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ketoconazole (Nizoral, Xolegel)

Tradename: Nizoral. Indications: 1) endemic fungal infections not responive to other antifungals or in patients intolerant to other antifungals [10] - no longer indicated for Candida & dermatophyte infections or for skin & nail infections [10] - blastomycosis (not severe) - histoplasmosis (3rd line agent) - paracoccidioidomycosis - prophylaxis for fungal infection in immunosuppressed patients 2) Acanthamoeba keratitis in combination with topical agents 3) metastatic prostate cancer [11] 4) Cushing's syndrome 5) seborrheic dermatitis, dandruff (topical) Contraindications: - concurrent therapy with astemizole, terfenadine, or cisapride - acute or chronic liver disease - treatment of nail infections (onychomycosis) & skin infections [12] Dosage: 1) systemic a) 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 [6] b) 200 mg PO QD for mild to moderate infections c) 200-400 mg PO QD or BID for moderate to severe infections c) prostate carcinoma: 400 mg PO TID 2) topical a) Tinea: 0.1% cream applied QD-BID, - Duration of therapy: 2 weeks, except Tinea pedis - (may require 6 weeks) b) Seborrheic dermatitis: - cream: apply BID for 4 weeks or until resolution - 2% gel Xelogel QD for 1 week [7] Cream: 2% (15 g, 30 g), 2% gel (Xelogel) Shampoo: 2% (4 oz, 120 mL). Tabs: 200 mg. Monitor: - liver function tests baseline, after 2 weeks & monthly or more frequently in the event of symptoms [9] a) serum ALT, serum AST b) serum alkaline phosphatase, serum GGT c) serum bilirubin [8] - therapeutic drug monitoring: Therapeutic range: - Peak: 1-4 ug/mL - Trough: < 1 ug/mL. Pharmacokinetics: 1) absorption is dose & pH dependent 2) absorption is reduced 20-40% when taken with food 3) absorption is further reduced by increased gastric pH 4) metabolized by liver by cyt P450 CYP3A4 5) eliminated in feces 6) enters sweat rapidly [6] 7) elimination 1/2life is 8-10 hours, decreasing to 3-4 hours with long-term therapy Antimicrobial activity: - Epidermophyton floccosum - Microsporum audouinii - Microsporum canis - Microsporum gypseum - Trichophyton mentagrophytes - Trichophyton rubrum - Trichophyton tonsurans - Malassezia furfur - Malassezia ovalis - Candida albicans Adverse effects: 1) not common (1-10%) - nausea/vomiting, pruritus, abdominal pain 2) uncommon (< 1%) - headache, dizziness, somnolence, fever/chills, photophobia, diarrhea, gynecomastia, impotence, thrombocytopenia, leukopenia, hemolytic anemia, bulging fontanelles 3) other a) hepatotoxicity (potentially fatal) [2,10] b) less well tolerated & more hepatotoxicity than fluconazole or itraconazole c) adrenal insufficiency [10] d) rash Drug interactions: 1) astemizole, terfenadine, cisapride in combination a) CONTRAINDICATED b) may result in prolongation of QT interval with risk of torsades de pointes 2) ketoconazole may increase the anticoagulant effects of warfarin 3) alcohol in combination may result in flushing & tachycardia 4) ketoconazole increases plasma levels of: a) phenytoin b) theophylline c) cyclosporine 5) antacids, H2-receptor antagonists, proton pump inhibitors in combination may decrease absorption by as much as 60% 6) didanosine (ddI) in combination may decrease ketoconazole levels; take at least 2 hours apart 7) indinavir in combination may affect levels of both 8) isoniazid SHOULD NOT BE USED in combination - decreased ketoconazole levels 9) ritonavir SHOULD NOT BE USED in combination - increased risk of toxicity 10) any drug that inhibits cyt P450 CYP3A4 may increase levels of ketoconazole 11) any drug that induces cyt P450 CYP3A4 may diminish levels of ketoconazole 13) ketoconazole inhibits cyt P450 CYP3A4 & CYP2C9 (weakly) a) inhibits its own metabolism b) inhibits metabolism of other cyt P450 CYP3A4 substrates c) inhibits metabolism of cyt P450 CYP2C9 substrates Laboratory: - ketoconazole in specimen - ketoconazole in blood - ketoconazole in serum/plasma - ketoconazole in urine Mechanism of action: 1) generally fungistatic 2) may be fungicidal at high concentrations 3) inhibits synthesis of fungal cell wall ergosterol by inhibiting fungal cyt P450 5) inhibits cyt P450 CYP3A4 a) inhibits synthesis of adrenal steroids b) inhibits synthesis of testosterone

Interactions

drug interactions

General

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

Properties

MISC-INFO: elimination route LIVER 1/2life 3-10 HOURS therapeutic-range 1-4 UG/ML {PEAK} pregnancy-category C safety in lactation - ?

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, American College of Physicians, Philadelphia 1998 - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  3. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  4. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  5. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  6. Prescriber's Letter 11(2):11 2004 Detail-Document#: 200208 (subscription needed) http://www.prescribersletter.com
  7. Prescriber's Letter 13(10): 2006 New Formulation: Xolegel (Ketoconazole Gel 2%) Detail-Document#: 221009 (subscription needed) http://www.prescribersletter.com
  8. deprecated reference
  9. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: 260704 (subscription needed) http://www.prescribersletter.com
  10. FDA MedWatch. July 26, 2013 Nizoral (ketoconazole): Drug Safety Communication - Potentially Fatal Liver Injury, Risk of Drug Interactions and Adrenal Gland Problems. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm362672.htm
  11. Matin K and Trump DL, Prostate Cancer, In: Geriatric Medicine: An Evidence-Based Approach, 4th ed, Cassel CK et al (eds), Springer-Verlag, New York, 2003
  12. FDA Safety Alert. May 19, 2016 Nizoral (ketoconazole) Oral Tablets: Drug Safety Communication - Prescribing for Unapproved Uses including Skin and Nail Infections Continues; Linked to Patient Death. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm502073.htm

Component-of

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