FLUCONAZOLE- fluconazole_tablet

CLINICAL PHARMACOLOGY
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 (C max In fasted normal volunteers, administration of a single oral 400 mg dose of fluconazole leads to a mean C max The C max DOSAGE AND ADMINISTRATION Table 1: Mean Pharmacokinetic Parameters of Fluconazole in Adult Healthy Volunteers Following the Administration of Fluconazole Tablets *AUC 0-inf. max max 0-24 50 mg oral (once daily x 7 days) 2. 6 100 mg oral (once daily x 7 days) 4. 7 150 mg single oral 2. 1 200 mg oral (once daily x 14 days) 10. 5 31 300 mg oral (once daily x 14 days) 15. 4 34 400 mg oral (once daily x 14 days) 18. 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. 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. 71 over the first 72 hours following dosing. Table 2: Ratio of Fluconazole Tissue (Fluid)/Plasma Concentration * Relative to concurrent concentrations in plasma in subjects with normal renal function. dagger Tissue or Fluid Ratio of Fluconazole Tissue (Fluid)/Plasma Concentration* Cerebrospinal fluid dagger 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. 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 fluconazole may need to be reduced in patients with impaired renal function. (See DOSAGE AND ADMINISTRATION 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. In pediatric patients from 2 days to 15 years of age, the following pharmacokinetic data have been reported following the administration of fluconazole: Table 3: Pharmacokinetic Parameters* of Fluconazole in Pediatric Patients Following the Administration of Fluconazole Tablets * max dss 0-inf 0-24 max dss Age Studied Dose (mg/kg) Clearance (mL/min/kg) Half-life (Hours) C max (mcg/mL) AUC (mcg*h/mL) Vdss (L/kg) 2 to 60 days IV 25 mg/kg on day one followed by IV 12 mg/kg once daily 0. 29 (35%) 54. 4 (29%) N=8 439 (25%)^ 1. 13 (31%) 9 months to Single-Oral 0. 4 (38%) 25 2. 9 (22%) N/A 9 months to Single-Oral 0. 51 (60%) 19. 8 (20%) N/A 5 to 15 years Multiple IV 0. 49 (40%) 17. 722 (36%) 5 to 15 years Multiple IV 0. 59 (64%) 15. 729 (33%) 5 to 15 years Multiple IV 0. 66 (31%) 17. 069 (37%) There are limited data available in patients 61 days to less than 9 months of age. In a study of 13 pediatric patients (preterm and term infants with median gestational age 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 AUC 0-24 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 AUC 0-24 DOSAGE AND ADMINISTRATION A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The C max max Oral contraceptives: Cimetidine: max max Antacid: registered Hydrochlorothiazide: max max PRECAUTIONS Warfarin: PRECAUTIONS PRECAUTIONS max max min max min PRECAUTIONS max max PRECAUTIONS in vitro in vivo CONTRAINDICATIONS PRECAUTIONS. ) Oral hypoglycemics: PRECAUTIONS max max PRECAUTIONS max max PRECAUTIONS max max PRECAUTIONS PRECAUTIONS PRECAUTIONS max max max max max PRECAUTIONS : max tau PRECAUTIONS Tofacitinib: max PRECAUTIONS PRECAUTIONS Mechanism of Action Fluconazole is a highly selective inhibitor of fungal cytochrome P450 dependent enzyme lanosterol 14-alpha-demethylase. This enzyme functions to convert lanosterol to ergosterol. 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. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. Resistance A potential for development of resistance to fluconazole is well known. Fungal isolates exhibiting reduced susceptibility to other azoles may also show reduced susceptibility to fluconazole. The frequency of drug resistance development for the various fungi for which this drug is indicated is not known. Fluconazole resistance may arise from a modification in the quality or quantity of the target enzyme (lanosterol 14-alpha-demethylase), reduced access to the drug target, or some combination of these mechanisms. Point mutations in the gene (ERG11) ERG11 The second major mechanism of drug resistance involves active efflux of fluconazole out of the cell through the activation of two types of multidrug efflux transporters; the major facilitators (encoded by MDR CDR MDR CDR Resistance in Candida glabrata CDR Antimicrobial Activity Fluconazole has been shown to be active against most isolates of the following microorganisms both in vitro Candida albicans Candida glabrata Candida parapsilosis Candida tropicalis Cryptococcus neoformans The following in vitro but their clinical significance is unknown. in vitro Candida dubliniensis Candida guilliermondii Candida kefyr Candida lusitaniae Candida krusei C. krusei Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.
