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WARNINGUse with extreme caution in patients with impaired renal function. Close monitoring of hematologic, renal and hepatic status of all patients is essential. These instructions should be thoroughly reviewed before administration of Ancobon. |
Ancobon (flucytosine), an antifungal agent, is available as 250-mg and 500-mg capsules for oral administration. Each capsule also contains corn starch, lactose and talc. Gelatin capsule shells contain parabens (butyl, methyl, propyl) and sodium propionate, with the following dye systems: 250-mg capsules--black iron oxide, FD&C Blue No. 1, FD&C Yellow No. 6, D&C Yellow No. 10 and titanium dioxide; 500-mg capsules--black iron oxide and titanium dioxide. Chemically, flucytosine is 5-fluorocytosine, a fluorinated pyrimidine which is related to fluorouracil and floxuridine. It is a white to off-white crystalline powder with a molecular weight of 129.09 and the following structural formula:
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Flucytosine is rapidly and virtually completely absorbed following oral administration. 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 blood concentrations of 30 to 40 mcg/mL were reached within 2 hours of administration of a 2-gm oral dose to normal subjects. The mean blood concentrations were approximately 70 to 80 mcg/mL 1 to 2 hours after a dose in patients with normal renal function who received 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 normal 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. Approximately 1% of the dose is present in the urine as the (alpha)-fluoro-(beta)-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. Studies in pregnant rats have shown that flucytosine injected intraperitoneally crosses the placental barrier (see PRECAUTIONS ).
Microbiology
Flucytosine has in vitro and in vivo activity against Candida and Cryptococcus. Although the exact mode of action is unknown, it has been proposed that flucytosine acts directly on fungal organisms by competitive inhibition of purine and pyrimidine uptake and indirectly by intracellular metabolism to 5-fluorouracil. Flucytosine enters the fungal cell via cytosine permease; thus, flucytosine is metabolized to 5-fluorouracil within fungal organisms. The 5-fluorouracil is extensively incorporated into fungal RNA and inhibits synthesis of both DNA and RNA. The result is unbalanced growth and death of the fungal organism. Antifungal synergism between Ancobon and polyene antibiotics, particularly amphotericin B, has been reported.
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Flucytosine has in vitro and in vivo activity against Candida and Cryptococcus. The exact mode of action against these fungi is not known. Ancobon is not metabolized significantly when given orally to man.
Cryptococcus: Most strains initially isolated from clinical material have shown flucytosine minimal inhibitory concentrations (MIC's) ranging from .46 to 7.8 mcg/mL. Any isolate with an MIC greater than 12.5 mcg/mL is considered resistant. In vitro resistance has developed in originally susceptible strains during therapy. It is recommended that clinical cultures for susceptibility testing be taken initially and at weekly intervals during therapy. The initial culture should be reserved as a reference in susceptibility testing of subsequent isolates.
Candida: As high as 40% to 50% of the pretreatment clinical isolates of Candida have been reported to be resistant to flucytosine. It is recommended that susceptibility studies be performed as early as possible and be repeated during therapy. An MIC value greater than 100 mcg/mL is considered resistant.
Interference with in vitro activity of flucytosine occurs in complex or semisynthetic media. In order to rely upon the recommended in vitro interpretations of susceptibility, it is essential that the broth medium and the testing procedure used be that described by Shadomy. 1
Ancobon is 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.
Ancobon should not be used in patients with a known hypersensitivity to the drug.
Ancobon must be given with extreme caution to patients with impaired renal function. Since Ancobon is excreted primarily by the kidneys, renal impairment may lead to accumulation of the drug. Ancobon blood concentrations should be monitored to determine the adequacy of renal excretion in such patients. 1 Dosage adjustments should be made in patients with renal insufficiency to prevent progressive accumulation of active drug.
Ancobon 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.
General: Before therapy with Ancobon is instituted, electrolytes (because of hypokalemia) and the hematologic and renal status of the patient should be determined (see ). Close monitoring of the patient during therapy is essential.
Laboratory Tests: Since renal impairment can cause progressive accumulation of the drug, blood concentrations and kidney function should be monitored during therapy. Hematologic status (leucocyte and thrombocyte count) and liver function (alkaline phosphatase, SGOT and SGPT) should be determined at frequent intervals during treatment as indicated.
Drug Interactions: Cytosine arabinoside, a cytostatic agent, has been reported to inactivate the antifungal activity of Ancobon by competitive inhibition. Drugs which impair glomerular filtration may prolong the biological half-life of flucytosine. Antifungal synergism between Ancobon and polyene antibiotics, particularly amphotericin B, has been reported.
