Azole antifungal (triazole; CYP2C9/CYP3A4 inhibitor)
Fluconazole is an antifungal used for Candida infections (mouth, throat, vagina) and for serious fungal infections, including cryptococcal meningitis. It is effective and well tolerated, but can affect the liver and interact with many medicines.
Also known as: Diflucan, Fluconazol
Fluconazole may raise Carbamazepine levels (metabolic inhibition), with a risk of toxicity.
Fluconazole inhibits CYP3A4, reducing carbamazepine clearance and potentially raising its concentrations to toxic levels (nystagmus, ataxia, diplopia, sedation). The effect depends on the fluconazole dose. Monitor carbamazepine plasma levels and reduce the dose if needed during and after antifungal treatment.
Fluconazole + carbamazepine: fluconazole inhibits CYP3A4 and may raise carbamazepine levels, with risk of toxicity. Monitor levels and intoxication signs.
CYP3A4 inhibition by fluconazole reduces carbamazepine metabolism.
Carbamazepine concentration, symptoms (diplopia, nystagmus, ataxia).
Diplopia, nystagmus, ataxia, drowsiness.
Monitor carbamazepine levels and toxicity symptoms; adjust the dose as needed.
DailyMed/FDA (NIH/NLM) — approved Fluconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7961c029-746c-48c3-888b-8f8344102873 ; approved Carbamazepine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f3d91cd-a959-4e07-a51b-8a4e9ba9ece2 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Rifampin reduces Fluconazole levels, risking antifungal treatment failure.
Rifampicin induces CYP2C9 and CYP3A4, pathways of fluconazole metabolism, and can reduce its concentrations by about 25–50% and shorten the half-life; the antifungal effect may be compromised in severe infections. Monitor the clinical response and consider increasing the fluconazole dose during the combination, monitoring liver function.
Fluconazole + rifampicin: rifampicin lowers fluconazole levels (~25–50%), potentially compromising antifungal treatment. Monitor and consider dose adjustment.
Enzymatic induction by rifampin accelerates fluconazole metabolism.
Clinical response, liver function tests.
Persistent or worsening fungal infection.
Monitor clinical response; a fluconazole dose increase or an alternative antifungal may be needed.
DailyMed/FDA (NIH/NLM) — approved Fluconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7961c029-746c-48c3-888b-8f8344102873 ; approved Rifampin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b389b1a3-672f-47e3-916c-4a9c044b211b — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Fluconazole plus Mefloquine carries a risk of QT prolongation and arrhythmias.
Mefloquine can prolong the QTc interval, especially when combined with other drugs that alter cardiac conduction or prolong the QT — the label explicitly contraindicates halofantrine and ketoconazole (risk of potentially fatal QT prolongation) and advises against quinine/quinidine; the patient guide recommends not taking it with QT-prolonging drugs. Fluconazole also prolongs the QT (torsade de pointes in post-marketing experience) and, as a CYP3A4 inhibitor, may also raise mefloquine levels. The combination should be avoided (in practice, antimalarial prophylaxis and antifungal treatment rarely overlap, but they can occur in patients with invasive fungal infections); if unavoidable, monitor the ECG, electrolytes and correct hypokalaemia/hypomagnesaemia.
Fluconazole + mefloquine: additive risk of QT prolongation. Avoid the combination; monitor the ECG if unavoidable.
Additive effect on cardiac repolarization (both prolong the QT).
ECG (QT interval), electrolytes (K+, Mg2+).
Syncope, palpitations, torsades de pointes.
Use with caution; monitor ECG (QT) and electrolytes; consider an alternative antimalarial.
DailyMed/FDA (NIH/NLM) — approved Fluconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7961c029-746c-48c3-888b-8f8344102873 ; approved Mefloquine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=09716a24-d7da-42b2-af29-c03a1b6670bd
Fluconazole plus Chloroquine carries a risk of QT prolongation.
Chloroquine prolongs the QT interval (torsade de pointes and ventricular arrhythmias reported, with a higher risk at high doses and with concomitant QT-prolonging drugs — the chloroquine label explicitly warns about this risk), and fluconazole can also prolong the QT (the label contraindicates fluconazole with QT-prolonging CYP3A4-metabolised drugs). The combination adds up the risk of ventricular arrhythmias, especially in patients with long QT, hypokalaemia, hypomagnesaemia, bradycardia or cardiac disease. Whenever possible, avoid or choose an alternative antifungal; if unavoidable, monitor the ECG and electrolytes and correct hypokalaemia/hypomagnesaemia.