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 (C max In fasted normal volunteers, administration of a single oral 400 mg dose of fluconazole leads to a mean C max The C max DOSAGE AND ADMINISTRATION Table 1: Mean Pharmacokinetic Parameters of Fluconazole in Adult Healthy Volunteers Following the Administration of Fluconazole Tablets *AUC 0-inf. max max 0-24 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 * Relative to concurrent concentrations in plasma in subjects with normal renal function. dagger Tissue or Fluid Ratio of Fluconazole Tissue (Fluid)/Plasma Concentration* Cerebrospinal fluid dagger 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 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 fluconazole may need to be reduced in patients with impaired renal function. (See DOSAGE AND ADMINISTRATION 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.

Fluconazole tablets are indicated for the treatment of: Vaginal candidiasis (vaginal yeast infections due to Candida Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively small numbers of patients, fluconazole tablets were also effective for the treatment of Candida Candida Cryptococcal meningitis cryptococcal meningitis CLINICAL STUDIES Prophylaxis: Fluconazole tablets are also indicated to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy.

DOSAGE AND ADMINISTRATION
Single Dose Vaginal candidiasis: Multiple Dose cryptococcal meningitis Candida Candida cryptococcal meningitis cryptococcal meningitis cryptococcal meningitis 3 3 Oropharyngeal candidiasis: Esophageal candidiasis: Systemic Candida infections: Candida 0-24 Table 6: Recommended Dosing Regimens for the Treatment of Systemic Candida Infections in Pediatric Patients Patient age Dosing regimen 3 months and older A loading dose of 25 mg/kg on the first day (not to exceed 800 mg) followed by 12 mg/kg once daily (not to exceed 400 mg). Birth to 3 months postnatal age and gestational age 30 weeks and above 25 mg/kg on the first day, followed by 12­mg/kg once daily Birth to 3 months postnatal age and gestational age less than 30 weeks 25 mg/kg on the first day, followed by 9­mg/kg once daily Patients with systemic candidiasis should be treated for a minimum of 3 weeks and for at least 2 weeks following the resolution of symptoms. Dosing in Pediatric Patients on ECMO The recommended dosage of fluconazole in pediatric patients 3 months and older on ECMO is 35 mg/kg on the first day (not to exceed 800 mg) followed by 12 mg/kg once daily (not to exceed 400 mg). For patients from birth to 3 months postnatal age, and gestational age less than 30 weeks, a loading dose of 35 mg/kg on the first day followed by 9 mg/kg once daily is recommended. For patients from birth to 3 months postnatal age and gestational age 30 weeks and above, a loading dose of 35 mg/kg on the first day followed by 12 mg/kg once daily is recommended Cryptococcal meningitis: cryptococcal meningitis cryptococcal meningitis cryptococcal meningitis Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust single dose therapy for vaginal candidiasis because of impaired renal function. In patients with impaired renal function who will receive multiple doses of fluconazole tablets, an initial loading dose of 50 mg to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following summary: Creatinine Recommended Dose (%) >50 100 <=50 (no dialysis) 50 Hemodialysis 100% after each hemodialysis Patients on hemodialysis should receive 100% of the recommended dose after each hemodialysis; on non-dialysis days, patients should receive a reduced dose according to their creatinine clearance. Fluconazole tablets are administered orally. Fluconazole tablets can be taken with or without food.
Administration
Fluconazole tablets are administered orally. Fluconazole tablets can be taken with or without food.

