Flucytosine
Rising Pharmaceuticals, Inc.
Sigmapharm Laboratories, Inc.
FLUCYTOSINE CAPSULES, USP RX only
FULL PRESCRIBING INFORMATION: CONTENTS*
- FLUCYTOSINE DESCRIPTION
- CLINICAL PHARMACOLOGY
- MICROBIOLOGY
- INDICATIONS & USAGE
- FLUCYTOSINE CONTRAINDICATIONS
- WARNINGS
- PRECAUTIONS
- PREGNANCY
- FLUCYTOSINE ADVERSE REACTIONS
- OVERDOSAGE
- DOSAGE & ADMINISTRATION
- HOW SUPPLIED
- Flucytosine 250 mg Container Label
- Flucytosine 500 mg Container Label
FULL PRESCRIBING INFORMATION
WARNING
Use 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 Flucytosine Capsules, USP
FLUCYTOSINE DESCRIPTION
Flucytosine Capsules, USP are an antifungal agent available as 250 mg and 500 mg capsules for oral administration. Each capsule also contains corn starch, lactose monohydrate and talc. The 250 mg capsule shell contains FD and C Yellow No.6, FD and C Green No. 3, D and C Yellow No. 10, titanium dioxide, sodium lauryl sulfate and gelatin. The 500 mg capsule shell contains iron oxide yellow, iron oxide black, titanium dioxide, carboxymethylcellulose, sodium lauryl sulfate and gelatin. The imprinting ink for both the 250 mg and 500 mg capsules contain black iron oxide. 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:
CLINICAL PHARMACOLOGY
Flucytosine is rapidly and virtually completely
absorbed following oral administration. Flucytosine Capsules are 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 μg/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 μg/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
MICROBIOLOGY
Mechanism of ActionFlucytosine
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
The following in vitro data are available, but their clinical significance is unknown.
Flucytosine exhibits in vitro
minimum inhibitory concentrations (MIC values) of 4 μg/mL, or less
against most (≥90%) strains of the following microorganisms, however,
the safety and effectiveness of flucytosine in treating clinical
infections due to these microorganisms have not been established in
adequate and well control trials.
Candida dubliniensis
Candida glabrata
Candida guilliermondii
Candida lusitaniae
Candida parapsilosis
Candida tropicalis
Candida krusei should be considered to be resistant to flucytosine.
In vitro activity of flucytosine is affected by the test conditions. It is essential to follow the approved standard method guidelines1.
Susceptibility Testing Methods
Cryptococcus neoformans :
No interpretive criteria have been established for Cryptococcus neoformans.
Candida Species:
Broth Dilution Techniques:
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida spp. to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth)1 with standardized inoculum concentrations and standardized concentrations of flucytosine powder. The MIC values should be interpreted according to the criteria in Table 1.
Table 1. Susceptibility Interpretive Criteria for Flucytosine
Broth Dilution at 48 hours (MIC in μg/mL)
|
|
|
|
|
| Antifungal agent | Susceptible (S) |
Intermediate (I) |
Resistant (R) |
| Flucytosine |
≤4.0 |
8.0-16 |
>32 |
|
QC Strain |
Macrodilution (MIC in μg/mL) @ 48 hours |
Microdilution (MIC in μg/mL) @ 48 hours |
| Candida parapsilosis ATCC 22019 | 0.12-0.5 | 0.12-0.5 |
| Candida krusei ATCC 6258 |
4.0-16 |
8.0-32 |
Candida krusei
Drug Combination
INDICATIONS & USAGE
Flucytosine Capsules 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.
Flucytosine Capsules 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 (see MICROBIOLOGY).
FLUCYTOSINE CONTRAINDICATIONS
Flucytosine Capsules should not be used in patients with a known hypersensitivity to the drug.
WARNINGS
Flucytosine Capsules must be given with extreme caution to patients with impaired renal function. Since Flucytosine Capsules is excreted primarily by the kidneys, renal impairment may lead to accumulation of the drug. Flucytosine Capsules 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 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.
