Fluconazole

Mechanism

Fluconazole prolongs QT by directly blocking the Ikr potassium current, in the words of its SmPC, which also contraindicates QT-prolonging drugs metabolised through CYP3A4. The citalopram SmPC lists ongoing treatment with any drug capable of prolonging the QT interval among its contraindications, with no exceptions. Kinetics adds a second layer: fluconazole inhibits CYP2C19, the main path for citalopram. The citalopram SmPC caps the dose at 20 mg a day in poor CYP2C19 metabolisers, and an enzyme inhibitor turns any patient into one.

Symptoms

QTc prolongation on ECG, palpitations, dizziness, syncope. The end point is polymorphic ventricular tachycardia of the torsade type progressing to ventricular fibrillation. The risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, decompensated heart failure and in women.

Management

The pair sits in the citalopram SmPC contraindications, so the question is which drug stays, not how far to cut the dose. In superficial mycoses topical forms give almost no systemic absorption and the question disappears. In systemic mycosis an echinocandin is chosen: caspofungin, micafungin or anidulafungin. Swapping fluconazole for another azole does not solve the problem, because the voriconazole and posaconazole SmPCs also describe QTc prolongation. If the pair continues anyway, potassium, magnesium and QTc stay under watch.

Mechanism

Fluconazole is a moderate CYP3A4 inhibitor (fluconazole SmPC), and colchicine is cleared through CYP3A4 and the P-glycoprotein transporter and has a narrow therapeutic margin (colchicine SmPC). In a study, fluconazole 200 mg/day raised colchicine exposure (area under the curve, AUC) by 40% (colchicine label, US Food and Drug Administration, FDA). With long-term colchicine use the risk of nerve and muscle toxicity grows, up to rhabdomyolysis (colchicine SmPC).

Symptoms

Profuse diarrhoea, vomiting, abdominal pain. With prolonged combination: muscle weakness, peripheral neuropathy, falling leukocytes and platelets.

Management

The combination is contraindicated: the Spanish colchicine SmPC forbids colchicine during use of CYP3A4 or P-glycoprotein inhibitors and for 14 days afterwards (colchicine SmPC), and fluconazole is a moderate CYP3A4 inhibitor (fluconazole SmPC). US labels are less strict: if there is no alternative, the colchicine dose is reduced with a moderate CYP3A4 inhibitor – for gout flare prophylaxis 0.3 mg twice daily or 0.6 mg once daily instead of 0.6 mg twice daily, for a flare 1.2 mg as a single dose, repeated no earlier than 3 days later (colchicine label, US Food and Drug Administration, FDA). In renal or hepatic impairment the combination is avoided (colchicine label, FDA). The fluconazole SmPC requires monitoring of patients who also take narrow therapeutic margin drugs metabolised by CYP3A4 (fluconazole SmPC). At the first sign of nausea, vomiting, abdominal pain or diarrhoea, colchicine is stopped and the patient needs urgent care (colchicine SmPC).

Mechanism

Fluconazole prolongs the QT interval on its own by directly inhibiting the delayed rectifier potassium current (IKr) in heart cells. Erythromycin also prolongs the QT interval, and the enzyme CYP3A4 breaks it down. Fluconazole moderately inhibits this enzyme. Its prescribing information warns that this can increase QT prolongation caused by drugs broken down by CYP3A4. Because fluconazole has a long half-life, its effect on the enzyme lasts 4 to 5 days after the last dose. The documents give no figures for the rise in erythromycin levels.

Symptoms

The electrocardiogram (ECG) shows a prolonged QT interval and ventricular extrasystoles, and the person may notice palpitations or skipped beats. The most dangerous rhythm disorders, listed in the erythromycin documents, are torsade de pointes, ventricular fibrillation and cardiac arrest. The fluconazole documents name sudden cardiac death as the risk of this combination. The risk is higher with low potassium or magnesium, advanced heart failure, a slow heart rate and in older people.

