FLUCONAZOLE — fluconazole tablet
Zydus Pharmaceuticals (USA) Inc.
Fluconazole is designated chemically as 2,4-difluoro-α,α1 -bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol with an molecular formula of C13 H12 F2 N6 O and molecular weight of 306.3. The structural formula is:
Fluconazole USP is a white or almost white crystalline powder which is freely soluble in methanol, soluble in alcohol and in acetone, sparingly soluble in isopropanol and in chloroform, slightly soluble in water, very slightly soluble in toluene.
Each fluconazole tablet, USP intended for oral administration contains 50 mg, 100 mg, 150 mg, or 200 mg of fluconazole USP. In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, dibasic calcium phosphate anhydrous, fd&c red no. 40 aluminum lake, magnesium stearate, microcrystalline cellulose and povidone.
Fluconazole tablet meets USP Dissolution Test 2.
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 mcg/mL to 8.08 mcg/mL) and after single oral doses of 50 mg to 400 mg, fluconazole plasma concentrations and area under the plasma concentration-time curve (AUC) are dose proportional.
The Cmax and AUC data from a food-effect study involving administration of fluconazole tablets to healthy volunteers under fasting conditions and with a high-fat meal indicated that exposure to the drug is not affected by food. Therefore, fluconazole may be taken without regard to meals. (See DOSAGE AND ADMINISTRATION.)
Steady-state concentrations are reached within 5 to 10 days following oral doses of 50 mg 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 cerebrospinal fluid (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 Fluconazole Tissue ( Fluid )/ Plasma Concentration *|
|Cerebrospinal fluid †||0.5 to 0.9|
|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 adrenocorticotropic hormone (ACTH)-stimulated cortisol response.
|Age Studied||Dose ( mg / kg )||Clearance ( mL / min / kg )||Half – life ( Hours )||Cm a x ( mcg / mL )||Vdss ( L / kg )|
|9 Months to13 years||Single-Oral 2 mg/kg||0.40 (38%)N=14||25||2.9 (22%)N=16||—|
|9 Months to13 years||Single-Oral 8 mg/kg||0.51 (60%)N=15||19.5||9.8 (20%)N=15||—|
|5 to 15 years||Multiple IV 2 mg/kg||0.49 (40%)N=4||17.4||5.5 (25%)N=5||0.722 (36%)N=4|
|5 to 15 years||Multiple IV 4 mg/kg||0.59 (64%)N=5||15.2||11.4 (44%)N=6||0.729 (33%)N=5|
|5 to 15 years||Multiple IV 8 mg/kg||0.66 (31%)N=7||17.6||14.1 (22%)N=8||1.069 (37%)N=7|
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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