ADVERSE REACTIONS
Fluconazole is generally well tolerated. During comparative clinical studies conducted in the United States, 448 patients with vaginal candidiasis were treated with fluconazole, 150 mg single dose. The overall incidence of side effects possibly related to fluconazole was 26%. In 422 patients receiving active comparative agents, the incidence was 16%. The most common treatment-related adverse events reported in the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%), nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion (1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema and anaphylactic reaction have been reported in marketing experience. Sixteen percent of over 4000 patients treated with fluconazole in clinical trials of 7 days or more experienced adverse events. Treatment was discontinued in 1. 5% of patients due to adverse clinical events and in 1. 3% of patients due to laboratory test abnormalities. WARNINGS cryptococcal meningitis Post-Marketing Experience Cardiovascular: PRECAUTIONS Central Nervous System: Hematopoietic Lymphatic: Metabolic: Gastrointestinal: WARNINGS The pattern and incidence of adverse events and laboratory abnormalities recorded during pediatric clinical trials are comparable to those seen in adults. In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients, ages 1 day to 17 years were treated with fluconazole at doses up to 15 mg/kg/day for up to 1,616 days. Thirteen percent of pediatric patients experienced treatment-related adverse events. The most commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea (2%). Treatment was discontinued in 2. 3% of patients due to adverse clinical events and in 1. 4% of patients due to laboratory test abnormalities. The majority of treatment-related laboratory abnormalities were elevations of transaminases or alkaline phosphatase. Percentage of Patients With Treatment-Related Side Effects Fluconazole Comparative Agents (N=577) (N=451) With any side effect 13 9. 3 Vomiting 5. 1 Abdominal pain 2. 6 Diarrhea 2. 2 Clinical Trials Experience in Pediatric Patients Safety in Prophylaxis of Invasive Candida In a Phase 3 clinical trial of pediatric patients (premature infants weighing less than 750 grams at birth), the incidence of intestinal perforation in infants receiving fluconazole prophylaxis was higher compared to infants receiving placebo (see PRECAUTIONS: Pediatric Use Safety in Pediatric Patients Receiving ECMO A cohort of 20 pediatric patients (1 day to 17 years of age) on ECMO received fluconazole in a prospective, open-label, single-center safety and PK ECMO study. The adverse reaction profile of fluconazole in these patients was similar to that of adult and pediatric non-ECMO patients (See PRECAUTIONS: Pediatric Use.
In Patients Receiving a Single Dose for Vaginal Candidiasis:
During comparative clinical studies conducted in the United States, 448 patients with vaginal candidiasis were treated with fluconazole, 150 mg single dose. The overall incidence of side effects possibly related to fluconazole was 26%. In 422 patients receiving active comparative agents, the incidence was 16%. The most common treatment-related adverse events reported in the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%), nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion (1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema and anaphylactic reaction have been reported in marketing experience.
In Patients Receiving Multiple Doses for Other Infections:
Sixteen percent of over 4000 patients treated with fluconazole in clinical trials of 7 days or more experienced adverse events. Treatment was discontinued in 1. 5% of patients due to adverse clinical events and in 1. 3% of patients due to laboratory test abnormalities. WARNINGS cryptococcal meningitis Post-Marketing Experience Cardiovascular: PRECAUTIONS Central Nervous System: Hematopoietic Lymphatic: Metabolic: Gastrointestinal: WARNINGS.
Adverse Reactions in Pediatric Patients:
The pattern and incidence of adverse events and laboratory abnormalities recorded during pediatric clinical trials are comparable to those seen in adults. In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients, ages 1 day to 17 years were treated with fluconazole at doses up to 15 mg/kg/day for up to 1,616 days. Thirteen percent of pediatric patients experienced treatment-related adverse events. The most commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea (2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4% of patients due to laboratory test abnormalities. The majority of treatment-related laboratory abnormalities were elevations of transaminases or alkaline phosphatase. Percentage of Patients With Treatment-Related Side Effects Fluconazole Comparative Agents (N=577) (N=451) With any side effect 13 9.3 Vomiting 5.4 5.1 Abdominal pain 2.8 1.6 Nausea 2.3 1.6 Diarrhea 2.1 2.2 Clinical Trials Experience in Pediatric Patients Safety in Prophylaxis of Invasive Candida In a Phase 3 clinical trial of pediatric patients (premature infants weighing less than 750 grams at birth), the incidence of intestinal perforation in infants receiving fluconazole prophylaxis was higher compared to infants receiving placebo (see PRECAUTIONS: Pediatric Use Safety in Pediatric Patients Receiving ECMO A cohort of 20 pediatric patients (1 day to 17 years of age) on ECMO received fluconazole in a prospective, open-label, single-center safety and PK ECMO study. The adverse reaction profile of fluconazole in these patients was similar to that of adult and pediatric non-ECMO patients (See PRECAUTIONS: Pediatric Use

