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 Guide Editors
 Editor In Chief
    Joel E. Gallant, MD, MPH

Pharmacology Editor
    Paul Pham, PharmD, BCPS

Zambia Guideline Team
   Peter Mwaba MMed PhD FRCP
   Alywn Mwinga MMed
   Isaac Zulu MMed MPH
   Velepie Mtonga MMed
   Albert Mwango MBChB
   Jabbin Mulwanda MMed FCS
 

 

 

Drugs>Antimicrobial Agents>
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Fluconazole

Paul A. Pham Pharm.D. and John G. Bartlett M.D.
11-29-2010

Zambia Specific Information

  • In vitro resistance to fluconazole remains uncommon (1% overall) among isolates of C. neoformans from 5 broad geographic regions including Africa. Has not increased over 15-year period.
  • Treatment of cryptococcal meningitis with fluconazole (400 mg x1, followed by 200 mg daily x 6 months) is suboptimal.
  • Induction treatment for cryptococcal meningitis with amphotericin B 0.7 mg/kg/day (+5FC) recommended for a minimum of14 days, followed by high dose fluconazole 400 mg x 8 weeks, then fluconazole 200 mg maintenance until immune reconstitution.
  • Empiric treatment of esophageal candidiasis with fluconazole recommended in pts with recent onset of retrosternal pain or odynophagia, especially if accompanied by oral candidiasis.
  • Limited drug interactions with ARVs, but fluconazole may increase amodiaquine (CYP2C8 substrate) and proguanil (CYP2C19) serum concentrations.
Zambia Information Author: Paul A. Pham, Pharm. D.

INDICATIONS

FDA

NON-FDA APPROVED USES

  • Coccidioidomycosis (treatment); itraconazole preferred (for non-meningeal)
  • Pityriasis versicolor
  • Histoplasmosis (treatment of mild disease); itraconazole preferred

FORMS

brand 
name
 
generic 
Mfg 
brand 
forms
 
cost* 
Diflucan and generic fluconazoleFluconazole Pfizer and generic manufacturersPO
tablet
50 mg
$8.01
      PO
tablet
100 mg
$12.58
      PO
tablet
150 mg
$20.03
      PO
tablet
200 mg
$20.59
      IV
piggyback
200 mg
128.00 
      IV
piggyback
400 mg
$187.75
      PO
suspension
10 mg/ml; 40 mg/ml
$132.45 (40 mg/ml; 35 mL); $35.80 (10 mg/mL; 35 mL)

*Prices represent cost per unit specified and are representative of "Average Wholesale Price" (AWP). AWP Prices were obtained and gathered by Lakshmi Vasist Pharm D using the Red Book, manufacturer's information, and the McKesson database.

^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

  • Cryptococcal meningitis,induction phase: 1200 mg PO once-daily + flucytosine (5FC) 100 mg/kg/d x 6 wks (alternative regimen; amphotericin B or lipid amphotericinB plus 5FC a minimum of 2 wks preferred);
  • Cryptococcal meningitis, consolidation phase after >2 wks of amphotericin + 5FC: 400 mg PO once-daily x 8 wks;
  • Cryptococcal meningitis, maintenance phase: 200 mg PO once-daily (until CD4>100-200 x >6 mos and after >1 yr of antifungal therapy)
  • Vaginal candidiasis: 150 mg PO x1. Multiple recurrences: fluconazole 150 mg PO q wk (topical azoles preferred)
  • Esophageal candidiasis: 200 mg PO once-daily x 14-21 days (or IV up to 800 mg/d). Use chronic maintenance therapy (same dose) for recurrent esophagitis
  • Oropharyngeal candidiasis (thrush): 100-200 mg PO once-daily x 7-14 days (topical therapy with clotrimazole preferred to avoid azole resistance)
  • Coccidioidomycosis, meningitis: 400-800 mg IV or PO. Non-meningeal (diffuse pulmonary or disseminated): fluconazole 400-800 mg PO once-daily (amphotericin B preferred); maintenance: 400 mg PO once-daily (itraconazole equally effective).
  • Histoplasmosis: 800 mg daily (itraconazole preferred).
  • For obese patients: 6 mg/kg/d up to 1200 mg/d.
  • Cryptococcemia or cryptococcal pneumonia: 6 mg/kg (400 mg) once daily x 6-12 months.

RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

Usual

DOSING FOR GLOMERULAR FILTRATION OF 10-50

50% of dose.

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

50% of dose; HD: 100% of dose post-HD

DOSING IN HEMODIALYSIS

100% of dose post-HD

DOSING IN PERITONEAL DIALYSIS

50% of dose daily

DOSING IN HEMOFILTRATION

CVVH: 200-400 mg once daily. CVVHD: 400-800 mg once daily.

ADVERSE DRUG REACTIONS

GENERAL

  • Generally well tolerated
OCCASIONAL

  • GI intolerance w/ bloating, nausea, vomiting, pain,anorexia
  • Reversible alopecia (with >400mg/d)
  • Transaminase elevation
RARE

  • Hepatitis (fatal hepatotoxicity in pts with serious underlying medical conditions; monitor LFTs)
  • Dizziness
  • Headache
  • Hypokalemia

DRUG INTERACTIONS

CYP2C8/9/19 and CYP3A4 inhibitor resulting in an increase in CYP2C8/9/19 and CYP3A4 substrate. No clinically significant drug-drug interactions with PIs.

