Fluconazole

CLASS OF DRUG

• Fluorinated bis-triazole
• Anti-fungal agent

PHARMACEUTICS

• Tablets of 50, 100, 150, and 200 mg
• Powder for oral suspension (10 and 40 mg/mL) 
• IV solutions containing 2 mg/mL in saline and in dextrose solution

DOSING

• Oral and IV (equivalent dosing); infuse over 10-30 minutes
• Dosage of 100–800 mg/day (3-12 mg/kg) for 7-14 days depending on the indication (8 weeks for cryptococcosis)
  • 150mg PO single dose for candidal balanititis or vaginal candidiasis
  • 150mg PO every 72h for 3 doses then weeky for 6 months for recurrent candidal vulvovaginitis
  • 50mg PO daily for 7-14d for oropharyngeal candidiasis 
  • 50-100 mg IV/PO daily for 14-30d for serious mucosal candidiasis (e.g. oesophagitis, non-invasive bronchopulmonary infection, candiduria)
  • 50mg PO daily for 2-4 weeks for tinea (up to 6 weeks for tinea pedis)
  • 50-400 mg (3-12 mg/kg) daily for prevention in immunosuppressed (e.g. neutropenia, bone-marrow transplant)
  • 200 mg PO daily for secondary prevention of crytpococcal meningitis in patients with HIV
  • 400-800 mg (6-12 mg/kg) then 200-400 mg (3-6 mg/kg) IV/PO daily for invasive candidiasis and cryptococcal infections (adjust dose and duration to severity and response to treatment, minimum 8 weeks for cryptococall meningitis) 

INDICATIONS

• Candidiasis (except C. krusei; C.glabrata)
  • Mucocutaneous (balanitis, vulvovaginal, other mucosal)
  • Dermal (tinea pedia, corporis, cruris)
  • Invasive/ systemic infections
• Cryptococcal meningitis (treatment and secondary prophylaxis)
• Pityriasis versicolor
• Prevention of fungal infections in immunocompromised pateints

CONTRA-INDICATIONS / PRECAUTIONS

• Known hypersensitivity
• QT prolongation
• Acute porphyrias

Precautions

• Renal disease: Decrease the dose and/or extend dosing interval
• Risk factors for QT prolongation

MECHANISM OF ACTION

• Azoles are fungistatic agents that impair the synthesis of ergosterol in fungal cell membranes leading to their disruption. 
  • Azoles inhibit 14-α-sterol demethylase, a CYP and the product of the gene ERG11
  • the toxic product 14α-methyl-3,6-diol accumulates leading to growth arrest, probably by disrupting the close packing of phospholipid acyl chains and membrane-bound enzyme systems
• Fluconazole is active against yeast including Candida species (except C. krusei; C.glabrata), Cryptococcus neoformans, Blastomyces, Histoplasma, and Coccidioides spp. 
  • Fluconazole is not effective against filamentous fungi (e.g. Aspergillus spp.; Mucormycosis) 
  • no antibacterial or anti- protozoal activity. 

PHARMACOKINETICS

• A: rapid oral absorption (peak levels at 1-2h) with complete bioavailability (>90%) unaffected by food or gastric pH
• D: high water solubility and good CSF penetration (reaches 50-90% of plasma concentrations) and other body fluids; 12% plasma protein bound
• M: hepatic metabolism by cytochrome P450 isoenzymes (10% of elimination)
• E: 90% renally excreted; t1/2 25-30h

DRUG-DRUG INTERACTIONS (DDIs)

Numerous potential drug interactions related to:

• CYP3A4 and CYP2C9 inhibition
  • May alter levels of phenytoin, benzodiazepines, terfenadine, rifampicin, cyclosporine, tacrolimus, sirolimus, warfarin
  • However, fluconazole has the least effect of all azoles on hepatic microsomal enzymes
• QT prolongation
  • e.g. ciprofloxacin, erythromycin, metoclopramide, ondansetron, amiodarone

PREGNANCY/ LACTATION

• category B3 drug (avoid use in pregnancy if possible)
• Likely enters breast milk (avoid if possible)

ADVERSE EFFECTS

• Hypersensitivity
• GI symptoms: Nausea, vomiting, abdominal pain, diarrhoea (<5%)
• QT interval prolongation and Torsades de pointes
• Hepatoxicity: dose-related liver function tests abnormalities; rarely hepatic failure
• Blood dyscrasias: Anaemia, Leukopenia, Thrombocytopenia
• Dylipidemia
• Antimicrobial resistance:  fluconazole-resistant moulds or yeasts may develop
• Reversible alopecia with prolonged therapy
• Skin: urticaria, Stevens-Johnson syndrome / toxic epidermal necrolysis, Photosensitivity reactions (more common in children), alopecia
• Angioedema

OTHER

Azole resistance can result from:

• ERG11 mutations in C. albicans
• Overexpression of ABC and/or major facilitator superfamily transporters that increase azole efflux in C. albicans and C. glabrata
• C5,6 sterol desaturase gene ERG3 mutations in some species result in the accumulation of less toxic sterols
• Primary azole resistance (e/g/ decreased ergosterol concentrations and increased azole export) occurs in some species such as A. fumigatus

REFERENCES

FOAM and web resources

• FDA product information – Fluconazole
• LITFL CCC – Fungi and anti-fungal agents

Journal articles and textbooks

• Brunton, L., Hilal-Dandan, R., Knollman, B. (2017). Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Edition. United States: McGraw-Hill Education. Ch 61.
• Dockrell, H., Goering, R., Chiodini, P. L., Zuckerman, M. (2018). Mims’ Medical Microbiology and Immunology. United Kingdom: Elsevier. Ch 34.