Fluconazole tablets are contraindicated in patients who have shown hypersensitivity to fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity between fluconazole and other azole antifungal agents. Caution should be used in prescribing fluconazole tablets to patients with hypersensitivity to other azoles. Coadministration of other drugs known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as erythromycin, pimozide, and quinidine are contraindicated in patients receiving fluconazole. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies PRECAUTIONS

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 fluconazole: Table 3: Pharmacokinetic Parameters* of Fluconazole in Pediatric Patients Following the Administration of Fluconazole Tablets * max dss 0-inf 0-24 max dss Age Studied Dose (mg/kg) Clearance (mL/min/kg) Half-life (Hours) C max (mcg/mL) AUC (mcg*h/mL) Vdss (L/kg) 2 to 60 days IV 25 mg/kg on day one followed by IV 12 mg/kg once daily 0.29 (35%) 54.2 23.4 (29%) N=8 439 (25%)^ 1.13 (31%) 9 months to Single-Oral 0.4 (38%) 25 2.9 (22%) N/A 9 months to Single-Oral 0.51 (60%) 19.5 9.8 (20%) N/A 5 to 15 years Multiple IV 0.49 (40%) 17.4 5.5 (25%) 0.722 (36%) 5 to 15 years Multiple IV 0.59 (64%) 15.2 11.4 (44%) 0.729 (33%) 5 to 15 years Multiple IV 0.66 (31%) 17.6 14.1 (22%) 1.069 (37%) There are limited data available in patients 61 days to less than 9 months of age. In a study of 13 pediatric patients (preterm and term infants with median gestational age 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 AUC 0-24 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 AUC 0-24 DOSAGE AND ADMINISTRATION
Pharmacokinetics in Elderly
A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The C max max
Pediatric Studies
Oropharyngeal candidiasis: Fluconazole Nystatin * Enrolled 96 90 Clinical Cure 76/88 (86%) 36/78 (46%) Mycological eradication * 55/72 (76%) 6/54 (11%) The proportion of patients with clinical relapse 2 weeks after the end of treatment was 14% for subjects receiving fluconazole and 16% for subjects receiving nystatin. At 4 weeks after the end of treatment, the percentages of patients with clinical relapse were 22% for fluconazole and 23% for nystatin.
Pregnancy
Potential for Fetal Harm: Use in pregnancy should be avoided except in patients with severe or potentially life-threatening fungal infections in whom fluconazole may be used if the anticipated benefit outweighs the possible risk to the fetus. A few published case reports describe a pattern of distinct congenital anomalies in infants exposed in utero WARNINGS: Potential for Fetal Harm Human Data Case reports describe a distinctive and rare pattern of birth defects among infants whose mothers received high-dose (400 to 800 mg/day) fluconazole during most or all of the first trimester of pregnancy. The features seen in these infants include brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease. These effects are similar to those seen in animal studies. Epidemiological studies suggest a potential risk of spontaneous abortion and congenital abnormalities in infants whose mothers were treated with 150 mg of fluconazole as a single or repeated dose in the first trimester, but these epidemiological studies have limitations and these findings have not been confirmed in controlled clinical trials. Animal Data Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies at doses of 5 mg/kg, 10 mg/kg, and 20 mg/kg and at 5 mg/kg, 25 mg/kg, and 75 mg/kg, respectively. Maternal weight gain was impaired at all dose levels (approximately 0.25 to 4 times the 400 mg clinical dose based on body surface area [BSA] comparison), and abortions occurred at 75 mg/kg (approximately 4 times the 400 mg clinical dose based on BSA); no adverse fetal effects were observed. In several studies in which pregnant rats received fluconazole orally during organogenesis, maternal weight gain was impaired and placental weights were increased at 25 mg/kg. There were no fetal effects at 5 mg/kg or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 mg/kg and 50 mg/kg and higher doses. At doses ranging from 80 to 320 mg/kg (approximately 2 to 8 times the 400 mg clinical dose based on BSA), embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate, and abnormal craniofacial ossification. These effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of known effects of lowered estrogen on pregnancy, organogenesis, and parturition.
