ZOCON 150 (Fluconazole)
ZOCON (Fluconazole) is a bis-triazole antifungal drug with novel pharmacological properties. It is structurally related to imidazole-derivative antifungal agents. Replacement of imidazole ring with a triazole ring results in increased antifungal activity and an expanded antifungal spectrum of activity.
ZOCON (Fluconazole) usually is fungistatic in action. Fluconazole presumably exerts its antifungal activity by altering cellular membranes resulting in increased membrane permeability, leakage of essential elements (e.g. amino acids, potassium), and impaired uptake of precursor molecules (e.g. purine and pyrimidine precursors of DNA).
Although the exact mechanism of action of Fluconazole and other triazoles has not been fully determined, the drugs inhibit cytochrome P-450 14-alpha-desmethylase in susceptible fungi, which leads to accumulation of C-14 methylated sterols (e.g. lanosterol) and decreased concentration of ergosterol.
ZOCON (Fluconazole) is active against many fungi, including yeast and dermatophytes. Fluconazole does not appear to have antibacterial activity.
In vitro, ZOCON (Fluconazole) is active against strains of Candida, including strains of C. albicans and C. kefyr (formerly C. pseudotropicalis) and Tolulopsis glabrata (formerly C. glabrata), Cryptococcus neoformans, Histoplasma capsulatum and Blastomyces dermatitidis.
The drug is rapidly and almost completely absorbed from the gastrointestinal tract, and there is no evidence of first-pass metabolism. Oral bioavailability of fluconazole exceeds 90% in healthy, fasting adults; peak plasma concentrations of the drug generally are attained within 1-2 hours after oral administration. The rate and extent of GI absorption of fluconazole are not affected by food and gastric pH.
Peak plasma fluconazole concentrations and AUCs increase in proportion to the dose over the oral dosage range of 50-400mg. Steady state plasma concentrations of fluconazole are attained within 5-10 days following oral doses of 50-400mg given once daily.
Fluconazole is widely distributed into body tissues and fluids following oral administration. In adult humans with normal renal function, concentrations of the drug attained in saliva, sputum, nails, blister fluid, blister skin and vaginal secretions are approximately equal to concurrent plasma concentrations; concentrations attained in urine and skin may be 10 times higher than concurrent plasma concentrations.
Fluconazole, unlike some azole-derivative antifungal agents distributes readily into CSF following oral administration; CSF concentrations of fluconazole may be 50%-94% of concurrent plasma concentrations regardless of the degree of meningeal inflammation.
Fluconazole is only 11-12% bound to plasma proteins. The plasma elimination half-life of fluconazole in adults with normal renal function is approximately 30 hours. The elimination half-life of fluconazole reportedly is not affected by impaired hepatic function.
Approximately 60-80% of a single oral dose of fluconazole is excreted in urine unchanged, and about 11% is excreted in urine as metabolites.
- In the treatment of systemic candidiasis, mucosal candidiasis and cryptococcosis.
- In the treatment of vaginal candidiasis.
- In prevention of fungal infections in patients with malignancy.
- In U.K the drug is also used in the treatment of fungal infections of the skin like tinea cruris, tinea corporis, tinea pedia, tinea versicolor
Dosage and administration
Dosage of the drug should be based on the type and severity of the infection, identity of the causative organism, and the patient’s renal function and response to therapy.
For superficial mucosal candidiasis (other than genital candidiasis) the usual dose of fluconazole in UK is 50mg daily, although 100mg daily may be given if necessary. Treatment usually continues for 7 to 14 days in oropharyngeal candidiasis (except in severely immunocompromised patients), for 14 days in atrophic oral candidiasis associated with dentures, and for 14 to 30 days in other mucosal candidal infections including oesophagitis.
Higher doses are recommended in US where an intial dose of fluconazole 200mg is followed by 100mg daily and where the minimum treatment period is 14 days for oropharyngeal infection, or a minimum of 21 days and at least 14 days after resolution of symptoms for oesophageal infections; doses of up to 400mg daily may be used for oesophargeal candidiasis if necessary.
Fluconazole 150mg by mouth as a single dose may be used for vaginal candidiasis.
Systemic candidiasis, cryptococcal meningitis and other cryptococcal infections may be treated with fluconazole by mouth or intravenous infusion; the initial dose is 400mg followed by 200 to 400mg daily. Duration of therapy is based on clinical and mycological response, but is usually at least 6 to 8 weeks in cryptococcal meningitis; in the USA, treatment for 10 to 12 weeks after the CSF becomes negative is recommended. Fluconazole may also be used in daily doses of 100 to 200 mg to prevent relapse following a primary course of anti-fungal treatment for acute cryptococcal meningitis in patients with AIDS.
In immunocompromised patients at risk of fungal infections fluconazole may be given prophylactically in a dose of 50 to 400mg daily
Tinea corporis, Tinea cruris, Tinea pedis: 150mg once a week up to 4 weeks
Cutaneous candidiasis: 150mg once a week up to 4 weeks
Onychomycosis: 150mg once a week for 6-12 months.
Tinea versicolor (Pityriasis vesicolor): 400mg single oral dose.
ZOCON (Fluconazole) is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation. Teratogenicity has occurred in animals given high doses of fluconazole and use of fluconazole is not recommended in pregnancy. Fluconazole should not be given to breast feeding women.
Side effects and adverse effects
Adverse effects reported with fluconazole most commonly affect the gastrointestinal tract and include abdominal pain, diarrhoea, nausea, and vomiting. Other adverse effects include headache, dizziness, leucopenia, thrombocytopenia, hyperlipidemias and raised liver enzyme values. Serious hepatotoxicity has been reported in patients with severe underlying disease. Anaphylaxis and angioedema has been reported rarely.
Skin reactions are rare but exfoliative cutaneous reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome have occurred, more commonly in patients with AIDS. Serious hepatotoxicity has been rarely reported in patients with serious underlying (AIDS or malignancy) receiving fluconazole in addition to other potentially hepatotoxic agents. Alopecia has occasionally been reported in patients receiving fluconazole especially during prolonged treatment.
Hypokalemia was associated with fluconazole administration in 3 patients with acute myeloid leukemia. Prolonged QT interval and torsade de pintes have been reported in 2 patients receiving fluconazole . Although severe hepatic reactions to fluconazole are rare they have been reported especially in patients with severe underlying diseases or hepatic dysfunction.
Precautions and warnings
Fluconazole should be used with caution in patients with impaired renal or hepatic function. Abnormalities in hematological, hepatic and renal function test have been observed in patients with serious underlying disease.
If abnormal liver function test results occur during fluconazole therapy, the patient should be monitored. Immunocompromised patients who develop rash during therapy should be monitored closely and the drug discontinued if the lesions progress.
Symptoms and treatment of overdose
There has been one reported case of overdosage with Fluconazole. A 42 year-old patient infected with HIV developed hallucinations and exhibited paranoid behaviour after reportedly ingesting 8200mg Fluconazole. The patient was admitted to hospital and his condition resolved within 48 hours. In the event of overdose symptomatic treatment (with supportive measures and gastric lavage if clinically indicated) should be instituted. Fluconazole is largely excreted in urine. A three hour hemodialysis session decreases plasma levels by approximately 50%