Chloroquine + fluconazole: additive risk of QT prolongation. Avoid or monitor the ECG in at-risk patients.
Additive effect on cardiac repolarization (both prolong the QT).
ECG (QT interval), electrolytes (K+, Mg2+).
Syncope, palpitations.
Use with caution; monitor ECG (QT) and electrolytes.
DailyMed/FDA (NIH/NLM) — approved Fluconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7961c029-746c-48c3-888b-8f8344102873 ; approved Chloroquine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=06c69e2b-211b-4746-9f3a-f86d36520570
Fluconazole raises Atorvastatin levels (CYP3A4 inhibition), with a risk of myopathy.
Fluconazole inhibits CYP3A4 (to a variable degree depending on dose) and can raise atorvastatin concentrations, increasing the risk of myopathy/rhabdomyolysis, especially with high fluconazole doses or prolonged courses. Monitor muscle symptoms and CK, use the lowest effective statin dose during antifungal treatment and instruct the patient to stop in the presence of muscle pain, weakness or dark urine. In patients with renal impairment, the risk is higher.
Atorvastatin + fluconazole: CYP3A4 inhibition raising statin levels. Monitor and consider dose reduction.
Moderate CYP3A4 inhibition by fluconazole reduces atorvastatin metabolism.
Creatine kinase (CK), myalgia, weakness.
Severe muscle pain, dark urine.
Watch for muscle symptoms and CK; consider an alternative statin or adjusted dose.
DailyMed/FDA (NIH/NLM) — approved Fluconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7961c029-746c-48c3-888b-8f8344102873 ; approved Atorvastatin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=86841382-4229-4e03-958e-3ac22639efd4 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Fluconazole plus Quinine carries a risk of QT prolongation and ventricular arrhythmias.
Quinine prolongs the QT interval consistently and in a dose-dependent way, with a risk of potentially fatal ventricular arrhythmias (torsade de pointes, ventricular fibrillation), and the label contraindicates its use in patients with QT prolongation and recommends avoiding other QT-prolonging drugs. Quinine is predominantly metabolised by CYP3A4, and inhibitors of this enzyme raise its concentrations — the label documents ketoconazole increasing quinine AUC by 45% and links CYP3A4 inhibition to a fatal torsade de pointes case (erythromycin+quinine). Fluconazole combines both risks: it prolongs the QT (torsade de pointes in post-marketing experience) and inhibits CYP3A4, potentiating quinine toxicity (cinchonism, cardiotoxicity, hypoglycaemia). Whenever possible, avoid the combination; if unavoidable, monitor the ECG, electrolytes (correct hypokalaemia/hypomagnesaemia) and signs of quinine toxicity.
Fluconazole + quinine: additive QT and increased quinine levels (CYP3A4 inhibition). Avoid; if unavoidable, ECG and monitoring.
Additive effect on cardiac repolarization; fluconazole may also raise quinine levels.
ECG (QT interval), electrolytes (K+, Mg2+), signs of arrhythmia.
Syncope, palpitations, torsades de pointes.
Use with caution; monitor ECG (QT) and electrolytes; prefer an alternative antimalarial regimen when possible.
DailyMed/FDA (NIH/NLM) — approved Fluconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7961c029-746c-48c3-888b-8f8344102873 ; approved Quinine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1f32f05c-a215-40be-b951-e41a7b54a8a0
Fluconazole may raise prednisolone levels (metabolic inhibition), with a risk of enhanced corticosteroid effects.
Prednisolone is partly metabolised by CYP3A4, and fluconazole is a CYP3A4 inhibitor (in addition to CYP2C9/2C19), which can raise corticosteroid concentrations and their effects. Although the interaction is less documented than with voriconazole, the same pharmacological principle applies: monitor for signs of corticosteroid excess (hyperglycaemia, fluid retention, hypertension, weight gain, Cushing syndrome symptoms) during the combination, especially at high doses or prolonged treatment, and adjust the prednisolone dose if needed.
Fluconazole + prednisolone: the azole can inhibit CYP3A4 and increase corticosteroid exposure. Monitor for signs of corticosteroid excess.
CYP3A4 inhibition by fluconazole reduces prednisolone metabolism.
