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fluconazole (Diflucan)

Tradename: Diflucan. Indications: - treatment of Candida infections - oropharyngeal candiasis, esophageal candidiasis - systemic Candida infections - candiduria - candida peritonitis - candida pneumonia - treatment of Cryptococcal meningitis - treatment of coccidioidomycosis - treatment of Tinea infection - Tinea capitis, Tinea manus, Tinea pedis, Tinea cruris, Tinea corporis, Tinea versicolor [8] - histoplasmosis [8] - blastomycosis [8] - cutaneous leishmaniasis [8] - empiric treatment of febrile neutropenia [8] Contraindications: Pregnancy category: D [6] - except single low-dose (150 mg) used to treat vaginal candidiasis remains Pregnancy category: C - FDA investigating possiblity that single 150 mg dose may be associated with miscarriage [10] - common doses of oral fuconazole safe during pregnancy [7] Dosage: 100-400 mg IV/PO QD. Candidiasis: 200 mg IV/PO first day, then 100-200 mg QD. Cryptococcal meningitis: 400 mg IV 1st day, then 200-400 mg QD. Vaginal candidiasis: 150 mg single dose. Tabs: 50, 100, 150, 200 mg. Suspension: 10 & 40 mg/mL. Injection: 2 mg/mL (100 mL, 200 mL) Maximum dose: > 2 g/day. Dose adjustment in renal failure: Creatinine clearance dose > 50 mL/min 100% 20-49 mL/min* 50% 10-19 mL/min 25% post-dialysis 100% * same dose for continuous arteriovenous hemofiltration Pharmacokinetics: 1) well absorbed orally (90% bioavailability), unaffected by GI pH 2) no effect of food or antacids on absorption 3) protein-binding 11-12% 4) wide tissue distribution a) penetrates well into CSF (60% of serum level) b) good penetration into eye c) good penetration into peritoneal cavity 5) peak serum levels in 2-4 hours after oral dose 6) intraperitoneal levels peak within 7 hours 7) 70-90% eliminated unchanged into the urine 8) 1/2life 22 hours (100 hours ESRD) Antimicrobial activity: Antifungal activity: - Candida albicans - Candida tropicalis - Cryptococcus - Histoplasma capsulatum - Blastomyces dermatitidis - Sporothrix - Penicillium marneffei - Coccidioides immitis - Phaeohyphomycosis (+/-) - Fusarium Drug resistance: Susceptible organisms have a MIC < 8 ug/mL. Fluconazole resistance is increasing in patients with mucosal candidiasis & HIV with low CD4 counts exposed to multiple doses of fluconazole for oral thrush. Candida albicans is uniformly the pathogen. Adverse effects: 1) most common (1-10%) - gastrointestinal - nausea/vomiting - abdominal pain - diarrhea - headache - skin rash 2) uncommon (< 1%) - pallor, dizziness, hypokalemia, hepatotoxicity - birth defects with high doses 3) other - increased risk of miscarriage between 7 & 22 weeks (RR=1.48) [9,10,11] - not associated with risk for stillbirth [11] Drug interactions: 1) hepatic cytochrome P450 induction by fluconazole decreases serum level of: a) rifampin b) rifabutin c) carbamazepine 2) coadministration increases levels of fluconazole: a) cyclosporine b) digoxin c) phenytoin d) terfenadine* e) astemizole* f) triazolam g) lovastatin 3) fluconazole may increase serum levels of: a) cyclosporine (with high doses of fluconazole) b) phenytoin c) terfenadine* d) astemizole* e) cisapride* f) rifabutin g) ritonavir 4) fluconazole inhibits CYP2C9 & CYP3A4 -> may increase levels of drugs metabolized by CYP2C9 CYP3A4 (including warfarin) 5) rifampin in combination decreases fluconazole levels 6) alcohol in combination may cause flushing & tachycardia 7) fluconazole increases hypoglycemic effects of sulfonylureas 8) in general, drug interactions with fluconazole greater than with itraconazole * may predispose to torsades de pointes; DO NOT administer concurrently Laboratory: - fluconazole in specimen - fluconazole in dried blood spot - fluconazole in serum/plasma - fluconazole in urine Mechanism of action: 1) generally fungistatic, may be fungicidal at high concentrations 2) potency is 1-2 orders of magnitude less than that of itraconazole 3) inhibits synthesis of fungal cell wall ergosterol by inhibiting fungal cytochrome P450

Interactions

drug interactions

Related

cytochrome P450 2C9; cytochrome P450 BP-1; cytochrome P450 MP-4; S-mephenytoin-4-hydroxylase; limonene 6-monooxygenase; limonene 7-monooxygenase (CYP2C9, CYP2C10) cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)

General

antifungal agent triazole; pyrrodiazole

Properties

MISC-INFO: elimination route KIDNEY 1/2life 24-30 HOURS protein-binding 11-12% pregnancy-category C safety in lactation -

Database Correlations

PUBCHEM cid=3365

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. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  4. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  5. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  6. FDA MedWatch: 08/03/2011 Diflucan (fluconazole): Drug Safety Communication - Long-term, High-dose Use During Pregnancy May Be Associated With Birth Defects http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm266468.htm
  7. Molgaard-Nielsen D et al. Use of oral fluconazole during pregnancy and the risk of birth defects. N Engl J Med 2013 Aug 29; 369:830 PMID: 23984730 http://www.nejm.org/doi/full/10.1056/NEJMoa1301066
  8. Deprecated Reference
  9. Molgaard-Nielsen D, Svanstrom H, Melbye M, Hviid A, Pasternak B. Association Between Use of Oral Fluconazole During Pregnancy and Risk of Spontaneous Abortion and Stillbirth. JAMA. 2016;315(1):58-67 PMID: 26746458 http://jama.jamanetwork.com/article.aspx?articleid=2480487
  10. FDA Safety Alert. April 26, 2015 Fluconazole (Diflucan): Drug Safety Communication - FDA Evaluating Study Examining Use of Oral Fluconazole (Diflucan) in Pregnancy. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm497656.htm
  11. Molgaard-Nielsen D, Svanstrom H, Melbye M et al Association Between Use of Oral Fluconazole During Pregnancy and Risk of Spontaneous Abortion and Stillbirth. JAMA. 2016;315(1):58-67. PMID: 26746458 https://jamanetwork.com/journals/jama/fullarticle/2480487