Nursing Mothers
Fluconazole was present in low levels in breast milk following administration of a single 150 mg dose, based on data from a study in 10 breastfeeding women who temporarily or permanently discontinued breastfeeding 5 days to 19 months postpartum. The estimated daily infant dose of fluconazole from breast milk (assuming mean milk consumption of 150 mL/kg/day) based on the mean peak milk concentration (2.61 mcg/mL [range: 1.57 to 3.65 mcg/mL] at 5.2 hours post-dose) was 0.39 mg/kg/day, which is approximately 13% of the recommended pediatric dose for oropharyngeal candidiasis. (Labeled pediatric dose is 6 mg/kg/day on the first day followed by 3 mg/kg/day; estimated infant dose is 13% of 3 mg/kg/day maintenance dose). There are no data on fluconazole levels in milk after repeated use or after high-dose fluconazole. A published survey of 96 breastfeeding women who were treated with fluconazole 150 mg every other day (average of 7.3 capsules [range 1 to 29 capsules]) for lactation-associated candida of the breasts reported no serious adverse reactions in infants. Caution should be exercised when fluconazole is administered to a nursing woman.
Pediatric Use
Use in Pediatric Patients for the Treatment of Oropharyngeal Candidiasis An open-label, randomized, controlled trial has shown fluconazole to be effective in the treatment of oropharyngeal candidiasis in pediatric patients 6 months to 13 years of age. (See CLINICAL STUDIES Use in Pediatric Patients for the Treatment of Candida Candida The use of fluconazole in pediatric patients with cryptococcal meningitis Candida Candida CLINICAL PHARMACOLOGY DOSAGE AND ADMINISTRATION In a noncomparative study of fluconazole administered to pediatric patients (from birth to less than 17 years) with serious systemic fungal infections, most of which were candidemia, the effectiveness of fluconazole was similar to that reported for the treatment of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with baseline symptoms (3 were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients had a mycologic cure at the end of treatment but two of these patients relapsed at 10 and 18 days, respectively, following cessation of therapy. The efficacy of fluconazole for the suppression of cryptococcal meningitis There are limited clinical data to support the efficacy of fluconazole for the primary treatment of cryptococcal meningitis The safety profile of fluconazole has been studied in 577 pediatric patients from 1 day to 17 years of age who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. (See ADVERSE REACTIONS Use in Pediatric Patients on Extracorporeal Membrane Oxygenation (ECMO) A prospective, open-label, single-center study was conducted to determine the PK and safety of fluconazole in pediatric patients (ages: from birth to 17 years of age) on ECMO (see CLINICAL PHARMACOLOGY DOSAGE AND ADMINISTRATION Use in Prophylaxis of Invasive Candida A prospective, randomized, double-blind, placebo-controlled, multicenter trial was conducted in premature infants weighing less than 750 grams at birth to evaluate the efficacy and safety of prophylactic fluconazole 6 mg/kg administered twice weekly for 6 weeks versus placebo (NCT00734539). Efficacy was assessed using the endpoint of death or candidiasis by study day 49. The results are summarized in Table 4. Table 4: Death or Candidiasis by Day 49 in Premature Infants Receiving Fluconazole Prophylaxis * Subjects with missing data are imputed as having candidiasis or died. Fluconazole (N=188) n (%) Placebo (N=173) n (%) P-value Difference (95% CI) Death or candidiasis* 33 (17.6) 38 (22.0) 0.2954 -4.4(-12.6, 3.8) Components of endpoint** The most common serious adverse reactions (>5%), reported in patients receiving fluconazole prophylaxis are displayed in Table 5. Table 5. Serious Adverse Reactions* Occurring in >5% of Infants Receiving Fluconazole Prophylaxis *All serious adverse reactions were assessed and recorded up through 30 days after the final dose of study drug. Serious adverse reactions included both fatal and non-fatal outcomes. Adverse Reaction Fluconazole (N=188) n(%) Placebo (N=173) n (%) Necrotizing Enterocolitis (NEC) 27 (14) 28 (16) Intestinal Perforation (includes ileal/small intestinal perforation) 13 (7) 7 (4) Neonatal Respiratory Arrest/Neonatal Respiratory Failure 13 (7) 4 (2) Bacterial Sepsis, Neonatal 10 (5) 12 (7)
Geriatric Use