PRECAUTIONS
General
Before therapy with Flucytosine Capsules is instituted, electrolytes (because of hypokalemia) and the hematologic and renal status of the patient should be determined (see WARNINGS). 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 Flucytosine Capsules by competitive inhibition.
Drugs which impair glomerular filtration may prolong the biological
half-life of flucytosine.
Drug/Laboratory Test Interactions
Measurement
of serum creatinine levels should be determined by the Jaffé reaction,
since Flucytosine Capsules does not interfere with the determination of
creatinine values by this method. Most automated equipment for
measurement of creatinine makes use of the Jaffé reaction.
Carcinogenesis, Mutagenesis, Impairment of Fertility
PREGNANCY
Teratogenic Effects. Pregnancy Category C
Flucytosine was shown to be teratogenic (vertebral fusions) in the rat at doses of 40 mg/kg/day (298 mg/M2/day or 0.051 times the human dose) administered on days 7 to 13 of gestation. At higher doses (700 mg/kg/day; 5208 mg/M2/day
or 0.89 times the human dose administered on days 9 to 12 of
gestation), cleft lip and palate and micrognathia were reported.
Flucytosine was not teratogenic in rabbits up to a dose of 100
mg/kg/day (1423 mg/M2/day or 0.243 times the human dose)administered on days 6 to 18 of gestation. In mice, 400 mg/kg/day of flucytosine (1380 mg/M2/day
or 0.236 times the human dose) administered on days 7 to 13 of
gestation was associated with a low incidence of cleft palate that was
not statistically significant. Studies in pregnant rats have shown that
flucytosine injected intraperitoneally crosses the placental barrier.
There are no adequate and well-controlled studies in pregnant women.
Flucytosine Capsules should be used during pregnancy only if the
potential benefit 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 Flucytosine Capsules,
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.
FLUCYTOSINE ADVERSE REACTIONS
The adverse reactions which have occurred during
treatment with Flucytosine Capsules 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 including
hepatic necrosis with possible fatal outcome in debilitated patients,
hepatic dysfunction, jaundice, ulcerative colitis, enterocolitis,
bilirubin elevation, increased hepatic enzymes.
Genitourinary: Azotemia, creatinine and BUN elevation, crystalluria, renal failure.
Hematologic: Anemia, agranulocytosis, aplastic anemia, eosinophilia, leukopenia, pancytopenia, thrombocytopenia, and fatal cases of bone marrow aplasia.
Neurologic: Ataxia, hearing loss, headache, paresthesia, parkinsonism, peripheral neuropathy, pyrexia, vertigo, sedation, convulsions.
Psychiatric: Confusion, hallucinations, psychosis.
OVERDOSAGE
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 μg/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 Flucytosine Capsules 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.
DOSAGE & ADMINISTRATION
The usual dosage of Flucytosine Capsules 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).
MICROBIOLOGYHOW SUPPLIED
Flucytosine Capsules, USP 250 mg (opaque green and opaque white) are imprinted " Σ 9" on cap and body.
Bottles of 100 capsules (NDC 64980-179-01).
Flucytosine Capsules, USP 500 mg (opaque grey and opaque yellow) are imprinted "
Σ 10" on cap and body.
Bottles of 100 capsules (NDC 64980-180-01).
Store at 25°C (77°F); excursions permitted to 15° - 30°C (59°- 86°F). [see USP Controlled Room Temperature].
REFERENCES
1. Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard-Second Edition. NCCLS Document M27-A2, 2002 Volume 22, No 15, NCCLS, Wayne, PA, August 2002.
Manufactured for:
Rising Pharmaceuticals, Inc.
3 Pearl Court,
Allendale, NJ 07401
Sigmapharm Laboratories, LLC
Bensalem, PA 19020
OS010-04 REV. 0611
Flucytosine 250 mg Container Label
Rising Pharmaceuticals, Inc.
NDC 64980-179-01
Flucytosine Capsules, USP
250 mg
100 Capsules
Flucytosine 500 mg Container Label
Rising Pharmaceuticals, Inc.
NDC 64980-180-01
Flucytosine Capsules, USP
500 mg
100 Capsules
Rx Only
FlucytosineFlucytosine CAPSULE
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FlucytosineFlucytosine CAPSULE
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