Fluconazole
Mechanism :
Fluconazole interacts with 14-a demethylase, a cytochrome P-450 enzyme necessary to convert lanosterol to ergosterol. As ergosterol is an essential component of the fungal cell membrane, inhibition of its synthesis results in increased cellular permeability causing leakage of cellular contents. Fluconazole may also inhibit endogenous respiration, interact with membrane phospholipids, inhibit the transformation of yeasts to mycelial forms, inhibit purine uptake, and impair triglyceride and/or phospholipid biosynthesis. Mammalian cell is much less sensitive to fluconazole inhibition.
Indication :
- Cryptococcosis
- Candidiasis
- Immunocompromised patients
Contraindications :
Fluconazole is contraindicated in patients who have shown hypersensitivity to fluconazole or to any of its excipients. Co-administration of cisapride or terfenadine contra-indicated.
Dosing :
Esophageal candidiasis, Oral thrush:
<2 weeks (gestational age 26 to 29 weeks):
3 to 12 mg/kg orally or IV every 72 hours.
>2 weeks:
6 mg/kg on the first day followed by 3 mg/kg orally or IV once a day; doses up to 12 mg/kg/day may be used.
Treatment should continue for at least 3 weeks and for at least 2 weeks following the resolution of symptoms in case of esophageal candidiasis, for 2 weeks for oral thrush.
Systemic Candida infections, Disseminated candidiasis, cryptococcal meningitis:
<2 weeks (gestational age 26 to 29 weeks):
6 to 12 mg/kg IV or orally every 72 hours.
>2 weeks:
6 to 12 mg/kg/day, IV or orally.
Treatment should continue for at least 3 weeks and for at least 2 weeks following negative culture in systemic candida and disseminated candida. Therapy should be continued for 10 to 12 weeks after cerebrospinal fluid culture is negative in immunocompetent hosts with cryptococcal meningitis and for 10-12 weeks in immunocompromised hosts.
Prophylaxis of fungal infection in immunocompromised:
3-12 mg/kg once daily (Max 400 mg) dose dependent on extent and duration of neutropenia.
Adverse Effect :
Anaphylaxis, torsade de pointes, QT prolongation, leukopenia, thrombocytopenia, seizures, dizziness, exfoliative skin disorders, Stevens-Johnson Syndrome, toxic epidermal necrolysis, hypertriglyceridemia, hypercholesterolemia, hypokalemia, dyspepsia, vomiting.
Interaction :
Oral hypoglycemics: Clinically significant hypoglycemia may be precipitated.
Coumarin-type anticoagulants: Prothrombin time may be increased in patients.
Phenytoin: Increases the plasma concentrations of phenytoin.
Cyclosporine: May significantly increase cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum creatinine is recommended.
Rifampin: Rifampin enhances the metabolism of fluconazole.
Theophylline: Increases the serum concentrations of theophylline.
Terfenadine: Serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals along with terfenadine have been seen.
Cisapride: Torsade de pointes in patients to whom fluconazole and cisapride were coadministered.
Astemizole: The use of fluconazole in patients concurrently taking astemizole may be associated with elevations in serum levels of these drugs.
Rifabutin: There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered.
Tacrolimus: There have been reports of nephrotoxicity in patients to whom fluconazole and tacrolimus were coadministered.
Short-acting Benzodiazepines: Substantial increases in midazolam concentrations and psychomotor effects.
Renal Dose :
Dose in Renal Impairment GFR (mL/min)
| 20-50 | Dose as in normal renal function |
| 10-20 | Dose as in normal renal function |
| <10 | 50% of normal dose |
Dose in Patients undergoing Renal Replacement Therapies
| CAPD | Dialysed. Dose as in GFR<10 mL/ min |
| HD | Dialysed. 50% of normal dose daily, or 100% of normal dose 3 times a week after dialysis |
| HDF/High flux | Dialysed. 50% of normal dose daily, or 100% of normal dose 3 times a week after dialysis |
| CAV/VVHD | Dialysed. Dose as in normal renal function |
| CVVHD/HDF | Dialysed. 400–800 mg every 24 hours |
Hepatic Dose :
No dosage adjustment required.