Fluconazole 200 MG Oral Tablet
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.
(4) Use in Pregnancy: There are no adequate and well-controlled studies of fluconazole in pregnant women.
Available human data do not suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg.
A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole (400-800 mg/day) during most or all of the first trimester.
These reported anomalies are similar to those seen in animal studies.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus.
(See PRECAUTIONS, Pregnancy )
OVERDOSAGE
There have been reports of overdose with fluconazole accompanied by hallucination and paranoid behavior.
In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if clinically indicated) should be instituted.
Fluconazole is largely excreted in urine.
A three-hour hemodialysis session decreases plasma levels by approximately 50%.
In mice and rats receiving very high doses of fluconazole, clinical effects in both species included decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence, loss of righting reflex and cyanosis; death was sometimes preceded by clonic convulsions.
DESCRIPTION
Fluconazole USP, the first of a new subclass of synthetic triazole antifungal agents, is available as tablets for oral administration.
Fluconazole USP is designated chemically as 2,4-difluoro-α,α1-bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol with an empirical formula of C13H12F2N6O and molecular weight of 306.3.
The structural formula is: Fluconazole USP is a white crystalline solid which is slightly soluble in water and saline.
Fluconazole tablets USP contain 50, 100, 150, or 200 mg of fluconazole USP and the following inactive ingredients: croscarmellose sodium, dibasic calcium phosphate anhydrous, FD&C Red No.
40 aluminum lake dye, magnesium stearate, microcrystalline cellulose and povidone.
Fluconazole Chemical Structure
CLINICAL STUDIES
Cryptococcal meningitis: In a multicenter study comparing fluconazole (200 mg/day) to amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS, a multivariate analysis revealed three pretreatment factors that predicted death during the course of therapy: abnormal mental status, cerebrospinal fluid cryptococcal antigen titer greater than 1:1024, and cerebrospinal fluid white blood cell count of less than 20 cells/mm3.
Mortality among high risk patients was 33% and 40% for amphotericin B and fluconazole patients, respectively (p=0.58), with overall deaths 14% (9 of 63 subjects) and 18% (24 of 131 subjects) for the 2 arms of the study (p=0.48).
Optimal doses and regimens for patients with acute cryptococcal meningitis and at high risk for treatment failure remain to be determined.
(Saag, et al.
N Engl JMed 1992; 326:83-9.) Vaginal candidiasis: Two adequate and well-controlled studies were conducted in the U.S.
usingthe 150 mg tablet.
In both, the results of the fluconazole regimen were comparable to the control regimen (clotrimazole or miconazole intravaginally for 7 days) both clinically and statistically at the one month post-treatment evaluation.
The therapeutic cure rate, defined as a complete resolution of signs and symptoms of vaginal candidiasis (clinical cure), along with a negative KOH examination and negative culture for Candida (microbiologic eradication),was 55% in both the fluconazole group and the vaginal products group.
Fluconazole PO 150 mg tablet Vaginal Product qhs x 7 days 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.
Substantially more gastrointestinal events were reported in the fluconazole group compared to the vaginal product group.
Most of the events were mild to moderate.
Because fluconazole was given as a single dose, no discontinuations occurred.
Parameter Fluconazole PO Vaginal Products 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%) Pediatric Studies Oropharyngeal candidiasis: An open-label, comparative study of the efficacy and safety of fluconazole (2-3 mg/kg/day) and oral nystatin (400,000 I.U.
4 times daily) in immunocompromised children with oropharyngeal candidiasis was conducted.
Clinical and mycological response rates were higher in the children treated with fluconazole.
Clinical cure at the end of treatment was reported for 86% of fluconazole treated patients compared to 46% of nystatin treated patients.
Mycologically, 76% of fluconazole treated patients had the infecting organism eradicated compared to 11% for nystatin treated patients.
Fluconazole Nystatin Enrolled 96 90 Clinical Cure 76/88 (86%) 36/78 (46%) Mycological eradication* 55/72 (76%) 6/54 (11%) * Subjects without follow-up cultures for any reason were considered nonevaluable for mycological response.
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
HOW SUPPLIED
NDC:50090-0947-1 30 TABLET in a BOTTLE NDC:50090-0947-3 2 TABLET in a BOTTLE
GERIATRIC USE
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 casual relationship to drug exposure.
Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 65 and older to evaluate whether they respond differently from younger patients in each indication.
Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
Fluconazole is primarily cleared by renal excretion as unchanged drug.
Because elderly patients are more likely to have decreased renal function, care should be taken to adjust dose based on creatinine clearance.
It may be useful to monitor renal function.
(See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
MECHANISM OF ACTION
Mechanism of Action Fluconazole is a highly selective inhibitor of fungal cytochrome P450 dependent enzyme lanosterol 14-α-demethylase.
This enzyme functions to convert lanosterol to ergosterol.
The subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole.
Mammalian cell demethylation is much less sensitive to fluconazole inhibition.
INDICATIONS AND USAGE
Fluconazole tablets USP are indicated for the treatment of: 1.Vaginal candidiasis (vaginal yeast infections due to Candida).
2.Oropharyngeal and esophageal candidiasis.