Management

The combination is contraindicated (fluconazole prescribing information from the Spanish Agency of Medicines and Medical Devices, AEMPS, and the US Food and Drug Administration, FDA). Fluconazole keeps inhibiting the enzyme CYP3A4 for 4 to 5 days after the last dose (fluconazole documents, AEMPS and FDA). Take this time into account if erythromycin is needed right after a course of fluconazole. Do not give erythromycin to people with a history of QT interval prolongation or ventricular arrhythmias, including torsade de pointes, or with low potassium or magnesium (erythromycin prescribing information, AEMPS). Use fluconazole with caution in conditions that predispose to arrhythmias. The risk is higher with low potassium and advanced heart failure (fluconazole prescribing information, AEMPS). If something may disturb electrolytes, such as diuretics, laxatives, vomiting, diarrhoea or kidney disease, check electrolyte levels (erythromycin prescribing information, AEMPS).

Mechanism

Fluconazole prolongs QT by directly blocking the Ikr potassium current, in the words of its SmPC, which also contraindicates QT-prolonging drugs metabolised through CYP3A4. The escitalopram SmPC contraindicates any QT-prolonging drug alongside it: the ban is written broadly, and the classes in brackets are examples. Kinetics adds a second layer: fluconazole inhibits CYP2C19, the main metabolic path for escitalopram, so antidepressant levels rise along with its dose-dependent QT effect.

Symptoms

QTc prolongation on ECG, palpitations, dizziness, syncope. The end point is polymorphic ventricular tachycardia of the torsade type progressing to ventricular fibrillation. The risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, decompensated heart failure and in women.

Management

The pair sits in the escitalopram SmPC contraindications, so the question is which drug stays, not how far to cut the dose. In superficial mycoses topical forms give almost no systemic absorption and the question disappears. In systemic mycosis an echinocandin is chosen. Switching to another azole does not lift the contraindication: the fluconazole SmPC links QT prolongation to other azoles as well. If the pair continues, potassium, magnesium and QTc stay under watch.

Mechanism

Pimozide is cleared in the liver mainly by CYP3A4, and fluconazole inhibits this enzyme. Pimozide levels rise, and pimozide itself prolongs the QT interval, so the risk of a dangerous ventricular arrhythmia, torsades de pointes, goes up (both SmPCs). Fluconazole keeps inhibiting the enzyme for 4–5 days after it is stopped (fluconazole SmPC).

Symptoms

QT prolongation on the ECG and ventricular arrhythmias, including torsades de pointes: palpitations, skipped beats, dizziness, fainting. Ventricular tachycardia, ventricular fibrillation and sudden death have been reported with pimozide (pimozide SmPC).

Management

The combination is contraindicated in the Spanish SmPCs of fluconazole and pimozide and in the FDA fluconazole label. Lowering the pimozide dose does not remove the risk, and no document allows it. For a fungal infection in a patient on pimozide, choose a drug that does not inhibit CYP3A4 or CYP2D6: the pimozide SmPC contraindicates inhibitors of both enzymes. If fluconazole has already been given, start pimozide no earlier than 4–5 days after fluconazole is stopped, when its effect on the enzyme has worn off (fluconazole SmPC). Do an ECG before starting pimozide and periodically during treatment. If QT prolongation or an arrhythmia appears, review the need for pimozide; pimozide is contraindicated with low potassium or magnesium (pimozide SmPC).

Mechanism

Fluconazole at 200 mg/day or above blocks CYP3A4 – the main alprazolam metabolic route. Alprazolam plasma levels rise 2- to 3-fold, with stronger and longer effect.

Symptoms

Deep sedation, drowsiness, ataxia. Particularly dangerous in older patients – fall and fracture risk. Symptoms appear within 1–2 days.

Management

During fluconazole therapy, halve the alprazolam dose. Alternative antifungals: terbinafine or echinocandins. Alternative benzodiazepines without CYP3A4 dependence: lorazepam or oxazepam.

