FLUCONAZOLE- fluconazole_powder, for suspension

CLINICAL PHARMACOLOGY
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. 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 Tissue or Fluid Ratio of Fluconazole Tissue (Fluid)/Plasma Concentration Relative to concurrent concentrations in plasma in subjects with normal renal function. Cerebrospinal fluid Independent of degree of meningeal inflammation. 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 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. 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 children, the following pharmacokinetic data {Mean (%cv)} have been reported: Age Studied Dose Clearance Half-life Cmax Vdss 9 monthsen dash13 years Single-Oral 0. 40 (38%) 25. 9 (22%) ___ 9 monthsen dash13 years Single-Oral 0. 51 (60%) 19. 8 (20%) ___ 5en dash15 years Multiple IV 0. 49 (40%) 17. 722 (36%) 5en dash15 years Multiple IV 0. 59 (64%) 15. 729 (33%) 5en dash15 years Multiple IV 0. 66 (31%) 17. 069 (37%) 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. 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: In a second study, twenty-five normal females received daily doses of both 200 mg fluconazole tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all subjects receiving fluconazole during one cycle and placebo during the other. The order of study treatment was random. Single doses of an oral contraceptive tablet containing levonorgestrel and ethinyl estradiol were administered on the final treatment day (Day 10) of both cycles. Following administration of 200 mg of fluconazole, the mean percentage increase of AUC for levonorgestrel compared to placebo was 25% (range: en dash12 to 82%) and the mean percentage increase for ethinyl estradiol compared to placebo was 38% (range: en dash11 to 101%). Both of these increases were statistically significantly different from placebo. max max registered max max PRECAUTIONS PRECAUTIONS PRECAUTIONS max max min max min PRECAUTIONS max max PRECAUTIONS in vitro in vivo CONTRAINDICATIONS PRECAUTIONS PRECAUTIONS max max PRECAUTIONS max max PRECAUTIONS max max PRECAUTIONS PRECAUTIONS PRECAUTIONS max max max max max PRECAUTIONS max PRECAUTIONS. max PRECAUTIONS. PRECAUTIONS 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 Candida krusei C. krusei There have been reports of cases of superinfection with Candida C. albicans Candida krusei 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 in vitro but their clinical significance is unknown. in vitro Candida guilliermondii Candida kefyr Candida lusitaniae Candida krusei C. albicans, Candida 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 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. 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 Tissue or Fluid Ratio of Fluconazole Tissue (Fluid)/Plasma Concentration Relative to concurrent concentrations in plasma in subjects with normal renal function. Cerebrospinal fluid Independent of degree of meningeal inflammation. 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 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. 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 children, the following pharmacokinetic data {Mean (%cv)} have been reported: Age Studied Dose Clearance Half-life Cmax Vdss 9 monthsen dash13 years Single-Oral 0. 40 (38%) 25. 9 (22%) ___ 9 monthsen dash13 years Single-Oral 0. 51 (60%) 19. 8 (20%) ___ 5en dash15 years Multiple IV 0. 49 (40%) 17. 722 (36%) 5en dash15 years Multiple IV 0. 59 (64%) 15. 729 (33%) 5en dash15 years Multiple IV 0. 66 (31%) 17. 069 (37%) 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. 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.

Fluconazole for oral suspension is indicated for the treatment of: Candida Candida Cryptococcal meningitis cryptococcal meningitis CLINICAL STUDIES

DOSAGE AND ADMINISTRATION
SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF FLUCONAZOLE IS THE SAME FOR ORAL (TABLETS AND SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of twice the daily dose is recommended on the first day of therapy to result in plasma concentrations close to steady-state by the second day of therapy. cryptococcal meningitis : : : Candida : Candida : cryptococcal meningitis cryptococcal meningitis cryptococcal meningitis : 3 3 The following dose equivalency scheme should generally provide equivalent exposure in pediatric and adult patients: Pediatric Patients Adults 3 mg/kg 100 mg 6 mg/kg 200 mg 12 Some older children may have clearances similar to that of adults. Absolute doses exceeding 600 mg/day are not recommended. 400 mg Experience with fluconazole for oral suspension in neonates is limited to pharmacokinetic studies in premature newborns. (See CLINICAL PHARMACOLOGY : : : Candida cryptococcal meningitis cryptococcal meningitis cryptococcal meningitis Fluconazole is cleared primarily by renal excretion as unchanged drug. In patients with impaired renal function who will receive multiple doses of fluconazole for oral suspension, 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 table: Creatinine Clearance (mL/min) 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. These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses. Further adjustment may be needed depending upon clinical condition. Weight (kg) x (140 en dash age) linear length or height (cm) Fluconazole for oral suspension is administered orally. Fluconazole for oral suspension can be taken with or without food. Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely. To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The concentrations of the reconstituted suspensions are as follows: Fluconazole Content per Bottle Concentration of Reconstituted Suspension 1400 mg 40 mg/mL Note: Shake oral suspension well before using. Store reconstituted suspension between 30°C (86°F) and 5°C (41°F) and discard unused portion after 2 weeks. Protect from freezing.
Administration
Fluconazole for oral suspension is administered orally. Fluconazole for oral suspension can be taken with or without food.
Directions for Mixing the Oral Suspension
Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely. To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The concentrations of the reconstituted suspensions are as follows: Fluconazole Content per Bottle Concentration of Reconstituted Suspension 1400 mg 40 mg/mL Note: Shake oral suspension well before using. Store reconstituted suspension between 30°C (86°F) and 5°C (41°F) and discard unused portion after 2 weeks. Protect from freezing.