Blood glucose, blood pressure, signs of iatrogenic Cushing.
Oedema, hyperglycaemia, Cushingoid facies.
Watch for corticosteroid effects (hyperglycaemia, fluid retention); adjust the steroid dose if overdosage symptoms occur.
DailyMed/FDA (NIH/NLM) — approved Fluconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7961c029-746c-48c3-888b-8f8344102873 ; approved Prednisolone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=52e6e21d-94b8-41a0-8d13-371c0e66bcee — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Taking fluconazole with glimepiride can lower blood sugar too much (hypoglycaemia). Watch for the signs and tell your doctor.
Glimepiride is metabolised by CYP2C9; fluconazole is one of the most potent inhibitors of this isoenzyme. An in vivo study cited in the SmPC (EMC-UK) shows an approximately 2-fold increase in glimepiride AUC with fluconazole. The resulting hypoglycaemia can be severe and prolonged, especially in the elderly and in patients with impaired renal function. This is a common combination in community pharmacy (vaginal/oral candidiasis in diabetic patients).
Fluconazole (a potent CYP2C9 inhibitor) increases glimepiride AUC by about 2-fold, with a risk of severe hypoglycaemia. If the combination is unavoidable, monitor blood glucose and consider reducing the sulfonylurea dose.
CYP2C9 inhibition by fluconazole, reducing glimepiride metabolism.
Capillary glucose; hypoglycaemia symptoms.
Sweating, tremor, confusion, intense hunger, loss of consciousness — treat hypoglycaemia immediately.
Avoid when possible; if needed, reduce the glimepiride dose and reinforce self-monitoring of blood glucose during and after antifungal treatment.
EMC-UK (MHRA) — approved Glimepiride SmPC: https://www.medicines.org.uk/emc/product/10742/smpc ; DailyMed/FDA (NIH/NLM) — approved Fluconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7961c029-746c-48c3-888b-8f8344102873 ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Fluconazole can increase the effect of gliclazide and lower blood sugar too much. Monitor blood glucose during the antifungal.
The gliclazide SmPC (EMC-UK) lists fluconazole among the drugs that potentiate the hypoglycaemic effect of sulfonylureas, with possible symptomatic hypoglycaemia or coma. The mechanism involves inhibition of CYP2C9 (gliclazide metabolism) and excretion. Blood glucose monitoring is mandatory during the combination.
Fluconazole potentiates the hypoglycaemic effect of gliclazide (CYP2C9 inhibition and reduced elimination). Caution with blood glucose monitoring; a dose adjustment may be needed.
CYP2C9 inhibition and reduced gliclazide elimination by fluconazole.
Capillary glucose; hypoglycaemia symptoms.
Severe hypoglycaemia — sweating, confusion, coma.
Prefer an alternative antifungal when possible; otherwise, monitor blood glucose and consider a sulfonylurea dose reduction.
EMC-UK (MHRA) — approved Gliclazide SmPC: https://www.medicines.org.uk/emc/product/1321/smpc ; DailyMed/FDA (NIH/NLM) — approved Fluconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7961c029-746c-48c3-888b-8f8344102873 ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Fluconazole potentiates the anticoagulant effect of Warfarin, markedly raising the INR and the bleeding risk.
Fluconazole is a potent inhibitor of CYP2C9, the isoenzyme that metabolises active S-warfarin; the effect is dose-dependent and more marked at high doses (e.g. 400 mg/day). The inhibition raises warfarin levels and the INR, with significant bleeding risk — a well-documented interaction mentioned in the approved fluconazole and warfarin labels. Reduce the warfarin dose when starting fluconazole, monitor the INR frequently and re-adjust after the antifungal is stopped; watch for bleeding signs.
Fluconazole inhibits CYP2C9 and can markedly raise the INR. Monitor the INR closely and reduce the warfarin dose when starting the antifungal.
CYP2C9 inhibition by fluconazole reduces the metabolism of the active S-warfarin isomer, raising the INR.
INR, signs of bleeding (gums, bruising, melena).
Unexplained bleeding, haematuria, melena.
Monitor the INR frequently (on starting and stopping fluconazole); reduce the warfarin dose as needed.
DailyMed/FDA (NIH/NLM) — approved Fluconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7961c029-746c-48c3-888b-8f8344102873 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Fluconazole potentiates the effect of Glyburide (Glibenclamide), with a risk of severe hypoglycaemia.
