Side Effects of Oral Fluconazole
Oral fluconazole is generally well tolerated, with the most common side effects being gastrointestinal symptoms (nausea, vomiting, abdominal pain, diarrhea) and headache, occurring in a minority of patients and typically mild in severity. 1, 2
Common Side Effects (Occur in >1% of Patients)
The FDA-approved labeling and CDC guidelines identify the following most frequent adverse effects 2, 3:
- Gastrointestinal symptoms: Nausea (3.7%), vomiting (1.7%), abdominal pain (1.7%), diarrhea (1.5%), dyspepsia (1%) 2
- Headache: 1.9% of patients in trials lasting ≥7 days 2
- Skin rash: 1.8% of patients 2
- Dizziness: 1% of patients 2
- Taste perversion: 1% of patients 2
For single-dose therapy (150 mg for vaginal candidiasis), the side effect profile is similar but with slightly higher headache rates (13%), nausea (7%), and abdominal pain (6%) 2.
Serious but Rare Hepatotoxicity
Hepatotoxicity is the most concerning serious adverse effect, though uncommon 1, 2:
- Asymptomatic transaminase elevations: Occur in 1-13% of patients, generally reversible upon discontinuation 1
- Clinically significant hepatitis: Rare cases ranging from mild transient elevations to fulminant hepatic failure with fatalities have been reported 2, 4
- Risk factors: Primarily occurs in patients with serious underlying conditions (AIDS, malignancy) taking multiple hepatotoxic medications 2
- Monitoring recommendation: If prolonged therapy (>21 days) is anticipated, periodic liver function monitoring should be considered 3
Warning signs requiring immediate medical attention include dark urine, light-colored stools, severe itching, yellowing of skin/eyes, severe fatigue, or loss of appetite 2.
Serious Allergic and Dermatologic Reactions
Rare but potentially life-threatening reactions include 1, 2:
- Anaphylaxis: Including angioedema, facial edema, shortness of breath, wheezing 2
- Stevens-Johnson syndrome: Rare exfoliative skin reactions 1, 5
- Serious skin problems: Some cases have resulted in death, particularly in patients with serious underlying conditions 2
Patients should stop fluconazole immediately and seek emergency care if they develop rash, blisters, skin peeling, hives, swelling of face/mouth/neck, or difficulty breathing 2.
Cardiovascular Effects
- QT prolongation and torsade de pointes: Documented in post-marketing surveillance 2
- Risk is increased in patients with pre-existing heart rhythm abnormalities or hypokalemia 2
Hematologic Effects
Hematologic toxicity is rare with fluconazole compared to other antifungals 6:
- Leukopenia and thrombocytopenia: Rare, with isolated case reports of agranulocytosis 6
- Much less common than with flucytosine (which causes significant bone marrow toxicity) or amphotericin B 6
Other Adverse Effects
- Adrenal insufficiency: Reversible cases reported; symptoms include persistent fatigue, muscle weakness, loss of appetite, weight loss 2
- Seizures: Can occur, particularly at higher doses 2
- Asthenia, fatigue, fever, malaise: Reported in post-marketing experience 2
Special Population Considerations
HIV-infected patients experience higher overall incidence of adverse events (21%) compared to non-HIV infected patients (13%), though the pattern of side effects is similar 2, 5. Discontinuation rates due to adverse events remain comparable (1.5%) 2.
Pregnancy: High-dose fluconazole (>150 mg/day) during first trimester is associated with congenital malformations (craniosynostosis, dysmorphic facies) and should be avoided 3. Single low doses (150 mg) are not associated with increased malformations 3.
Important Drug Interactions Leading to Adverse Effects
Fluconazole inhibits CYP2C9 and CYP3A4, leading to significant interactions 7:
- Warfarin: Increased INR and bleeding risk, including gastrointestinal bleeding; requires dose reduction and frequent INR monitoring 1, 7
- Statins (simvastatin, atorvastatin): Increased myopathy risk 7
- Immunosuppressants (cyclosporine, tacrolimus): Significantly elevated levels requiring 30-50% dose reduction 7
Clinical Context
Treatment discontinuation due to adverse events occurs in only 1.5% of patients, indicating good overall tolerability 2. The side effect profile compares favorably to other azoles, particularly ketoconazole, which causes gastrointestinal symptoms in 10-40% of patients 1. Most adverse effects are mild, transient, and resolve without intervention 3, 8, 9.