Fluconazole

FLUCONAZOLE- fluconazole solution
Apotex Inc.

DESCRIPTION

Fluconazole, the first of a new subclass of synthetic triazole antifungal agents, is available as a sterile solution for intravenous use in plastic containers.

Fluconazole is designated chemically as 2,4-difluoro-α,α1 -bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol with a molecular formula of C13 H12 F2 N6 O and molecular weight 306.3. The structural formula is:

Image from Drug Label Content

Fluconazole is a white crystalline solid which is slightly soluble in water and saline.

Fluconazole injection is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a sodium chloride or dextrose diluent. Each mL contains 2 mg of fluconazole and 9 mg of sodium chloride USP or 56 mg of dextrose monohydrate USP. The pH ranges from 4.0 to 8.0 in the sodium chloride diluent and from 3.5 to 6.5 in the dextrose diluent. Injection volumes of 100 mL and 200 mL are packaged in plastic containers.

The plastic container is fabricated from a specially formulated plastic. The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. However, the suitability of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.

CLINICAL PHARMACOLOGY

Mode of Action

Fluconazole is a highly selective inhibitor of fungal cytochrome P-450 sterol C-14 alpha-demethylation. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. The subsequent loss of normal sterols correlates with the accumulation of 14 alpha-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole.

Pharmacokinetics and Metabolism

The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral routes. In normal volunteers, the bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. Bioequivalence was established between the 100 mg tablet and both suspension strengths when administered as a single 200 mg dose.

Peak plasma concentrations (Cmax ) in fasted normal volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of approximately 30 hours (range: 20 to 50 hours) after oral administration.

In fasted normal volunteers, administration of a single oral 400 mg dose of fluconazole leads to a mean Cmax of 6.72 mcg/mL (range: 4.12 to 8.08 mcg/mL) and after single oral doses of 50 to 400 mg, fluconazole plasma concentrations and AUC (area under the plasma concentration-time curve) are dose proportional.

Administration of a single oral 150 mg tablet of fluconazole to ten lactating women resulted in a mean Cmax of 2.61 mcg/mL (range: 1.57 to 3.65 mcg/mL).

Steady-state concentrations are reached within 5 to 10 days following oral doses of 50 to 400 mg given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose results in plasma concentrations close to steady-state by the second day. The apparent volume of distribution of fluconazole approximates that of total body water. Plasma protein binding is low (11 to 12%). Following either single- or multiple-oral doses for up to 14 days, fluconazole penetrates into all body fluids studied (see table below). In normal volunteers, saliva concentrations of fluconazole were equal to or slightly greater than plasma concentrations regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum concentrations of fluconazole following a single 150 mg oral dose were equal to plasma concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole concentrations in the CSF are approximately 80% of the corresponding plasma concentrations.

A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal tissue, resulting in tissue: plasma ratios ranging from 0.94 to 1.14 over the first 48 hours following dosing.

A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal fluid, resulting in fluid: plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following dosing.

Tissue or Fluid Ratio of FluconazoleTissue (Fluid)/PlasmaConcentration *
*
Relative to concurrent concentrations in plasma in subjects with normal renal function.
Independent of degree of meningeal inflammation.
Cerebrospinal fluid 0.5 to 0.9
Saliva 1
Sputum 1
Blister fluid 1
Urine 10
Normal skin 10
Nails 1
Blister skin 2
Vaginal tissue 1
Vaginal fluid 0.4 to 0.7

In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites.

The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of fluconazole may need to be reduced in patients with impaired renal function. (See DOSAGE AND ADMINISTRATION). A 3-hour hemodialysis session decreases plasma concentrations by approximately 50%.

In normal volunteers, fluconazole administration (doses ranging from 200 mg to 400 mg once daily for up to 14 days) was associated with small and inconsistent effects on testosterone concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol response.

Pharmacokinetics in Children

In children, the following pharmacokinetic data {Mean(%cv)} have been reported:

Age Studied Dose(mg/kg) Clearance(mL/min/kg) Half-life(Hours) Cmax (mcg/mL) Vdss (L/kg)
9 Months to 13 years Single-Oral2 mg/kg 0.40 (38%)N=14 25.0 2.9 (22%)N=16
9 Months to 13 years Single-Oral8 mg/kg 0.51 (60%)N=15 19.5 9.8 (20%)N=15
5 to 15 years Multiple IV2 mg/kg 0.49 (40%)N=4 17.4 5.5 (25%)N=5 0.722 (36%)N=4
5 to 15 years Multiple IV4 mg/kg 0.59 (64%)N=5 15.2 11.4 (44%)N=6 0.729 (33%)N=5
5 to 15 years Multiple IV8 mg/kg 0.66 (31%)N=7 17.6 14.1 (22%)N=8 1.069 (37%)N=7

Clearance corrected for body weight was not affected by age in these studies. Mean body clearance in adults is reported to be 0.23 (17%) mL/min/kg.

In premature newborns (gestational age 26 to 29 weeks), the mean (%cv) clearance within 36 hours of birth was 0.180 (35%, N=7) mL/min/kg, which increased with time to a mean of 0.218 (31%, N=9) mL/min/kg six days later and 0.333 (56%, N=4) mL/min/kg 12 days later. Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours six days later and 46.6 hours 12 days later.

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