Fluconazole is indicated for the treatment of:

• Vaginal Candidiasis
• Oropharyngeal Candidiasis
• Esophageal Candidiasis
• Tinea infections including Tinea corporis, Tinea cruris, Tinea pedis, and other Tinea
• Kerion
• Pityriasis versicolor
• Onychomycosis
• Invasive candidal infections and cryptococcal infections, including cryptococcal meningitis
• Prevention of cryptococcal meningitis
• Prevention of fungal infections in immunocompromised patients
• Systemic candidiasis and cryptococcal infections
• Superficial candidiasis

Other indications include:

• fungal urinary tract infections,
• disseminated candidiasis,
• prophylaxis of fungal infections in neutropenic cancer patients,
• acute treatment of systemic fungal infections such as coccidioidomycosis and histoplasmosis.

Fluconazole is a triazole antifungal agent. It acts as a potent inhibitor of fungal cytochrome P-450 dependent enzymes. The cytochrome P-450 enzyme system is a crucial component of the fungal cell membrane and is responsible for synthesizing ergosterol, an essential structural component of the fungal membrane.

Adults:

• Vaginal Candidiasis: 150 mg as a single dose.
• Oropharyngeal Candidiasis: 200 mg on the first day followed by 100 mg daily for 14 days.
• Esophageal Candidiasis: 200 mg on the first day followed by 100 mg daily for 14–30 days.
• Tinea corporis/Tinea cruris/Tinea pedis/Other Tinea: 150 mg weekly for 4–6 weeks.
• Kerion: 50 mg daily for 20 days.
• Pityriasis versicolor: 400 mg as a single dose.
• Onychomycosis: 150 mg weekly for 12 months.
• Invasive candidal infections and cryptococcal infections (including meningitis): Orally or by IV infusion, 400 mg on the first day then 200–400 mg daily.
• Prevention of cryptococcal meningitis: Orally or by IV infusion, 200 mg daily.
• Prevention of fungal infections in immunocompromised patients: Orally or by IV infusion, 50–400 mg daily.

Child over 1 year

• In Superficial Candidiasis: 1–2 mg/kg daily.
• In Systemic Candidiasis & Cryptococcal infection: 3–6 mg/kg daily.

In serious life-threatening infections, up to 12 mg/kg daily has been given to children aged 5–13 years (Maximum 400 mg daily). Guideline by age/weight (measuring spoon):
1 year: 9 kg: ½ measuring spoonful
1–2 years: 12 kg: 1 measuring spoonful
2–3 years: 14 kg: 1½ measuring spoonful
3–4 years: 16 kg: 2 measuring spoonful
4–6 years: 20 kg: 2½ measuring spoonful

Use in Specific Population
Elderly patient: The normal dose should be used if there is no evidence of renal impairment.

Renal Impairment: No adjustment in single-dose therapy is required. In multiple-dose therapy of patients with renal impairment, normal doses should be given on days 1 and 2 of treatment, thereafter the dosage intervals should be modified as follows:

• Creatinine clearance (>41 ml/min): Dosage interval 24 hours
• Creatinine clearance (21–40 ml/min): Dosage interval 48 hours
• Creatinine clearance (10–20 ml/min): Dosage interval 72 hours
• Patients receiving regular dialysis: One dose after every dialysis session

Children: Renal clearance in children may be proportionately more rapid than in adults, and doses up to 12 mg/kg are recommended.

In an interaction study, fluconazole increased the prothrombin time after warfarin administration in healthy males. Though the magnitude of change was small (12%), careful monitoring of prothrombin time in patients receiving coumarin-type anticoagulants is recommended.

Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulfonylureas (chlorpropamide, glibenclamide, glipizide, and tolbutamide) in healthy volunteers. Fluconazole and oral sulfonylureas may be co-administered to diabetic patients, but the possibility of a hypoglycemic episode should be borne in mind.

In a kinetic interaction study, co-administration of multiple-dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%. This magnitude of effect does not necessitate a change in the fluconazole dose regimen, although prescribers should be aware.

Concomitant administration of fluconazole and phenytoin may increase phenytoin levels to a clinically significant degree. Co-administration with rifampicin has resulted in a 25% decrease in the AUC and a 20% shorter half-life of fluconazole. In such cases, an increase in fluconazole dose should be considered.