ADVERSE REACTIONS
Fluconazole is generally well tolerated. 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. Hepato-biliary: WARNINGS cryptococcal meningitis In addition, the following adverse events have occurred during post-marketing experience. Body as a Whole: Cardiovascular: PRECAUTIONS Hematopoietic Lymphatic: Metabolic: WARNINGS The pattern and incidence of adverse events and laboratory abnormalities recorded during pediatric clinical trials are comparable to those seen in adults. Percentage of Patients With Treatment-Related Side Effects Fluconazole Comparative Agents With any side effect 13. 3 Vomiting 5. 1 Abdominal pain 2. 6 Diarrhea 2.
In Patients Receiving Multiple Doses:
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. Hepato-biliary: WARNINGS cryptococcal meningitis
Post-Marketing Experience
In addition, the following adverse events have occurred during post-marketing experience. Body as a Whole: Cardiovascular: PRECAUTIONS Hematopoietic Lymphatic: Metabolic: WARNINGS
Adverse Reactions in Children:
The pattern and incidence of adverse events and laboratory abnormalities recorded during pediatric clinical trials are comparable to those seen in adults. Percentage of Patients With Treatment-Related Side Effects Fluconazole Comparative Agents With any side effect 13.0 9.3 Vomiting 5.4 5.1 Abdominal pain 2.8 1.6 Nausea 2.3 1.6 Diarrhea 2.1 2.2

Fluconazole for oral suspension is 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 for oral suspension 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 for oral suspension. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies PRECAUTIONS

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
An open-label, randomized, controlled trial has shown fluconazole to be effective in the treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. (See CLINICAL STUDIES cryptococcal meningitis Candida Candida CLINICAL PHARMACOLOGY DOSAGE AND ADMINISTRATION cryptococcal meningitis cryptococcal meningitis ADVERSE REACTIONS CLINICAL PHARMACOLOGY
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

Oral contraceptives: In a second study, twenty-five normal females received daily doses of both 200 mg fluconazole tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all subjects receiving fluconazole during one cycle and placebo during the other. The order of study treatment was random. Single doses of an oral contraceptive tablet containing levonorgestrel and ethinyl estradiol were administered on the final treatment day (Day 10) of both cycles. Following administration of 200 mg of fluconazole, the mean percentage increase of AUC for levonorgestrel compared to placebo was 25% (range: en dash12 to 82%) and the mean percentage increase for ethinyl estradiol compared to placebo was 38% (range: en dash11 to 101%). Both of these increases were statistically significantly different from placebo. max max registered max max PRECAUTIONS PRECAUTIONS PRECAUTIONS max max min max min PRECAUTIONS max max PRECAUTIONS in vitro in vivo CONTRAINDICATIONS PRECAUTIONS PRECAUTIONS max max PRECAUTIONS max max PRECAUTIONS max max PRECAUTIONS PRECAUTIONS PRECAUTIONS max max max max max PRECAUTIONS max PRECAUTIONS . max PRECAUTIONS . PRECAUTIONS

Before reconstitured: Store dry powder at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. registered registered registered Hainan Poly Pharm Co., Ltd.

CLINICAL STUDIES
Cryptococcal meningitis: cryptococcal meningitis 3 cryptococcal meningitis et al Pediatric Studies Oropharyngeal candidiasis: Fluconazole Nystatin Enrolled 96 90 Clinical Cure 76/88 (86%) 36/78 (46%) Mycological eradication Subjects without follow-up cultures for any reason were considered nonevaluable for mycological response. 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. (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. (4) Potential for fetal harm: There are no adequate and well-controlled clinical trials of fluconazole in pregnant women. Case reports describe a pattern of distinct congenital anomalies in infants exposed 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. Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in four strains of S. typhimurium, in vivo in vitro Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5 mg/kg, 10 mg/kg, or 20 mg/kg or with parenteral doses of 5 mg/kg, 25 mg/kg, or 75 mg/kg, although the onset of parturition was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5 mg/kg, 20 mg/kg, and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg (approximately 5 to 15 times the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The disturbances in parturition were reflected by a slight increase in the number of still born pups and decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent with the species specific estrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole. (See CLINICAL PHARMACOLOGY
OVERDOSAGE
There have been reports of overdose with fluconazole accompanied by hallucination and paranoid behavior.

Hainan Poly Pharm. Co., Ltd.

• Founded in:

  1992-07-14

• Address:

  Guilinyang Economic Development Zone, Meilan District, Haikou City

• Tax NO.:

  91460000620000247L

• Registered Funds:

  448.350021 million yuan

• Website:

  Log in to view

• Email:

  Log in to view

FLUCONAZOLE- fluconazole_powder, for suspension Product manual source documgent