Mechanism

Fluconazole prolongs the QT interval on its own by blocking the cardiac Ikr potassium current. It is also a moderate CYP3A4 inhibitor, and amiodarone is partly cleared by CYP3A4, so, per the fluconazole label, the QT prolongation caused by amiodarone can be amplified. The risk is higher with high-dose fluconazole (800 mg a day).

Symptoms

QTc above 500 ms, syncope, torsades de pointes risk.

Management

ECG monitoring. If possible – terbinafine for superficial infections.

Mechanism

Fluconazole moderately inhibits CYP2C9 and CYP3A4 and strongly inhibits CYP2C19 (fluconazole SmPC). The liver breaks down amitriptyline mainly through CYP2D6 and CYP2C19, with CYP3A4 and CYP2C9 also involved (amitriptyline SmPC). Fluconazole raises the levels of amitriptyline and its metabolite nortriptyline and increases their effect (both SmPCs). Each drug can prolong the QT interval on its own. The enzyme effect of fluconazole lasts 4–5 days after it is stopped (fluconazole SmPC).

Symptoms

Stronger amitriptyline side effects: dry mouth, constipation, urinary retention, drowsiness, fast heartbeat. Fainting and torsades de pointes have been reported with this combination (amitriptyline SmPC). The risk of dangerous arrhythmia is higher with low potassium and advanced heart failure (fluconazole SmPC).

Management

The amitriptyline SmPC lists fluconazole among combinations that are not recommended: it raises the levels and toxicity of tricyclic antidepressants. If fluconazole cannot be avoided, measure nortriptyline and amitriptyline levels when co-treatment starts and after one week, and adjust the amitriptyline dose if needed (fluconazole SmPC). Use fluconazole with caution in conditions that predispose to arrhythmia (fluconazole SmPC), and amitriptyline with caution in significant bradycardia, decompensated heart failure and with other QT-prolonging drugs (amitriptyline SmPC). The fluconazole effect lasts 4–5 days after the last dose, so do not stop monitoring as soon as fluconazole is stopped (fluconazole SmPC). Terbinafine is not a substitute: the amitriptyline SmPC names it together with fluconazole, as it also raises tricyclic levels.

Mechanism

Fluconazole inhibits CYP2C19, the key enzyme converting clopidogrel into its active metabolite. Active levels fall by 25–50% and the antiplatelet effect weakens.

Symptoms

The patient feels no symptoms – the weakened antiplatelet effect is silent. Risk of recurrent coronary events and stent thrombosis rises.

Management

For a short fluconazole course, the effect is clinically minor. For prolonged systemic therapy (>14 days), an alternative antiplatelet is ticagrelor (not CYP2C19-dependent). Alternative antifungal: echinocandins for systemic mycoses.

Mechanism

Dual mechanism. Fluconazole blocks CYP3A4 (the main dronedarone clearance route) and prolongs QT itself. Dronedarone plasma levels rise; QT effects add up.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.

Management

Avoid the combination. Alternative antifungals: echinocandins (micafungin, caspofungin) for systemic mycoses or terbinafine for dermatophytosis. If fluconazole is needed: ECG before start and every 3 days during therapy.

Mechanism

Fluconazole at 200 mg/day or above blocks CYP2C9 – the main glibenclamide metabolic route. Glibenclamide plasma levels rise 2- to 3-fold; hypoglycaemic effect intensifies.

Symptoms

Severe hypoglycaemia: sweating, tremor, hunger, tachycardia, confusion; severe cases progress to seizures and coma. Symptoms appear within 1–7 days, especially in older patients and chronic kidney disease.

Management

For short fluconazole courses, monitor glucose 4 times daily; if needed, halve glibenclamide. Alternative antifungals: terbinafine for dermatophytosis or echinocandins for systemic mycoses.

