta 2008)

Tinea pedis/manuum (off-label use): Oral: 250 mg once daily for 2 weeks (Gupta 2008; Tausch 1998)

Sporotrichosis, lymphocutaneous and cutaneous (off-label use): Oral: 500 mg twice daily as alternative therapy; treat for 2 to 4 weeks after resolution of all lesions (usual duration: 3 to 6 months) (Kauffman 2007)

Dosing: Geriatric

Use with caution; refer to adult dosing.

Dosing: Pediatric

Tinea capitis: Oral: Granules: Children ≥4 years and Adolescents:

<25 kg: 125 mg once daily for 6 weeks

25 to 35 kg: 187.5 mg once daily for 6 weeks

>35 kg: 250 mg once daily for 6 weeks

Onychomycosis (off-label use) (Gupta 1997): Oral: Tablet: Children and Adolescents:

10 to 20 kg: 62.5 mg once daily for 6 weeks (fingernails) or 12 weeks (toenails)

20 to 40 kg: 125 mg once daily for 6 weeks (fingernails) or 12 weeks (toenails)

>40 kg: 250 mg once daily for 6 weeks (fingernails) or 12 weeks (toenails)

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); however, clearance is decreased 50% in patients with CrCl ≤50 mL/minute.

Dosing: Hepatic Impairment

Contraindicated in chronic or active hepatic disease.

Extemporaneously Prepared

A 25 mg/mL oral suspension may be made using tablets. Crush twenty 250 mg tablets and reduce to a fine powder. Add small amount of a 1:1 mixture of Ora-Sweet® and Ora-Plus® and mix to a uniform paste; mix while adding the vehicle in geometric proportions to almost 200 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 200 mL. Label "shake well" and "refrigerate". Stable 42 days.

Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.

Administration

Administer tablets without regard to meals. Administer granules with food; sprinkle granules on a spoonful of pudding or other soft, nonacidic food (eg, mashed potatoes); swallow entire spoonful without chewing; do not mix granules with applesauce or other fruit-based foods.

Storage

Granules: Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

Tablet: Store below 25°C (77°F). Protect from light.

Drug Interactions

Ajmaline: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Ajmaline. Monitor therapy

Amitriptyline: Terbinafine (Systemic) may increase the serum concentration of Amitriptyline. Management: Monitor for increased effects/toxicity of amitriptyline during concomitant administration with terbinafine. Reduced dosages of amitriptyline may be needed. Consider therapy modification

ARIPiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Brexpiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: If brexpiprazole is to be used together with both a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor, the brexpiprazole dose should be reduced to 25% of the usual dose. Monitor therapy

CloZAPine: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of CloZAPine. Monitor therapy

Codeine: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Monitor therapy

CYP2D6 Substrates: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates. Exceptions: Tamoxifen. Monitor therapy

Desipramine: Terbinafine (Systemic) may increase the serum concentration of Desipramine. Management: Monitor for increased effects/toxicity of desipramine during concomitant administration with terbinafine. Reduced dosages of desipramine may be needed. Consider therapy modification

DOXOrubicin (Conventional): CYP2D6 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP2D6 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Eliglustat: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Reduce the eliglustat dose to 84 mg daily. Avoid use of eliglustat in combination with a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor. Consider therapy modification

Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Monitor therapy

Imipramine: Terbinafine (Systemic) may increase the serum concentration of Imipramine. Management: Monitor for increased effects/toxicity of imipramine during concomitant administration with terbinafine. Reduced dosages of imipramine may be needed. Consider therapy modification

Indoramin: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Indoramin. Monitor therapy

Metoprolol: CYP2D6 Inhibitors may increase the serum concentration of Metoprolol. Management: Consider an alternative for one of the interacting drugs in order to avoid metoprolol toxicity. If the combination must be used, monitor response to metoprolol closely. Metoprolol dose reductions may be necessary. Consider therapy modification

Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Monitor therapy

Nortriptyline: Terbinafine (Systemic) may increase the serum concentration of Nortriptyline. Management: Monitor for increased effects/toxicity of nortriptyline during concomitant administration with terbinafine. Reduced dosages of nortriptyline may be needed. Consider therapy modification

Perhexiline: CYP2D6 Inhibitors may increase the serum concentration of Perhexiline. Management: Consider alternatives to this combination if possible. If combined, monitor for increased perhexiline serum concentrations and toxicities (eg, hypoglycemia, neuropathy, liver dysfunction). Perhexiline dose reductions will likely be required. Consider therapy modification

Propafenone: May increase the serum concentration of CYP2D6 Inhibitors (Moderate). Monitor therapy

RifAMPin: May decrease the serum concentration of Terbinafine (Systemic). Monitor therapy

Saccharomyces boulardii: Antifungal Agents (Systemic, Oral) may diminish the therapeutic effect of Saccharomyces boulardii. Avoid combination

Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Management: Consider alternatives with less of an inhibitory effect on CYP2D6 activity when possible. Consider therapy modification

Thioridazine: CYP2D6 Inhibitors may increase the serum concentration of Thioridazine. Avoid combination

TraMADol: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Monitor therapy

Adverse Reactions

Adverse events listed for tablets unless otherwise specified. Granules were studied in patients 4-12 years of age.

