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Drug Reference

fluconazole

triazole antifungal· Brands: DiflucanIVPO

Mechanism of action
Fluconazole inhibits fungal cytochrome P450 14α-demethylase (CYP51), which is necessary for conversion of lanosterol to ergosterol, a key component of the fungal cell membrane. This disrupts membrane integrity and function, leading to cell death. It is generally fungistatic.
Pharmacokinetics
Fluconazole is well absorbed after oral administration with bioavailability exceeding 90%. It is widely distributed into body fluids and tissues, including CSF. It is metabolised minimally, primarily by CYP2C9 and CYP3A4, and excreted unchanged in urine. Half-life is approximately 30 hours, allowing once-daily dosing. It is removed by haemodialysis.
Indications & dosing

Cryptococcal meningitis

Loading dose 400 mg on day 1; duration at least 8 weeks.

  • adult · IV: 200–400 mg once daily · Loading dose 400 mg on day 1; duration at least 8 weeks.

Esophageal candidiasis

Loading dose 200 mg on day 1; continue for 14-21 days.

  • adult · PO: 100 mg once daily · Loading dose 200 mg on day 1; continue for 14-21 days.

Oropharyngeal candidiasis

Loading dose 200 mg on day 1; continue for 7-14 days.

  • adult · PO: 100 mg once daily · Loading dose 200 mg on day 1; continue for 7-14 days.

Prophylaxis of candidiasis in immunocompromised patients

Dose depends on risk; continue until neutrophil recovery.

  • adult · PO: 200–400 mg once daily · Dose depends on risk; continue until neutrophil recovery.

Systemic candidiasis (including candidemia)

Loading dose 400 mg on day 1; continue for at least 7 days after blood cultures negative.

  • adult · IV: 200–400 mg once daily · Loading dose 400 mg on day 1; continue for at least 7 days after blood cultures negative.

Vaginal candidiasis

Single oral dose.

