Prescription Drug Information: Diflucan

DIFLUCAN- fluconazole tablet
DIFLUCAN- fluconazole powder, for suspension
Roerig

DESCRIPTION

DIFLUCAN® (fluconazole), the first of a new subclass of synthetic triazole antifungal agents, is available as a sterile solution for intravenous use in glass and in Viaflex® Plus plastic containers.

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

Chemical Structure
(click image for full-size original)

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

DIFLUCAN 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 or 56 mg of dextrose, hydrous. 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 glass and in Viaflex® Plus plastic containers.

The Viaflex® Plus plastic container is fabricated from a specially formulated polyvinyl chloride (PL 146® Plastic) (Viaflex and PL 146 are registered trademarks of Baxter International, Inc.). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexylphthalate (DEHP), up to 5 parts per million. 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

Pharmacokinetics and Metabolism

The pharmacokinetic properties (PK) 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 DIFLUCAN (fluconazole) leads to a mean Cmax of 6.72 mcg/mL (range: 4.12 to 8.08 mcg/mL) and after single or multiple oral doses of 50 to 400 mg, fluconazole plasma concentrations and area under the plasma concentration time curve (AUC) are dose proportional (Table 1).

Table 1: Mean Pharmacokinetic Parameters of Fluconazole in Adult Healthy Volunteers Following the Administration of DIFLUCAN
*
AUC0-inf. Cmax= Peak plasma concentrations, AUC =area under the plasma concentration time curve.

Dose regimen

Cmax (mcg/mL)

AUC0-24 (mcg*h/mL)

Half-life (hours)

50 mg oral (once daily x 7 days)

2.21

37.6

26.6

100 mg oral (once daily x 7 days)

4.81

82.5

27.7

150 mg single oral

2.70

137*

34.1

200 mg oral (once daily x 14 days)

10.12

169.5

31

300 mg oral (once daily x 14 days)

15.98

299.4

34

400 mg oral (once daily x 14 days)

18.89

349.9

31

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 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.

Table 2: Ratio of Fluconazole Tissue (Fluid)/Plasma Concentration
Tissue or Fluid Ratio of Fluconazole Tissue (Fluid)/Plasma Concentration *
*
Relative to concurrent concentrations in plasma in subjects with normal renal function.
Independent of degree of meningeal inflammation.

Cerebrospinal fluid

0.5–0.9

Saliva

1

Sputum

1

Blister fluid

1

Urine

10

Normal skin

10

Nails

1

Blister skin

2

Vaginal tissue

1

Vaginal fluid

0.4–0.7

Mean body clearance in adults is reported to be 0.23 (17%) mL/min/kg. 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 DIFLUCAN 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, DIFLUCAN 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.

Pharmacokinetics in Pediatric Patients

In pediatric patients from 2 days to 15 years of age, the following pharmacokinetic data have been reported following the administration of DIFLUCAN:

Table 3: Pharmacokinetic Parameters * of Fluconazole in Pediatric Patients Following the Administration of DIFLUCAN
Age Studied Dose (mg/kg) Clearance (mL/min/kg) Half-life (Hours) Cmax (mcg/mL) AUC (mcg*h/mL) Vdss (L/kg)
Abbreviations: Cmax=Peak plasma concentrations, AUC =area under the plasma concentration time curve; and Vdss=volume of distribution at steady state.
There are limited data available in patients 61 days to less than 9 months of age.
*
Data for Clearance, Cmax, AUC and Vdss are presented as arithmetic mean (CV%) and Half-life as arithmetic mean only.
AUC0-24
AUC0-inf

2 to 60 days

IV 25 mg/kg on day one followed by

IV 12 mg/kg once daily

0.29 (35%)

N=8

54.2

23.4 (29%)

N=8

439 (25%)

1.13 (31%)

9 months to 13 years

Single-Oral2 mg/kg

0.40 (38%)N=14

25.0

2.9 (22%)N=16

94.7 (34%)

N=14

N/A

9 months to 13 years

Single-Oral8 mg/kg

0.51 (60%)N=15

19.5

9.8 (20%)N=15

362.5 (58%)

N=14

N/A

5 to 15 years

Multiple IV2 mg/kg

0.49 (40%)N=4

17.4

5.5 (25%)N=5

67.4 (26%)

N=4

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

139.1 (46%)

N=5

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

196.7 (25%)

N=7

1.069 (37%)N=7

In pediatric patients (premature newborns; gestational age 26 to 29 weeks and postnatal age from birth to 1 day), 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 6 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 6 days later and 46.6 hours 12 days later.

In a study of 13 pediatric patients (preterm and term infants with median gestational age (GA) of 37 weeks, GA range 24 to 39 weeks; median postnatal age [PNA] 19 days, PNA range 5 to 262 days) 12 infants received a 25 mg/kg loading dose, and 9/12 (75%) achieved an AUC0-24 of >400-mg*h/L in the first 24 hours. A population pharmacokinetic model using data from 55 pediatric patients (GA 23 to 40 weeks, PNA 1-88 days) found that a loading dose of 25 mg/kg is necessary to reach target AUC >400-mg*h/L within 24 hours of initiating therapy in pediatric patients younger than 3 months of age. A maintenance dose of 9 mg/kg daily should be used in pediatric patients born at GA less than 30 weeks and 12 mg/kg daily in pediatric patients with GA equal or greater than 30 weeks. (See DOSAGE AND ADMINISTRATION.)

A population PK model using data from 21 pediatric patients ages from birth to 17 years supported with extracorporeal membrane oxygenation (ECMO), and 19 pediatric non-ECMO patients ages from birth to 2 years found that clearance was related to serum creatinine while a higher volume of distribution was related to presence of ECMO support. The median volume of distribution was 1.3 L/kg in pediatric patients on ECMO and 0.9 L/kg in those not on ECMO. Simulations suggested that a loading dose of 35 mg/kg is needed to achieve the target AUC0-24 >400 mg*h/L within the first 24 hours in pediatric patients on ECMO. (See DOSAGE AND ADMINISTRATION.)

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