FLUCORIC Capsule Ref.[50943] Active ingredients: Fluconazole

The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral route.

Absorption

After oral administration in adults, fluconazole is well absorbed, and plasma levels (and systemic bioavailability) are over 90 % of the levels achieved after intravenous administration. Oral absorption is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur between 0,5 and 1,5 hours post dose. Plasma concentrations are proportional to dose. 90% steady state levels are reached by day 4–5 with multiple once daily dosing. Administration of a loading dose (on day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady-state levels by day 2.

Distribution

The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11–12%).

Fluconazole achieves good penetration in all body fluids studied. The levels of fluconazole in saliva and sputum are similar to plasma levels. In patients with fungal meningitis, fluconazole levels in the CSF are approximately 80 % the corresponding plasma levels.

High skin concentration of fluconazole, above serum concentrations, are achieved in the stratum corneum, epidermis-dermis and eccrine sweat. Fluconazole accumulates in the stratum corneum. At a dose of 50 mg once daily, the concentration of fluconazole after 12 days was 73 μg/g and 7 days after cessation of treatment the concentration was still 5,8 μg/g. At the 150 mg once-a-week dose, the concentration of fluconazole in stratum corneum on day 7 was 23,4 μg/g and 7 days after the second dose was still 7,1 μg/g.

Concentration of fluconazole in nails after 4 months of 150 mg once-a-week dosing was 4,05 μg/g in healthy and 1,8 μg/g in diseased nails; fluconazole was still measurable in nail samples 6 months after the end of therapy.

Elimination

Plasma elimination half-life for fluconazole is approximately 30 hours. The major route of excretion is renal with approximately 80% of the administered dose appearing in the urine as unchanged medicine. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of circulating metabolites, but accumulation is significant over 15 days and concentrations may rise 2–3 fold.

The long plasma elimination half-life (approximately 30 hours) provides the basis for once daily dosing in the treatment of systemic conditions and single dose therapy for vaginal candidiasis and once-weekly dosing for other indications.

A pharmacokinetic study in 10 lactating women, who had temporarily or permanently stopped breastfeeding their infants, evaluated fluconazole concentrations in plasma and breast milk for 48 hours following a single 150 mg dose of fluconazole. Fluconazole was detected in breast milk at an average concentration of approximately 98 % of those in maternal plasma. The mean peak breast milk concentration was 2,61 mg/L at 5,2 hours post-dose.

Paediatric population

Pharmacokinetic studies performed in children have shown that fluconazole is cleared faster than in adults, with a half-life of 23 hours. The volume of distribution of fluconazole in children under 1 year of age (950 mL/kg) is higher than in adults (700 mL/kg). Accumulation on multiple daily dosing is therefore less and steady state plasma levels are achieved faster than in adults.

In neonates, the half-lives determined over the first 2 weeks of life are considerably longer than adult values with a mean of 74 hours at day 1 and 47 hours at day 13 of life. The volume of distribution is about 1 200 mL/kg in neonates.