In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in fewer patients aged 65 and older (9%, n =339) than for younger patients (14%, n=2240). However, there was no consistent difference between the older and younger patients with respect to individual side effects. Of the most frequently reported (>1%) side effects, rash, vomiting, and diarrhea occurred in greater proportions of older patients. Similar proportions of older patients (2.4%) and younger patients (1.5%) discontinued fluconazole therapy because of side effects. In post-marketing experience, spontaneous reports of anemia and acute renal failure were more frequent among patients 65 years of age or older than in those between 12 and 65 years of age. Because of the voluntary nature of the reports and the natural increase in the incidence of anemia and renal failure in the elderly, it is however not possible to establish a causal relationship to drug exposure. CLINICAL PHARMACOLOGY DOSAGE AND ADMINISTRATION

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CLINICAL STUDIES
Cryptococcal meningitis: cryptococcal meningitis 3 cryptococcal meningitis et al Candida Fluconazole Vaginal Product Enrolled 448 422 Evaluable at Late Follow-up 347 (77%) 327 (77%) Clinical cure 239/347 (69%) 235/327 (72%) Mycologic eradication 213/347 (61%) 196/327 (60%) Therapeutic cure 190/347 (55%) 179/327 (55%) Approximately three-fourths of the enrolled patients had acute vaginitis (<4 episodes/12 months) and achieved 80% clinical cure, 67% mycologic eradication, and 59% therapeutic cure when treated with a 150 mg fluconazole tablet administered orally. These rates were comparable to control products. The remaining one-fourth of enrolled patients had recurrent vaginitis (>=4 episodes/12 months) and achieved 57% clinical cure, 47% mycologic eradication, and 40% therapeutic cure. The numbers are too small to make meaningful clinical or statistical comparisons with vaginal products in the treatment of patients with recurrent vaginitis. Parameter Fluconazole Vaginal Evaluable patients 448 422 With any adverse event 141 (31%) 112 (27%) Nervous System 90 (20%) 69 (16%) Gastrointestinal 73 (16%) 18 (4%) With drug-related event 117 (26%) 67 (16%) Nervous System 61 (14%) 29 (7%) Headache 58 (13%) 28 (7%) Gastrointestinal 68 (15%) 13 (3%) Abdominal pain 25 (6%) 7 (2%) Nausea 30 (7%) 3 (1%) Diarrhea 12 (3%) 2 (<1%) Application site event 0 (0%) 19 (5%) Taste Perversion 6 (1%) 0 (0%) Oropharyngeal candidiasis: Fluconazole Nystatin * Enrolled 96 90 Clinical Cure 76/88 (86%) 36/78 (46%) Mycological eradication * 55/72 (76%) 6/54 (11%) The proportion of patients with clinical relapse 2 weeks after the end of treatment was 14% for subjects receiving fluconazole and 16% for subjects receiving nystatin. At 4 weeks after the end of treatment, the percentages of patients with clinical relapse were 22% for fluconazole and 23% for nystatin.
WARNINGS
(1) Hepatic injury: Fluconazole should be administered with caution to patients with liver dysfunction. Fluconazole has been associated with rare cases of serious hepatic toxicity, including fatalities primarily in patients with serious underlying medical conditions. In cases of fluconazole-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex, or age of the patient has been observed. Fluconazole hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during fluconazole therapy should be monitored for the development of more severe hepatic injury. Fluconazole should be discontinued if clinical signs and symptoms consistent with liver disease develop that may be attributable to fluconazole. (2) Anaphylaxis: In rare cases, anaphylaxis has been reported. (3) Dermatologic: Exfoliative skin disorders during treatment with fluconazole have been reported. Fatal outcomes have been reported in patients with serious underlying diseases. Patients with deep seated fungal infections who develop rashes during treatment with fluconazole should be monitored closely and the drug discontinued if lesions progress. Fluconazole should be discontinued in patients treated for superficial fungal infection who develop a rash that may be attributed to fluconazole. in utero PRECAUTIONS: Pregnancy
Carcinogenesis,Mutagenesis, and Impairment of Fertility
Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5 mg/kg/day, 5 mg/kg/day, or 10 mg/kg/day (approximately 2 to 7 times the recommended human dose). Male rats treated with 5 mg/kg/day and 10 mg/kg/day had an increased incidence of hepatocellular adenomas. S. typhimurium, in vivo in vitro CLINICAL PHARMACOLOGY
OVERDOSAGE
There have been reports of overdose with fluconazole accompanied by hallucination and paranoid behavior.

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