>10%: Central nervous system: Headache (13%; granules 7%)

1% to 10%:

Dermatologic: Skin rash (6%; granules 2%), pruritus (3%; granules 1%), urticaria (1%)

Gastrointestinal: Diarrhea (6%; granules 3%), vomiting (<1%; granules 5%), dyspepsia (4%), dysgeusia (may be severe and result in weight loss and depression; 3%), nausea (3%; granules 2%), abdominal pain (2%; granules 2% to 4%), flatulence (2%), sore throat (granules 2%), toothache (granules 1%)

Hepatic: Liver enzyme disorder (3%)

Infection: Influenza (granules 2%)

Ophthalmic: Visual disturbance (1%)

Respiratory: Nasopharyngitis (granules 10%), cough (granules 6%), upper respiratory tract infection (granules 5%), nasal congestion (granules 2%), rhinorrhea (granules 2%)

Miscellaneous: Fever (granules 7%)

<1% (Limited to important or life-threatening): Acute generalized exanthematous pustulosis, acute pancreatitis, agranulocytosis, alopecia, altered sense of smell, anaphylaxis, angioedema, depression, DRESS syndrome, exacerbation of psoriasis, exacerbation of systemic lupus erythematosus, hepatic disease, hepatic failure, hypersensitivity reaction, pancytopenia, rhabdomyolysis, severe neutropenia, Stevens-Johnson syndrome, thrombocytopenia, toxic epidermal necrolysis, vasculitis, visual field loss

Warnings/Precautions

Concerns related to adverse effects:

• Allylamine antifungal hypersensitivity: Use caution in patients sensitive to allylamine antifungals (eg, naftifine, butenafine); cross-sensitivity to terbinafine may exist.

• Depression: Has been reported with use; instruct patients to report depressive symptoms/mood changes.

• Gastrointestinal effects: Taste disturbance (including loss of taste) may occur and severe cases resulting in decreased food intake, weight loss, anxiety or depression have been reported; resolution may be delayed (eg, several weeks to >1 year) following discontinuation of therapy or in some cases, disturbance may be permanent. Discontinue therapy in patients with symptoms of taste disturbance.

• Hematologic effects: Transient decreases in absolute lymphocyte counts were observed in clinical trials; severe neutropenia (reversible upon discontinuation) has also been reported. Monitor CBC in patients with preexisting immunosuppression if therapy is to continue >6 weeks. Discontinue therapy if ANC ≤1000/mm3.

• Hepatic failure: Cases of hepatic failure, some leading to liver transplant or death, have been reported. May occur in patients with and without preexisting hepatic disease; severity of hepatic events and/or outcomes may be worse in patients with active or chronic hepatic disease. Perform baseline and periodic liver function tests; discontinue use if clinical evidence of liver injury develops (eg, nausea, anorexia, fatigue, vomiting, right upper abdominal pain, jaundice, dark urine, pale stools) or elevated liver function tests occur.

• Hypersensitivity: Serious skin and hypersensitivity reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, bullous dermatitis, drug reaction with eosinophilia and systemic symptoms [DRESS] syndrome) have occurred. If progressive skin rash or signs and symptoms of a hypersensitivity reaction occur, discontinue treatment.

• Ocular effects: Although rare, changes in the ocular lens and retina have been reported; discontinuation of therapy may be required.

• Respiratory effects: Smell disturbance (including loss of smell) has been reported; resolution may be delayed (eg, >1 year) following discontinuation of therapy or in some cases, disturbance may be permanent. Discontinue therapy in patients with symptoms of smell disturbance.

Disease-related concerns:

• Autoimmune disease (Lupus): Precipitation or exacerbation of cutaneous or systemic lupus erythematosus has been observed; discontinue if signs and/or symptoms develop.

• Hepatic impairment: Use is contraindicated in patients with active or chronic hepatic disease; clearance is reduced by ~50% in hepatic cirrhosis.

• Renal impairment: Use with caution in patients with renal dysfunction (CrCl ≤50 mL/minute); clearance is reduced by ~50%.

Other warnings/precautions:

• Appropriate use: Due to potential toxicity, confirmation of diagnostic testing of nail or skin specimens prior to treatment of onychomycosis or dermatomycosis is recommended.

Monitoring Parameters

Liver function tests at baseline and periodically during treatment; CBC (if used >6 weeks; immunosuppressed patients only); taste and/or smell disturbances

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies. Avoid use in pregnancy since treatment of onychomycosis is postponable.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, abdominal pain, diarrhea, bloating, flatulence, or nausea. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of lupus (rash on the cheeks or other body parts, sunburn easy, muscle or joint pain, angina or shortness of breath, or swelling in the arms or legs), difficulty swallowing, swollen glands, cough, angina, tachycardia, hematuria, painful urination, pale skin, change in taste, loss of taste, change in smell, loss of smell, weight loss, depression, lack of appetite, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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