Fluconazole

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 QT (5-10 ms) + inhibits CYP3A4 and CYP2C9 (amiodarone metabolism). Dual risk.

Symptoms

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

Management

ECG monitoring. If possible – terbinafine for superficial infections.

Mechanism

Fluconazole at 200 mg/day or above moderately inhibits CYP3A4; at 400 mg/day, strongly. Atorvastatin plasma levels rise 2- to 4-fold depending on fluconazole dose.

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), halve atorvastatin or hold it. For prolonged systemic therapy, alternative antifungals: echinocandins (micafungin, caspofungin); or switch to pravastatin/rosuvastatin.

Mechanism

Dual risk. Fluconazole blocks CYP2C19 (strongly) and CYP3A4 (moderately) and prolongs QT itself. Citalopram plasma levels rise, plus additive QT prolongation.

Symptoms

QT prolongation on ECG. Clinically: dizziness, syncope, palpitations. Severe cases progress to polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.

Management

Cap citalopram at 20 mg/day when combined. ECG before start and every 3 days during therapy. Alternative antifungals: echinocandins for systemic mycoses or terbinafine for dermatophytosis.

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

Fluconazole at 200 mg/day or above blocks CYP3A4 – the main colchicine clearance route. Colchicine plasma levels rise; myopathy risk grows with prolonged therapy.

Symptoms

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

Management

For short fluconazole courses (up to 7 days), no special measures are needed. For prolonged systemic therapy with preserved renal function, colchicine 0.3 mg every other day. In chronic kidney disease, do not prescribe; alternative for gout: intra-articular glucocorticoid.

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

Fluconazole inhibits CYP3A4 and CYP2B6 – the main methadone metabolism enzymes. Methadone concentration rises by 35% with QT prolongation. Methadone alone prolongs QT above 80 mg/day; fluconazole amplifies this.

Symptoms

Drowsiness, respiratory depression (rate below 12/min), miosis, ECG QTc above 500 ms. Severe cases: fatal arrhythmia.

Management

Reduce methadone by 25% when starting fluconazole, ECG before and after. With methadone above 80 mg/day or QT risk factors, choose an alternative antifungal (isavuconazole, terbinafine for superficial infections).

Mechanism

Fluconazole is a moderate CYP3A4 inhibitor. Pimozide rises 2–3 fold. QT prolongation is clinically significant. FDA recommends avoidance.

Symptoms

QT prolongation, dizziness within 5–7 days.

Management

If fluconazole is needed, ECG at baseline and every 3 days, reduce pimozide by 50%. Better: terbinafine for superficial infections.

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 inhibits CYP2C9, the main enzyme of S-warfarin (the more active isomer). INR rises to 8–12 with risk of major bleeding: gastrointestinal, intracranial, retroperitoneal.

Symptoms

By days 3–5: gum and nose bleeding, petechiae, haematuria, bloody stool. INR above 6 without clinical bleeding still requires action.

Management

If fluconazole is required, reduce warfarin by 25–50% from day 1 and check INR on days 3 and 7. Short courses (3 single doses) – INR check on day 5. After fluconazole withdrawal, retitrate warfarin upward.