flucytosine 500 MG Oral Capsule [Ancobon]

INDICATIONS AND USAGE Flucytosine Capsules, USP are indicated only in the treatment of serious infections caused by susceptible strains of Candida and/or Cryptococcus . Candida: Septicemia, endocarditis and urinary system infections have been effectively treated with flucytosine. Limited trials in pulmonary infections justify the use of flucytosine. Cryptococcus: Meningitis and pulmonary infections have been treated effectively. Studies in septicemias and urinary tract infections are limited, but good responses have been reported. Flucytosine Capsules, USP should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis because of the emergence of resistance to Flucytosine Capsules, USP (see MICROBIOLOGY ).

DOSAGE AND ADMINISTRATION The usual dosage of Flucytosine Capsules, USP is 50 to 150 mg/kg/day administered in divided doses at 6-hour intervals. Nausea or vomiting may be reduced or avoided if the capsules are given a few at a time over a 15-minute period. If the BUN or the serum creatinine is elevated, or if there are other signs of renal impairment, the initial dose should be at the lower level (see WARNINGS ). Flucytosine Capsules, USP should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis because of the emergence of resistance to Flucytosine Capsules, USP (see MICROBIOLOGY ).

WARNINGS Flucytosine Capsules USP must be given with extreme caution to patients with impaired renal function. Since Flucytosine Capsules USP is excreted primarily by the kidneys, renal impairment may lead to accumulation of the drug. Flucytosine Capsules USP serum concentrations should be monitored to determine the adequacy of renal excretion in such patients. Dosage adjustments should be made in patients with renal insufficiency to prevent progressive accumulation of active drug. Flucytosine Capsules USP must be given with extreme caution to patients with bone marrow depression. Patients may be more prone to depression of bone marrow function if they: 1) have a hematologic disease, 2) are being treated with radiation or drugs which depress bone marrow, or 3) have a history of treatment with such drugs or radiation. Bone marrow toxicity can be irreversible and may lead to death in immunosuppressed patients. Frequent monitoring of hepatic function and of the hematopoietic system is indicated during therapy. 5-Fluorouracil is a metabolite of flucytosine. Dihydropyrimidine dehydrogenase is a key enzyme involved in the metabolism and elimination of 5-fluorouracil. Therefore, the risk of severe drug toxicity is increased when Flucytosine Capsules, USP is used in individuals with deficiency in DPD. Possible drug toxicities include mucositis, diarrhea, neutropenia, and neurotoxicity. Determination of DPD activity may be considered where drug toxicity is confirmed or suspected. In the event of suspected drug toxicity, consider stopping Flucytosine Capsules USP, treatment.

CONTRAINDICATIONS Flucytosine Capsules, USP is contraindicated in patients with a known hypersensitivity to the drug. Flucytosine Capsules, USP is contraindicated in patients with known complete dihydropyrimidine dehydrogenase (DPD) enzyme deficiency (see WARNINGS ).

CLINICAL PHARMACOLOGY Flucytosine is rapidly and virtually completely absorbed following oral administration. Flucytosine Capsules USP is not metabolized significantly when given orally to man. Bioavailability estimated by comparing the area under the curve of serum concentrations after oral and intravenous administration showed 78% to 89% absorption of the oral dose. Peak serum concentrations of 30 to 40 mcg/mL were reached within 2 hours of administration of a 2 g oral dose to normal subjects. Other studies revealed mean serum concentrations of approximately 70 to 80 mcg/mL 1 to 2 hours after a dose in patients with normal renal function receiving a 6-week regimen of flucytosine (150 mg/kg/day given in divided doses every 6 hours) in combination with amphotericin B. The half-life in the majority of healthy subjects ranged between 2.4 and 4.8 hours. Flucytosine is excreted via the kidneys by means of glomerular filtration without significant tubular reabsorption. More than 90% of the total radioactivity after oral administration was recovered in the urine as intact drug. Flucytosine is deaminated (probably by gut bacteria) to 5-fluorouracil. The area under the curve (AUC) ratio of 5-fluorouracil to flucytosine is 4%. Approximately 1% of the dose is present in the urine as the α-fluoro-β-ureido-propionic acid metabolite. A small portion of the dose is excreted in the feces. The half-life of flucytosine is prolonged in patients with renal insufficiency; the average half-life in nephrectomized or anuric patients was 85 hours (range: 29.9 to 250 hours). A linear correlation was found between the elimination rate constant of flucytosine and creatinine clearance. In vitro studies have shown that 2.9% to 4% of flucytosine is protein-bound over the range of therapeutic concentrations found in the blood. Flucytosine readily penetrates the blood-brain barrier, achieving clinically significant concentrations in cerebrospinal fluid. Pharmacokinetics in Pediatric Patients Limited data are available regarding the pharmacokinetics of Flucytosine Capsules USP administered to neonatal patients being treated for systemic candidiasis. After five days of continuous therapy, median peak levels in infants were 19.6 mcg/mL, 27.7 mcg/mL, and 83.9 mcg/mL at doses of 25 mg/kg (N=3), 50 mg/kg (N=4), and 100 mg/kg (N=3), respectively. Mean time to peak serum levels was of 2.5 ± 1.3 hours, similar to that observed in adult patients. A good deal of interindividual variability was noted, which did not correlate with gestational age. Some patients had serum levels > 100 mcg/mL, suggesting a need for drug level monitoring during therapy. In another study, serum concentrations were determined during flucytosine therapy in two patients (total assays performed =10). Median serum flucytosine concentrations at steady state were calculated to be 57 ± 10 mcg/mL (doses of 50 to 125 mg/kg/day, normalized to 25 mg/kg per dose for comparison). In three infants receiving flucytosine 25 mg/kg/day (four divided doses), a median flucytosine half-life of 7.4 hours was observed, approximately double that seen in adult patients. The concentration of flucytosine in the cerebrospinal fluid of one infant was 43 mcg/mL 3 hours after a 25 mg oral dose, and ranged from 20 to 67 mg/L in another neonate receiving oral doses of 120 to 150 mg/kg/day. MICROBIOLOGY Mechanism of Action Flucytosine is taken up by fungal organisms via the enzyme cytosine permease. Inside the fungal cell, flucytosine is rapidly converted to fluorouracil by the enzyme cytosine deaminase. Fluorouracil exerts its antifungal activity through the subsequent conversion into several active metabolites, which inhibit protein synthesis by being falsely incorporated into fungal RNA or interfere with the biosynthesis of fungal DNA through the inhibition of the enzyme thymidylate synthetase. Activity In Vitro Flucytosine has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections. Candida albicans Cryptococcus neoformans 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.fda.gov/STIC. Drug Resistance Flucytosine resistance may arise from a mutation of an enzyme necessary for the cellular uptake or metabolism of flucytosine or from an increased synthesis of pyrimidines, which compete with the active metabolites of flucytosine (fluorinated antimetabolites). Resistance to flucytosine has been shown to develop during monotherapy after prolonged exposure to the drug. Drug Combination Antifungal synergism between flucytosine and polyene antibiotics, particularly amphotericin B has been reported in vitro. Flucytosine Capsules USP is usually administered in combination with amphotericin B due to lack of cross-resistance and reported synergistic activity of both drugs.