What are the side effects of fluconazole?

Fluconazole Side Effects

Fluconazole is generally well tolerated with most adverse effects being mild to moderate, but serious hepatotoxicity, severe skin reactions, and cardiac effects can occur, particularly in patients with underlying serious medical conditions.

Common Side Effects

The most frequently reported adverse effects are generally mild and include:

• Gastrointestinal symptoms: Nausea (3.7%), vomiting (1.7%), abdominal pain (1.7%), diarrhea (1.5%), and dyspepsia (1%) 1
• Neurological symptoms: Headache (13% in single-dose therapy, 1.9% in prolonged therapy) and dizziness (1%) 1
• Dermatological effects: Skin rash (1.8%), pruritus, and taste perversion (1%) 2
• Long-term therapy effects: Xerosis (16.9%), alopecia (16.1%), and fatigue (11.3%) in patients receiving prolonged treatment 3

Notably, in a study of 124 patients receiving long-term fluconazole therapy, 51.6% experienced adverse effects, with 65.6% of those requiring therapeutic intervention such as dose reduction, discontinuation, or switch to alternative antifungal 3.

Serious Adverse Effects

Hepatotoxicity

Liver toxicity represents the most concerning serious adverse effect, though it remains rare:

• Hepatic reactions range from mild transient transaminase elevations (1-13% of patients) to clinical hepatitis, cholestasis, and fulminant hepatic failure including fatalities 2, 1
• Fatal hepatic reactions occur primarily in patients with serious underlying conditions (predominantly AIDS or malignancy) taking multiple concomitant medications 1
• Transient hepatic reactions can occur even in patients with no identifiable risk factors, with liver function typically returning to baseline upon discontinuation 1
• The British Association of Dermatologists recommends baseline liver function tests before starting therapy, with monitoring at 2 and 4 weeks after initiation, then every 3 months during therapy 4

Severe Skin Reactions

• Rare cases of Stevens-Johnson syndrome have been reported 2
• Serious skin problems that have caused death have occurred in some patients with serious medical conditions 1
• Patients should be instructed to stop fluconazole and seek immediate medical attention if they develop a rash 1

Cardiac Effects

• QT prolongation can occur with fluconazole, particularly when combined with other QT-prolonging medications (fluoroquinolones, macrolides, ondansetron) 2
• Torsade de pointes has been reported in post-marketing experience 1
• Fluconazole is contraindicated with quinidine, erythromycin, and pimozide due to cardiac arrhythmia risk 1

Hematologic Effects

• Thrombocytopenia and leukopenia have been reported, though these are uncommon 2
• Anemia can occur, particularly in patients with serious underlying diseases 2

Allergic Reactions

• Anaphylaxis (including angioedema, face edema, and pruritus) has been reported rarely 1
• Symptoms include shortness of breath, coughing, wheezing, fever, skin rash, hives, blisters, skin peeling, swelling of eyelids, face, mouth, or neck 1

Other Serious Effects

• Adrenal insufficiency: Reversible adrenal insufficiency has been reported, presenting with fatigue, muscle weakness, loss of appetite, weight loss, and dizziness 1
• Seizures and neurological effects: Dizziness and seizures can occur, warranting caution with driving or operating machinery 1

Drug Interactions

Fluconazole has substantial drug interaction potential due to cytochrome P-450 enzyme inhibition:

• Inhibits CYP3A4, CYP2C9, and CYP2C19 enzymes, leading to increased plasma concentrations of co-administered drugs 2
• Higher rates of transaminase elevations occur when combined with rifampin, phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents 1
• Interactions with antiretroviral drugs require careful evaluation before initiation 2
• Can increase levels of immunosuppressants, statins, NSAIDs, and anticoagulants 2, 1

Clinical Context and Monitoring

Important considerations for clinical practice:

• Adverse effects are reported more frequently in HIV-infected patients (21%) compared to non-HIV infected patients (13%), though patterns are similar 1
• Treatment discontinuation due to adverse events occurs in approximately 1.5% of patients 1
• Patients receiving higher total daily doses (6.7 vs 5.7 mg/kg) are more likely to experience adverse effects 3
• Overall, fluconazole and posaconazole are generally well tolerated with serious adverse events (primarily liver toxicity) being rare 2