Drug-to-Drug Interactions

Drug-to-Drug Interaction

DrugEffect of InteractionRecommendations/Comments
Rifampin May significantly decrease fluconazole serum concentrations. Avoid co-administration. Consider rifabutin.
Zidovudine (AZT) AZT AUC increased by 74%. Monitor for AZT-associated toxicity.
Efavirenz (EFV) No significant interaction Usual dose
Nevirapine NVP clearance decreased by 2-fold Monitor LFTs closely with co-administration.
Etravirine May increase ETR serum concentrations. No data. Monitor for LFTs and rash with co-administration.
Maraviroc May increase MVC serum concentrations No data. Use standard dose.
Astemizole May increase astemizole serum concentrations. Contraindicated
Benzodiazepines (alprazolam, diazepam, midazolam, triazolam) May increase benzodiazepine serum concentrations. Use with caution. Benzodiazepine dose may need to be decreased.
Cisapride May increase cisapride serum concentrations. Contraindicated
Clopidogrel May decrease the efficacy of clopidogrel Avoid co-administration.
Cyclosporine Cyclosporine concentrations may be significantly increased Monitor cyclosporine concentrations closely.Cyclosporine dose may need to be decreased.
Fentanyl Fentanyl serum concentrations may be significantly increased. Use with caution. Fentanyl dose may need to be decreased.
Lovastatin May increase lovastatin serum concentrations Consider pravastatin or rosuvastatin
Oral hypoglycemics Risk of hypoglycemia may may be increased Monitor closely.
Phenytoin Phenytoin AUC was increased by 88% Monitor phenytoin concentrations closely with co-administration.
Raltegravir Interaction unlikely Use standard dose.
Rifabutin No effect on fluconazole, but rifabutin serum concentrations increased by 80%. Monitor for rifabutin-associated toxicity (i.e uveitis). Rifabutin dose may need to be decreased.
Simvastatin: May increase simvastatin serum concentrations Consider pravastatin or rosuvastatin
Sirolimus Sirolimus concentrations may be significantly Monitor sirolimus concentrations closely. Sirolimus dose may need to be significantly decreased.
Tacrolimus Tacrolimus levels may be significantly (monitor tacrolimus levels closely) Monitor tacrolimus concentrations closely. Tacrolimus dose may need to be significantly decreased.
Terfenadine
May increase terfenadine serum concentrations. Contraindicated
Warfarin INR may be significantly increased. Monitor INR closely with co-administration.

SPECTRUM

H. capsulatum, C. neoformans, C. immitisC. albicans, C. glabrata (up to 30-40% azole-resistant), C. tropicalis (some azole-resistant), C. parapsilosis. Not C. lusitaniae.

PHARMACOLOGY

Pharmacology

COMMENTS

Oral and parenteral azole with best oral bioavailability, independent of gastric pH. Use of fluconazole for treatment or suppression of thrush not recommended due to risk of azole-resistance; topical therapy (e.g. clotrimazole) preferred. However, if recurrences are frequent or mucocutaneous candidiasis is severe, oral fluconazole maintenance can be considered. Preferred drug for esophageal candidiasis. Fatal hepatotoxicity has been described. Fluconazole preferred over itraconazole for consolidation phase and maintenance of cryptococcal meningitis. Itraconazole has better in vitro activity against Coccidioides immitis, however due to better CNS penetration, fluconazole is recommended for meningitis.

Basis for Recommendations

  • Perfect JR. Dismukes WE, Dromer F et al. ; Clinical practice guidelines for the management of dryptococcal disease: 2010 update by the Infectious Diseases Society of America ; Clin Infect Dis ; 2010 ; Vol. 50 ; pp. 291-322. ;
    Rating: Basis for recommendation
    Comments:Fluconazole 1200 mg/day plus 5FC x 6 wks OR fluconazole 1200 mg/d monotherapy (up to 2000 mg/d) x 10-12 wks can be considered during induction/consolidation phase as an alternative regimen in patients unable to tolerate amphotericin.

  • NIH, CDC, and HIVMA/IDSA ; Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents ; aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=211&ClassID=4 ; 2008 (June 18). ; Vol.
    Rating: Basis for recommendation
    Comments:Treatment guidelines recommend topical clotrimazole troches or nystatin suspension for the treatment of initial episodes of oropharyngeal candidiasis Secondary prophylaxis for recurrent oropharyngeal or vulvovaginal candidiasis is generally not recommended because of the potential for resistant candidiasis. However, if recurrences are frequent or mucocutaneous candidiasis is severe, oral fluconazole can be used for either oropharyngeal or vulvovaginal. In addition, it is prudent to institute secondary prophylaxis in pts with fluconazole-refractory oropharyngeal or esophageal candidiasis who have responded to echinocandins, voriconazole, or posaconazole therapy because of high relapse rate until ART produces immune reconstitution.

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