Fluconazole inhibits CYP2C9 and CYP3A4, the enzymes that metabolise glyburide (a sulfonylurea); in the pharmacokinetic study of the fluconazole label with 20 volunteers, glyburide (5 mg single dose) AUC and Cmax increased significantly after fluconazole administration — AUC +44% ± 29% and Cmax +19% ± 19% — and 5 of the 20 volunteers required oral glucose after glyburide ingestion at 7 days of fluconazole. Across the three sulfonylurea studies (tolbutamide, glipizide, glyburide), 47.8% of fluconazole-treated patients experienced symptoms consistent with hypoglycaemia. The label recommends carefully monitoring blood glucose and adjusting the sulfonylurea dose as necessary. In practice, warn the patient about hypoglycaemia signs (sweating, tremor, palpitations, confusion) and consider reducing the glyburide dose or preferring a sulfonylurea less dependent on CYP2C9 for the duration of the antifungal.
Fluconazole + glyburide: fluconazole inhibits CYP2C9 and raises glyburide levels (AUC +44%), with a risk of hypoglycaemia. Monitor glycaemia and adjust the sulfonylurea dose.
CYP2C9 inhibition by fluconazole reduces glibenclamide metabolism, increasing its concentrations.
Capillary glucose, hypoglycaemia symptoms (tremor, sweating, confusion).
Severe hypoglycaemia (loss of consciousness, seizures).
Monitor blood glucose more frequently; a sulfonylurea dose reduction may be needed.
DailyMed/FDA (NIH/NLM) — approved Fluconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7961c029-746c-48c3-888b-8f8344102873 ; approved Glyburide (Glibenclamide) label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=524eec41-37ee-419a-b7a1-d23e888ae6ab — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Fluconazole absorption is not significantly affected by food.
May take with or without food.
DailyMed/FDA (NIH/NLM) — approved Fluconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7961c029-746c-48c3-888b-8f8344102873
Alcohol increases the risk of fluconazole hepatotoxicity.
Avoid alcohol during treatment.
DailyMed/FDA (NIH/NLM) — approved Fluconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7961c029-746c-48c3-888b-8f8344102873
Fluconazole is renally eliminated; renal impairment requires dose reduction.
Adjust the dose according to creatinine clearance.
DailyMed/FDA (NIH/NLM) — approved Fluconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7961c029-746c-48c3-888b-8f8344102873
Fluconazole can cause hepatotoxicity, including fatal hepatic necrosis; the risk increases with prior liver disease.
Monitor transaminases, especially in prolonged treatment.
DailyMed/FDA (NIH/NLM) — approved Fluconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7961c029-746c-48c3-888b-8f8344102873
Low, short fluconazole doses are not associated with malformations; prolonged high doses (≥ 400 mg/day) are associated with increased risk.
Use the lowest effective dose for the shortest time; avoid prolonged high doses in pregnancy.
Excreted into breast milk; compatible with breastfeeding at usual doses.
No specific additional contraception.
DailyMed/FDA (NIH/NLM) — approved Fluconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7961c029-746c-48c3-888b-8f8344102873
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Triazole antifungal. Similar pharmacokinetics after oral and intravenous administration; oral bioavailability above 90%. Volume of distribution approximates total body water and plasma protein binding is low (11 to 12%). It penetrates into all fluids studied: CSF about 80% of plasma, urine 10-fold, skin 10-fold, saliva and sputum equal to plasma.
It inhibits the synthesis of ergosterol, an essential component of the fungal cell membrane, by blocking the fungal cytochrome P450-dependent enzyme (lanosterol 14α-demethylase).
Oral bioavailability above 90%; peak plasma concentrations 1 to 2 hours after dosing; steady state in 5 to 10 days with daily doses (or by day 2 with a loading dose). Exposure is not affected by food, so it may be taken with or without meals.
Eliminated mainly by renal excretion: about 80% of the dose appears unchanged in the urine and 11% as metabolites. Pharmacokinetics are markedly affected by reduced renal function (inverse relationship between half-life and creatinine clearance); a 3-hour haemodialysis session reduces plasma concentrations by about 50%.
Terminal elimination half-life of about 30 hours (range 20 to 50 hours) after oral administration; mean clearance of 0.23 mL/min/kg. In premature neonates the half-life can reach 73.6 hours.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
