fluconazole (Diflucan)
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Introduction
Tradename: Diflucan.
Indications
- treatment of Candida infections
- treatment of Cryptococcal meningitis
- treatment of coccidioidomycosis
- treatment of Tinea infection
- histoplasmosis[8]
- blastomycosis[8]
- cutaneous leishmaniasis[8]
- empiric treatment of febrile neutropenia[8]
Contraindications
- 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
- well absorbed orally (90% bioavailability), unaffected by GI pH
- no effect of food or antacids on absorption
- protein-binding 11-12%
- wide tissue distribution
- penetrates well into CSF (60% of serum level)
- good penetration into eye
- good penetration into peritoneal cavity
- peak serum levels in 2-4 hours after oral dose
- intraperitoneal levels peak within 7 hours
- 70-90% eliminated unchanged into the urine
- 1/2life 22 hours (100 hours ESRD)
elimination via kidney
1/2life = 24-30 hours
protein binding = 11-12 %
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
- most common (1-10%)
- uncommon (< 1%)
- pallor, dizziness, hypokalemia, hepatotoxicity
- birth defects with high doses
- other
- increased risk of miscarriage between 7 & 22 weeks (RR=1.48)[9][10][11]
- not associated with risk for stillbirth[11]
Drug interactions
- hepatic cytochrome P450 induction by fluconazole decreases serum level of:
- coadministration increases levels of fluconazole:
- fluconazole may increase serum levels of:
- cyclosporine (with high doses of fluconazole)
- phenytoin
- terfenadine*
- astemizole*
- cisapride*
- rifabutin
- ritonavir
- fluconazole inhibits CYP2C9 & CYP3A4
- may increase levels of drugs metabolized by CYP2C9 CYP3A4 (including warfarin)
- rifampin in combination decreases fluconazole levels
- alcohol in combination may cause flushing & tachycardia
- fluconazole increases hypoglycemic effects of sulfonylureas
- in general, drug interactions with fluconazole greater than with itraconazole
* may predispose to torsades de pointes; DO NOT administer concurrently
Laboratory
Mechanism of action
- generally fungistatic, may be fungicidal at high concentrations
- potency is 1-2 orders of magnitude less than that of itraconazole
- inhibits synthesis of fungal cell wall ergosterol by inhibiting fungal cytochrome P450
More general terms
Additional terms
- 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)
References
- ↑ The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
- ↑ Medical Knowledge Self Assessment Program (MKSAP) 11, American College of Physicians, Philadelphia 1998
- ↑ Kaiser Permanente Northern California Regional Drug Formulary, 1998
- ↑ Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
- ↑ Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=220233&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 6.0 6.1 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
- ↑ 7.0 7.1 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23984730 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1301066
- ↑ 8.0 8.1 8.2 8.3 8.4 8.5 Deprecated Reference
- ↑ 9.0 9.1 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/26746458 <Internet> http://jama.jamanetwork.com/article.aspx?articleid=2480487
- ↑ 10.0 10.1 10.2 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
- ↑ 11.0 11.1 11.2 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: https://www.ncbi.nlm.nih.gov/pubmed/26746458 https://jamanetwork.com/journals/jama/fullarticle/2480487