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itraconazole (Sporanox, Tulsura)

Tradename: Sporanox. In general, itraconazole is 10-100 times more potent than fluconazole. Indications: - preferred agent for treatment of nonmeningeal histoplasmosis - onychomycosis - dermatophytes, tinea versicolor - griseofulvin-resistant ringworm - Candida - oropharyngeal candidiasis - esophageal candidiasis - vaginal candidiasis - pulmonary infections or extrapulmonary infections caused by: - aspergillosis - blastomycosis - coccidioidomycosis - chromoblastomycosis [9] - neutropenic fever [6] Contraindications: - concurrent therapy with: a) cisapride b) terfenadine c) astemizole - may lead to prolongation of QT interval, tachycardia & ventricular fibrillation Dosage: 1) systemic infection a) 200-600 mg PO QD in 2-3 divided doses for 6-12 months b) 600 mg dose is generally only 1st 3-4 days of therapy 2) onychomycosis a) 200 mg PO QD for 3 months b) 200 mg PO BID for 1st 7 days of the month 1] 3 months for onychomycosis of fingernails 2] 4 months for onychomycosis of toenails 3) 100-200 mg PO BID. Max 800 mg/day 4) intravenous infusion: a) dilute in normal saline b) 200 mg BID (not for bolus injection) c) infuse 200 mg over 60 minutes Tabs: 100 mg. Solution: for injection 1) 25 mL containing 200 mg itraconazole 2) mix with 50 mL normal saline (provided) Liquid: formulation has both topical & systemic effect Dosage adjustment in renal failure: creatinine clearance dosage > 50-90 mL/min 100% 10-50 mL/min 100% < 10 mL/min 50% Pharmacokinetics: 1) oral absorption is increased by gastric acidity 2) food increases absorption 3) antacids decrease absorption 4) 99% is bound to albumin 5) concentrations are higher in tissue than in serum 6) metabolized by liver by cyt P450 3A4 -> also strongly inhibits cyt P450 3A4 7) 1/2life 24-28 hours a) non-linear elimination b) elimination slower at higher doses & with daily administration c) 1/2life virually unchanged with ESRD 8) therapeutic level > 1 ug/mL Monitor: - liver function tests a) patients with hepatic dysfunction b) consider monitoring in all patients [8] Antimicrobial activity: Antifungal activity: - Candida albicans - Candida krusei - Candida tropicalis - Cryptococcus - Histoplasma capsulatum - Blastomyces dermatitidis - Sporothrix - Penicillium marneffei - Aspergillus - Coccidioides immitis - Phaeohyphomycosis - Fusarium (+/-) Adverse effects: 1) generally well tolerated at 200 mg QD 2) GI distress at 400 mg/day 3) nausea/vomiting 10% 4) hypertriglyceridemia 9% 5) hypokalemia 6% 6) increased serum transaminases 5% 7) rash 2% 8) hepatotoxicity 9) hypertension 10) headache 11) decreased libido 12) congestive heart failure [4] 13) at least one side effect in 39% Drug interactions: 1) hepatic cytochrome P450 induction by itraconazole decreases serum level of: a) rifampin b) rifabutin (+/-) c) carbamazepine 2) itraconazole increases plasma levels of: a) phenytoin b) cyclosporine c) midazolam d) triazolam e) saquinavir (possibly) 3) coadministration may increase levels of itraconazole: a) cyclosporin b) digoxin c) phenytoin d) triazolam e) lovastatin 4) coadministration may decrease levels of itraconazole a) amphotericin B b) isoniazid c) phenytoin 4) antacids, H2 blockers (cimetidine, famotidine, ranitidine) 5 & proton pump inhibitors (omeprazole, lansoprazole) may diminish absorption of itraconazole by as much as 60% 6) HMG CoA reductase inhibitors (simvastatin, lovastatin etc) in combination may result in rhabdomyolysis 7) may increase effects of warfarin 8) terfenadine, astemizole, cisapride a) contraindicated b) may result in QT prolongation, tachycardia & ventricular fibrillation 9) in general, drug interactions with fluconazole greater than with itraconazole 10) any drug that inhibits cyt P450 3A4 may increase levels of itraconazole 11) any drug that induces cyt P450 3A4 may diminish levels of itraconazole 12) itraconazole inhibits cyt P450 3A4, thus inhibits its own metabolism & metabolism of other cyt P450 3A4 substrates Mechanism of action: 1) inhibits fungal cytochrome P450 2) inhibits synthesis of fungal cell wall ergosterol 3) disrupts fungal cell wall

Interactions

drug interactions

Related

aspergillosis Blastomycosis candidiasis cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4) histoplasmosis (Ohio Valley fever) onychomycosis pityriasis Tinea versicolor (Pityriasis versicolor)

General

antifungal agent triazole; pyrrodiazole

Properties

MISC-INFO: elimination route LIVER 1/2life >40 HOURS therapeutic-range >1 UG/ML 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
  3. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  4. Prescriber's Letter 8(6):33 2001
  5. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  6. Journal Watch 21(21):171, 2001 Boogaerts et al, Ann Intern Med 135:412, 2001
  7. PDR 2000
  8. 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
  9. Deprecated Reference