  • adult · PO: 150 mg single dose · Single oral dose.
Contraindications & precautions
  • Hypersensitivity to fluconazole or other azole antifungals · Cross-sensitivity may occur with other azoles.
  • Concomitant administration with QT-prolonging drugs (terfenadine, cisapride, pimozide, quinidine) · Risk of serious cardiac arrhythmias.
  • Pregnancy, especially first trimester or high-dose/prolonged use · Single-dose therapy for vulvovaginal candidiasis may be considered when benefits outweigh risks.
  • Monitor liver function before and during treatment, especially in patients with hepatic impairment or abnormal liver tests.
  • Use caution in patients with renal impairment; adjust dose according to creatinine clearance.
  • Be aware of numerous drug interactions (e.g., warfarin, sulfonylureas, phenytoin, cyclosporine) via CYP2C9/CYP3A4 inhibition.
  • Use caution with concurrent QT-prolonging drugs and in patients with cardiac disease or electrolyte disturbances.
  • Discontinue treatment if severe skin reactions or hepatotoxicity develop.
Adverse effects
  • Nausea, vomiting, diarrhoea, abdominal pain
  • Headache
  • Rash
  • Elevated liver enzymesserious
  • Hepatotoxicity (including hepatic necrosis)serious
  • QT interval prolongation / torsades de pointesserious
  • Severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis)serious
  • Anaphylaxis / angioedemaserious
Interactions
  • atorvastatinmoderateMonitor for muscle pain, weakness, and signs of rhabdomyolysis. Consider limiting the atorvastatin dose or using an alternative antifungal. If coadministration is necessary, use the lowest effective atorvastatin dose and monitor creatine kinase.
  • phenytoinmajorMonitor phenytoin plasma concentrations and clinical signs of toxicity when starting, stopping, or changing the dose of fluconazole. Consider reducing the phenytoin dose if toxicity develops, especially with high-dose or prolonged fluconazole use. Recheck phenytoin levels after any change in the antifungal regimen and adjust the dose accordingly. Antifungal response should also be monitored to ensure adequate efficacy.
  • glibenclamidemajorMonitor blood glucose closely, especially when starting or stopping fluconazole. Consider reducing the glibenclamide dose or switching to an alternative hypoglycaemic agent with a lower interaction potential.
  • carbamazepinemajorIf co-prescription is necessary, monitor plasma carbamazepine concentrations and clinical signs of toxicity, especially at the start of fluconazole therapy. Reduce the carbamazepine dose as required. Advise patients to report neurological symptoms.
  • warfarinmajorPrescribers should avoid co-prescribing fluconazole with warfarin when possible. If concurrent use is unavoidable, a reduction in the warfarin dose may be required, and the INR must be monitored closely, especially during the first week of combined therapy and after any change in fluconazole dose. Alternative antifungal agents that do not inhibit CYP2C9 should be considered.
  • simvastatinmajorAvoid concurrent use of simvastatin and fluconazole. If necessary, consider alternative antifungal agents that do not inhibit CYP3A4, or use a statin that is not metabolised by CYP3A4, such as pravastatin or rosuvastatin. If co-administration is unavoidable, reduce the simvastatin dose and monitor creatine kinase levels and symptoms of myopathy.
  • gliclazidemajorMonitor blood glucose closely before and during therapy. Consider reducing the gliclazide dose or selecting an antifungal that does not inhibit CYP2C9, such as terbinafine. Advise the patient about the signs and symptoms of hypoglycaemia and to carry a fast-acting carbohydrate. If gliclazide dose is adjusted, reassess after stopping fluconazole.
  • tacrolimusmajorAvoid co-prescription if possible. If unavoidable, reduce the tacrolimus dose, typically by 50-70%, and monitor tacrolimus trough concentrations frequently (e.g., every 2-3 days) until stable, then adjust accordingly. Monitor renal function, electrolytes, and signs of toxicity. Fluconazole should be stopped or changed to an alternative if possible.
  • methotrexatemajorAvoid concurrent use if possible. If unavoidable, reduce the methotrexate dose and monitor closely. Monitor full blood count, liver and renal function, and methotrexate plasma levels, with dose adjustment as needed.
  • cyclosporinemajorIf co-administration is necessary, monitor cyclosporine trough concentrations before starting fluconazole and then at frequent intervals (e.g., twice weekly) during therapy and after discontinuation of fluconazole. Adjust the cyclosporine dose according to the measured levels and clinical response. Monitor renal function and serum creatinine. Consider an alternative antifungal with less CYP3A4 inhibition, such as an echinocandin, but fluconazole may be used with careful monitoring and dose adjustment.
Renal & hepatic adjustment
  • eGFR 10–50: Reduce the usual dose by 50%.
  • eGFR 0–10: Give 50% of the usual dose after a loading dose of the usual dose. For haemodialysis, give a normal dose after each session.
Monitoring, pregnancy & toxicity
  • Liver function tests (ALT, AST) · Baseline and periodically (e.g., every 2-4 weeks) during treatment
  • Serum creatinine / creatinine clearance · Baseline and periodically, especially in patients with renal impairment
  • Signs of hepatotoxicity (e.g., jaundice, dark urine) · At each review
  • Pregnancy: Not recommended for use in pregnancy, particularly in the first trimester. High-dose fluconazole has been associated with congenital anomalies; use only if the potential benefit clearly outweighs the risk to the fetus.
  • Toxicity: Hepatotoxicity (elevated aminotransferases, hepatitis, hepatic failure) · Discontinue fluconazole; monitor liver function; provide supportive care.
  • Toxicity: QT prolongation and risk of torsades de pointes, particularly when used with other QT-prolonging agents · Discontinue fluconazole; correct serum electrolytes; perform ECG monitoring; consider cardiac monitoring.
  • Toxicity: Severe skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) · Stop treatment immediately; provide supportive care; consider specialist dermatological input.
  • Toxicity: Overdose · Supportive treatment; fluconazole is haemodialysable; consider haemodialysis in severe overdose.
Clinical notes
Fluconazole is used for candidiasis (oral, vaginal, oesophageal, systemic), cryptococcal meningitis, and prophylaxis in immunocompromised patients. Doses range from 150 mg single dose for vaginal candidiasis to higher daily doses for systemic infections. Common adverse effects include nausea, headache, rash, and transient liver enzyme elevations. It is a potent inhibitor of CYP2C9 and CYP3A4, leading to numerous drug interactions. Fluconazole is teratogenic in high doses, so caution in pregnancy. Resistance is a concern, particularly in Candida glabrata and Candida krusei.

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BNF; local formulary