ketoconazole (Nizoral, Xolegel)

Introduction

Tradename: Nizoral.

Indications

• endemic fungal infections not responive to other antifungals or in patients intolerant to other antifungals
  • no longer indicated for Candida & dermatophyte infections or for skin & nail infections
  • blastomycosis (not severe)
  • histoplasmosis (3rd line agent)
  • paracoccidioidomycosis
  • prophylaxis for fungal infection in immunosuppressed patients
• Acanthamoeba keratitis in combination with topical agents
• metastatic prostate cancer
• Cushing's syndrome
• seborrheic dermatitis, dandruff (topical)

Contraindications

• concurrent therapy with astemizole, terfenadine, or cisapride
• acute or chronic liver disease
• treatment of nail infections (onychomycosis) & skin infections

pregnancy category = c

safety in lactation = -

safety in lactation = ?

Dosage

• systemic
  • taken on an empty stomach, no antacids
    • exercise to work up a sweat; avoid showering for 4 hours may concentrate ketoconazole in sweat on skin
  • 200 mg PO QD for mild to moderate infections
  • 200-400 mg PO QD or BID for moderate to severe infections
  • prostate carcinoma: 400 mg PO TID
• topical
  • Tinea: 0.1% cream applied QD-BID,
    • Duration of therapy: 2 weeks, except Tinea pedis
    • (may require 6 weeks)
  • Seborrheic dermatitis:
    • cream: apply BID for 4 weeks or until resolution
    • 2% gel Xelogel QD for 1 week

Cream: 2% (15 g, 30 g), 2% gel (Xelogel)

Shampoo: 2% (4 oz, 120 mL).

Tabs: 200 mg.

Pharmacokinetics

• absorption is dose & pH dependent
• absorption is reduced 20-40% when taken with food
• absorption is further reduced by increased gastric pH
• metabolized by liver by cyt P450 CYP3A4
• eliminated in feces
• enters sweat rapidly
• elimination 1/2life is 8-10 hours, decreasing to 3-4 hours with long-term therapy

elimination via liver

1/2life = 3-10 hours

Monitor

• liver function tests baseline, after 2 weeks & monthly or more frequently in the event of symptoms
  • serum ALT, serum AST
  • serum alkaline phosphatase, serum GGT
  • serum bilirubin
• therapeutic drug monitoring: Therapeutic range:
  • Peak: 1-4 ug/mL
  • Trough: < 1 ug/mL.

Antimicrobial activity

• Epidermophyton floccosum
• Microsporum audouinii
• Microsporum canis
• Microsporum gypseum
• Trichophyton mentagrophytes
• Trichophyton rubrum
• Trichophyton tonsurans
• Malassezia furfur
• Malassezia ovalis
• Candida albicans

Adverse effects

• not common (1-10%)
  • nausea/vomiting, pruritus, abdominal pain
• uncommon (< 1%)
  • headache, dizziness, somnolence, fever/chills, photophobia, diarrhea, gynecomastia, impotence, thrombocytopenia, leukopenia, hemolytic anemia, bulging fontanelles
• other
  • hepatotoxicity (potentially fatal)
  • less well tolerated & more hepatotoxicity than fluconazole or itraconazole
  • adrenal insufficiency
  • rash

Drug interactions

• astemizole, terfenadine, cisapride in combination
  • CONTRAINDICATED
  • may result in prolongation of QT interval with risk of torsades de pointes
• ketoconazole may increase the anticoagulant effects of warfarin
• alcohol in combination may result in flushing & tachycardia
• ketoconazole increases plasma levels of:
  • phenytoin
  • theophylline
  • cyclosporine
• antacids, H2-receptor antagonists, proton pump inhibitors in combination may decrease absorption by as much as 60%
• didanosine (ddI) in combination may decrease ketoconazole levels; take at least 2 hours apart
• indinavir in combination may affect levels of both
• isoniazid SHOULD NOT BE USED in combination
  • decreased ketoconazole levels
• ritonavir SHOULD NOT BE USED in combination
  • increased risk of toxicity
• any drug that inhibits cyt P450 CYP3A4 may increase levels of ketoconazole
• any drug that induces cyt P450 CYP3A4 may diminish levels of ketoconazole
• ketoconazole inhibits cyt P450 CYP3A4 & CYP2C9 (weakly)
  • inhibits its own metabolism
  • inhibits metabolism of other cyt P450 CYP3A4 substrates
  • inhibits metabolism of cyt P450 CYP2C9 substrates

• drug interaction(s) of antibiotics with warfarin
• drug interaction(s) of eplerenone with ketoconazole

Laboratory

• ketoconazole in specimen
  • ketoconazole in blood
  • ketoconazole in serum/plasma
  • ketoconazole in urine

Mechanism of action

• generally fungistatic
• may be fungicidal at high concentrations
• inhibits synthesis of fungal cell wall ergosterol by inhibiting fungal cyt P450
• inhibits cyt P450 CYP3A4
  • inhibits synthesis of adrenal steroids
  • inhibits synthesis of testosterone

More general terms

• antifungal agent
• imidazole; glyoxaline; 1,3-diazole; iminazole

Component of

• ketoconazole/salicylic acid
• ketoconazole/phytosphingosine
• chlorhexidine/ketoconazole/salicyloyl phytosphingosine
• chlorhexidine/cortisol/ketoconazole
• acetic acid/chlorhexidine/ketoconazole
• ketoconazole/zinc pyrithione
• ketoconazole/lactic acid/salicylic acid
• chloroxylenol/ketoconazole
• chlorhexidine/ketoconazole
• cortisol/ketoconazole

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=47576
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=456201
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3823