Mechanism

Dual mechanism. Fluconazole prolongs QT and blocks CYP3A4 and CYP2D6 – haloperidol metabolic routes. Haloperidol plasma levels rise; QT effects add up.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Severe cases: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia and hypomagnesaemia.

Management

Avoid the combination. Alternative antifungals: terbinafine or echinocandins. Alternative antipsychotics with minimal QT effect: olanzapine or aripiprazole.

Mechanism

Rifampicin strongly induces CYP3A4, which partly metabolises fluconazole. Fluconazole plasma levels fall by 25%; antifungal efficacy decreases.

Symptoms

Recurrence of mycosis symptoms: ongoing fever, skin or mucosal lesions; in immunocompromised patients, risk of systemic mycosis progression.

Management

When combined, increase fluconazole by 50–100% with efficacy monitoring. Alternative antifungal during anti-TB therapy: echinocandins (micafungin, caspofungin; no CYP3A4 dependence).

Mechanism

Fluconazole at 200 mg/day or above moderately inhibits CYP3A4 – the main simvastatin metabolic route. Simvastatin plasma levels rise 2- to 3-fold, with increased myopathy risk.

Symptoms

Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Severe cases progress to rhabdomyolysis with acute kidney injury. Symptoms appear within 1–4 weeks of co-administration.

Management

For short fluconazole courses (up to 7 days), hold simvastatin or halve the dose. For prolonged systemic therapy, switch to pravastatin/rosuvastatin or use an alternative antifungal (echinocandins).

Mechanism

Fluconazole at 200 mg/day or above blocks CYP3A4 – the main tacrolimus metabolic route. Tacrolimus plasma levels rise 2- to 3-fold, with nephrotoxicity and neurotoxicity risks.

Symptoms

Acute nephrotoxicity: rising creatinine and falling glomerular filtration rate. Tremor, headache, hypertension, hyperglycaemia, hyperkalaemia. In transplant patients: accelerated graft function decline.

Management

For short fluconazole courses (up to 7 days), reduce tacrolimus by 30% and check trough (C0) daily. For prolonged systemic therapy, alternative antifungals (echinocandins) or titrate tacrolimus to level.

Mechanism

Fluconazole is a moderate CYP3A4 inhibitor (fluconazole SmPC), and CYP3A4 takes part in amlodipine metabolism. Amlodipine levels may rise, and with them the risk of hypotension. The effect can be stronger in older patients (both SmPCs). Fluconazole has a long half-life, so its effect on the enzyme lasts 4–5 days after it is stopped (fluconazole SmPC). The documents do not give the size of the rise.

Symptoms

Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk.

Management

The combination is acceptable with monitoring. While both drugs are taken, check frequently for amlodipine adverse effects (fluconazole SmPC). Watch for signs of hypotension and leg oedema and use them to decide whether the amlodipine dose should be lowered (amlodipine labels). Monitor older patients with particular care (amlodipine SmPC). The effect of fluconazole on the enzyme lasts 4–5 days after the last dose, so continue monitoring during those days (fluconazole SmPC).

Mechanism

Fluconazole moderately inhibits CYP3A4, the enzyme that metabolises atorvastatin (fluconazole and atorvastatin SmPCs). Atorvastatin blood levels can rise, and with them the risk of muscle damage up to rhabdomyolysis (fluconazole SmPC).

Symptoms

Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Severe cases progress to rhabdomyolysis with acute kidney injury.

Management

The combination is not contraindicated. The atorvastatin SmPC classes fluconazole as a moderate CYP3A4 inhibitor: consider a lower maximum atorvastatin dose while the drugs are combined, and monitor the patient, especially after fluconazole is started or its dose changed (atorvastatin SmPC). While both drugs are taken, watch for muscle pain and weakness and check creatine kinase. If creatine kinase rises markedly or myopathy or rhabdomyolysis is suspected, stop atorvastatin (fluconazole SmPC).