Two kinetic studies with combined oral contraceptives using multiple doses of fluconazole have been performed. No significant effect was seen at 50 mg, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel increased by 40% and 4%, respectively. Fluconazole 50 mg daily does not affect endogenous steroid levels in females. 200–400 mg daily has no clinically significant effect on endogenous steroid levels or on ACTH-stimulated response in healthy male volunteers.

In renal transplant patients, fluconazole 200 mg daily slowly increased cyclosporin concentrations. Another study with 100 mg daily in bone marrow transplant patients showed no effect. Monitoring cyclosporin plasma concentrations is recommended.

Interaction studies indicate that co-administration of fluconazole with food, cimetidine, antacids, or following total body irradiation for bone marrow transplantation does not significantly impair fluconazole absorption.

In a placebo-controlled interaction study, fluconazole 200 mg for 14 days resulted in an 18% decrease in mean plasma clearance of theophylline. Patients on theophylline or at risk of toxicity should be monitored for signs of toxicity, and therapy adjusted if necessary.

Physicians should note that drug-drug interaction studies with other medications have not been conducted, but interactions may occur.

Fluconazole should not be used in patients with known hypersensitivity to fluconazole or related triazole compounds.

Fluconazole is generally well tolerated. The most common side effects involve the gastrointestinal tract, including nausea, abdominal discomfort, diarrhea, and flatulence. Rash is rarely seen (<1%). In rare cases, anaphylaxis has been reported.

Adverse fetal effects of fluconazole have been seen in animals only at dose levels associated with maternal toxicity, much higher than therapeutic doses. Limited human use has been reported. Fluconazole should not be used during pregnancy or in women of childbearing potential unless effective contraception is employed.

In some patients, particularly those with serious underlying diseases such as AIDS and cancer, abnormalities of hepatic, renal, hematological, and other biochemical function tests have been observed during treatment with fluconazole, but the clinical significance and relationship to treatment is uncertain.

Very rarely, patients who died with severe underlying disease and had received multiple doses of fluconazole had post-mortem findings that included hepatic necrosis. These patients were receiving multiple concomitant medications, some known to be potentially hepatotoxic, and/or had underlying diseases which could have caused the hepatic necrosis. Consequently, because a causal relationship with fluconazole cannot be excluded, the risk-benefit ratio of continued fluconazole treatment should be assessed in those patients in whom a significant rise of liver enzymes occurs.

Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson Syndrome and toxic epidermal necrolysis, during treatment with fluconazole. AIDS patients are more prone to severe cutaneous reactions to many drugs.

If a rash develops in patients treated for a superficial fungal infection that is considered attributable to fluconazole, further therapy with this agent should be discontinued. In patients with invasive/systemic fungal infections who develop rashes, they should be monitored closely, and fluconazole should be discontinued if bullous lesions or erythema multiforme develop.

Use during lactation: Fluconazole is found in human breast milk at concentrations similar to plasma. Hence its use in nursing mothers is not recommended.

Driving/Use of machinery: Experience with fluconazole indicates that therapy is unlikely to impair a patient's ability to drive or use machinery.

Use in the elderly: The normal dose should be used if there is no evidence of renal impairment. In patients with renal impairment (creatinine clearance less than 40 ml/min), the dosage intervals or oral dosage should be adjusted as described below.

Use in renal impairment: Fluconazole is excreted predominantly in the urine as unchanged drug. No adjustments in single-dose therapy are required. In multiple-dose therapy of patients with renal impairment, the normal dose should be given on days 1 and 2 of treatment; thereafter, the dosage intervals or daily dosage should be modified according to creatinine clearance as follows:

• CrCl >40: Dosage interval 24 hours (normal dosage regimen)
• CrCl 21–40: Dosage interval 48 hours or half normal daily dose
• CrCl 10–20: Dosage interval 72 hours or one-third normal daily dose
• Patients receiving regular hemodialysis: One dose after every dialysis session

In the event of overdosage, supportive measures and symptomatic treatment with gastric lavage if necessary may be adequate. As fluconazole is excreted largely in the urine, forced volume diuresis would probably increase the elimination rate. A three-hour session of hemodialysis decreases plasma levels by approximately 50%.

Drugs for subcutaneous and mycoses

Keep in a dry place, away from light and heat. Keep out of the reach of children.