In open noncomparative studies of relatively small numbers of patients, fluconazole was also effective for the treatment of Candida urinary tract infections, peritonitis, and systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia.
3.Cryptococcal meningitis.
Before prescribing fluconazole tablets USP for AIDS patients with cryptococcal meningitis, please see CLINICAL STUDIES section.
Studies comparing fluconazole to amphotericin B in non-HIV infected patients have not been conducted.
Prophylaxis.
Fluconazole tablets USP are also indicated to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy.
Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms.
Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.
PEDIATRIC USE
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.) The use of fluconazole in children with cryptococcal meningitis, Candida esophagitis, or systemic Candida infections is supported by the efficacy shown for these indications in adults and by the results from several small noncomparative pediatric clinical studies.
In addition, pharmacokinetic studies in children (see CLINICAL PHARMACOLOGY ) have established a dose proportionality between children and adults.
(See DOSAGE AND ADMINISTRATION.) In a noncomparative study of children 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 was successful in 4 of 5 children treated in a compassionate-use study of fluconazole for the treatment of life-threatening or serious mycosis.
There is no information regarding the efficacy of fluconazole for primary treatment of cryptococcal meningitis in children.
The safety profile of fluconazole in children has been studied in 577 children ages 1 day to 17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days.
(See ADVERSE REACTIONS.) Efficacy of fluconazole has not been established in infants less than 6 months of age.
(See CLINICAL PHARMACOLOGY.) A small number of patients (29) ranging in age from 1 day to 6 months have been treated safely with fluconazole.
PREGNANCY
Pregnancy Teratogenic Effects.
Pregnancy Category C: Single 150 mg tablet use for Vaginal Candidiasis: There are no adequate and well-controlled studies of fluconazole in pregnant women.
Available human data do not suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg.
Pregnancy Category D: All other indications: A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole (400-800 mg/day) during most or all of the first trimester.
These reported anomalies are similar to those seen in animal studies.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus.
(See WARNINGS , Use in Pregnancy) Human Data Several published epidemiologic studies do not suggest an increased risk of congenital anomalies associated with low dose exposure to fluconazole in pregnancy (most subjects received a single oral dose of 150 mg).
A few published case reports describe a distinctive and rare pattern of birth defects among infants whose mothers received high-dose (400-800 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.
Animal Data Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies at doses of 5, 10, and 20 mg/kg and at 5, 25, 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 BSA), 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 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 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 cranio-facial 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.
NUSRING MOTHERS
Nursing Mothers Fluconazole is secreted in human milk at concentrations similar to maternal plasma concentrations.
Caution should be exercised when fluconazole is administered to a nursing woman.
DOSAGE AND ADMINISTRATION
Dosage and Administration in Adults: Single Dose Vaginal candidiasis: The recommended dosage of fluconazole for vaginal candidiasis is150 mg as a single oral dose.
Multiple Dose SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF FLUCONAZOLE IS THE SAME FOR ORAL TABLETS 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.
The daily dose of fluconazole for the treatment of infections other than vaginal candidiasis should be based on the infecting organism and the patient’s response to therapy.
Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided.
An inadequate period of treatment may lead to recurrence of active infection.
Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse.
Oropharyngeal candidiasis: The recommended dosage of fluconazole for oropharyngealcandidiasis is 200 mg on the first day, followed by 100 mg once daily.
Clinical evidence of oropharyngeal candidiasis generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse.
Esophageal candidiasis: The recommended dosage of fluconazole for esophageal candidiasis is 200 mg on the first day, followed by 100 mg once daily.
Doses up to 400 mg/day may be used, based on medical judgment of the patient’s response to therapy.
Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms.
Systemic Candida infections: For systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy have not been established.
In open, noncomparative studies of small numbers of patients, doses of up to 400 mg daily have been used.
Urinary tract infections and peritonitis: For the treatment of Candida urinary tract infections and peritonitis, daily doses of 50-200 mg have been used in open, noncomparative studies of small numbers of patients.
Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily.
A dosage of 12 mg/kg once daily may be used, based on medical judgment of the patient’s response to therapy.
The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks after the cerebrospinal fluid becomes culture negative.
For suppression of relapse of cryptococcal meningitis in children with AIDS, the recommended dose of fluconazole is 6 mg/kg once daily.
Dosage In Patients With Impaired Renal Function: 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, an initial loading dose of 50 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) Percent of Recommended Dose >50 100% ≤50 (no dialysis) 50% Regular dialysis 100% after each dialysis Patients on regular dialysis should receive 100% of the recommended dose after each dialysis; 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.
When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance in adults: Males: Weight (kg) × (140 – age) 72 × serum creatinine (mg/100 mL) Females: 0.85 × above value Although the pharmacokinetics of fluconazole has not been studied in children with renal insufficiency, dosage reduction in children with renal insufficiency should parallel that recommended for adults.
The following formula may be used to estimate creatinine clearance in children: K × linear length or height (cm) serum creatinine (mg/100 mL) (Where K=0.55 for children older than 1 year and 0.45 for infants.) Administration Fluconazole is administered orally.
Fluconazole can be taken with or without food.