Mechanism

Additive QT prolongation – both drugs prolong QTc dose-dependently.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Rarely: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.

Management

For short courses of both (azithromycin 3–5 days, fluconazole single dose for candidiasis), the combination is acceptable. For prolonged systemic fluconazole therapy: alternative antibiotics (doxycycline, a cephalosporin) or antifungals (terbinafine, echinocandins).

Mechanism

Fluconazole moderately inhibits CYP3A4 and CYP2C9 and strongly inhibits CYP2C19 (fluconazole SmPC). All of them take part in methadone metabolism, so methadone blood levels can rise (fluconazole and methadone labels). Both drugs prolong the QT interval: fluconazole blocks cardiac potassium channels directly, and methadone prolongs QT especially at high doses, above 100 mg a day according to the Spanish methadone SmPC.

Symptoms

Methadone excess: drowsiness, slow shallow breathing, pinpoint pupils; in severe cases life-threatening respiratory depression. QT prolongation on the ECG, palpitations, fainting, torsades de pointes.

Management

The combination is not contraindicated but needs monitoring. Fluconazole can raise methadone levels, and the methadone dose may need adjustment (fluconazole SmPC). The US methadone label (FDA) advises considering a methadone dose reduction until the effect is stable when an inhibitor is added, and frequent checks for respiratory depression and sedation; after fluconazole is stopped, methadone levels fall and withdrawal signs can appear. Use fluconazole with caution in conditions that predispose to arrhythmia; low potassium and advanced heart failure raise the risk (fluconazole SmPC). The Spanish methadone SmPC lists CYP3A4 inhibitors, fluconazole among them, as a QT risk factor and advises an ECG before methadone starts, two weeks later and before a dose increase (methadone SmPC).

Mechanism

Fluconazole moderately inhibits CYP2C9, which clears the more potent S-warfarin, and also CYP3A4 (fluconazole and warfarin labels). The warfarin effect increases: prothrombin time was prolonged up to 2-fold during co-administration (fluconazole SmPC). Bleeding events have been reported with this combination.

Symptoms

Bruising, nosebleeds, blood in the urine, black tarry stools and gastrointestinal bleeding, with a prolonged prothrombin time and a rising INR.

Management

The combination is not contraindicated but needs frequent coagulation checks. While both drugs are taken, monitor prothrombin time carefully and adjust the warfarin dose if needed (fluconazole SmPC). The Spanish warfarin SmPC requires close coagulation control whenever a concomitant medicine is added or stopped, and the US warfarin label (FDA) asks for close INR monitoring when any antifungal is started or stopped. So check the INR more often after the fluconazole course ends as well.

Mechanism

Fluconazole is a moderate inhibitor of the CYP3A4 enzyme (fluconazole SmPC), and apixaban is partly cleared through this enzyme. The apixaban SmPC of the European Medicines Agency (EMA) lists fluconazole among inhibitors expected to raise apixaban levels to a lesser degree than strong inhibitors. There are no figures for this pair: the European Heart Rhythm Association (EHRA) reports no data yet (EHRA 2021). Fluconazole keeps inhibiting the enzyme for 4–5 days after the last dose (fluconazole SmPC).

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools, haematuria. Higher risk in older patients, prior peptic ulcer disease, and chronic kidney disease.

Management

Do not change the apixaban dose during a fluconazole course. The apixaban SmPC of the European Medicines Agency (EMA) requires no dose adjustment with inhibitors that are not strong and names fluconazole among them (apixaban SmPC, EMA). Choose the apixaban dose by its usual rules: in atrial fibrillation, use 2.5 mg twice daily if two of three criteria are present (age 80 years or older, body weight 60 kg or less, serum creatinine 133 µmol/L or higher) or if creatinine clearance is 15–29 mL/min (apixaban SmPC, EMA). Tell the patient about signs of bleeding, and stop apixaban in severe bleeding (apixaban SmPC, EMA).