Drug/Laboratory Test Interactions: Measurement of serum creatinine levels should be determined by the Jaffe method, since Ancobon does not interfere with the determination of creatinine values by this method, as it does when the dry-slide enzymatic method with the Kodak Ektachem analyzer is used.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Flucytosine has not undergone adequate animal testing to evaluate carcinogenic potential. The mutagenic potential of flucytosine was evaluated in Ames-type studies with five different mutants of S. typhimurium and no mutagenicity was detected in the presence or absence of activating enzymes. Flucytosine was nonmutagenic in three different repair assay systems.
There have been no adequate trials in animals on the effects of flucytosine on fertility or reproductive performance. The fertility and reproductive performance of the offspring (F 1 generation) of mice treated with 100, 200 or 400 mg/kg/day of flucytosine on days 7 to 13 of gestation was studied; the in utero treatment had no adverse effect on the fertility or reproductive performance of the offspring.
Pregnancy: Teratogenic Effects. Pregnancy Category C. Although standard segment II studies have not been done, flucytosine was shown to be teratogenic (vertebral fusions) in the rat at doses of 40 mg/kg/day (0.27 times the maximum human dose, based on nominal dose). At higher doses (700 mg/kg/day, 4.7 times the maximum human dose, based on nominal dose), cleft lip and palate and micrognathia were reported. Flucytosine was not teratogenic in rabbits up to a dose of 100 mg/kg/day (0.68 times the maximum human dose, based on nominal dose). In mice, 400 mg/kg/day of flucytosine (2.7 times the maximum human dose, based on nominal dose) was associated with a low incidence of cleft palate that was not statistically significant. There are no adequate and well-controlled studies in pregnant women. Ancobon should be used during pregnancy only if the potential benefits justifies the potential risk to the fetus.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Ancobon, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Safety and effectiveness in children have not been established.
The adverse reactions which have occurred during treatment with Ancobon are grouped according to organ system affected.
Cardiovascular: Cardiac arrest, myocardial toxicity, ventricular dysfunction.
Respiratory: Respiratory arrest, chest pain, dyspnea.
Dermatologic: Rash, pruritus, urticaria, photosensitivity.
Gastrointestinal: Nausea, emesis, abdominal pain, diarrhea, anorexia, dry mouth, duodenal ulcer, gastrointestinal hemorrhage, acute hepatic injury with possible fatal outcome in debilitated patients, hepatic dysfunction, jaundice, ulcerative colitis, bilirubin elevation.
Genitourinary: Azotemia, creatinine and BUN elevation, crystalluria, renal failure.
Hematologic: Anemia, agranulocytosis, aplastic anemia, eosinophilia, leukopenia, pancytopenia, thrombocytopenia.
Neurologic: Ataxia, hearing loss, headache, paresthesia, parkinsonism, peripheral neuropathy, pyrexia, vertigo, sedation, convulsions.
Psychiatric: Confusion, hallucinations, psychosis.
Miscellaneous: Fatigue, hypoglycemia, hypokalemia, weakness, allergic reactions, Lyell' syndrome.
There is no experience with intentional overdosage. It is reasonable to expect that overdosage may produce pronounced manifestations of the known clinical adverse reactions. Prolonged serum concentrations in excess of 100 mcg/mL may be associated with an increased incidence of toxicity, especially gastrointestinal (diarrhea, nausea, vomiting), hematologic (leukopenia, thrombocytopenia) and hepatic (hepatitis).
In the management of overdosage, prompt gastric lavage or the use of an emetic is recommended. Adequate fluid intake should be maintained, by the intravenous route if necessary, since Ancobon is excreted unchanged via the renal tract. The hematologic parameters should be monitored frequently; liver and kidney function should be carefully monitored. Should any abnormalities appear in any of these parameters, appropriate therapeutic measures should be instituted. Since hemodialysis has been shown to rapidly reduce serum concentrations in anuric patients, this method may be considered in the management of overdosage.
The usual dosage of Ancobon 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 ).
Capsules, 250 mg (gray and green), imprinted ANCOBON® 250 ROCHE; bottles of 100 (NDC 0004-0077-01). Capsules, 500 mg (gray and white), imprinted ANCOBON® 500 ROCHE, bottles of 100 (NDC 0004-0079-01).
Revised: December 1996