Tozene

Flucytosine.

Each capsule contains Flucytosine 500 mg.

Pharmacology: Pharmacodynamics: Flucytosine, a fluorinated pyrimidine analog, is a synthetic antifungal agent. Two possible mechanisms of action have been identified for Flucytosine. Flucytosine appears to enter fungal cells via the action of fungal-specific cytosine permease. Inside the cell, Flucytosine is converted into fluorouracil (5-FU) by cytosine deaminase and then after several intermediate steps is converted into 5-fluorouridine triphosphate (FUTP). FUTP is incorporated into fungal RNA and interferes with protein synthesis. Flucytosine also appears to be converted to 5-fluorodeoxyuridine monophosphate, which noncompetitively inhibits thymidylate synthetase and interferes with DNA synthesis. Flucytosine does not appear to have antineoplastic activity. Flucytosine has been demonstrated to be effective against the following organisms: Aspergillus spp. (rare strains), Candida spp., Cryptococcus spp., Torulopsis glabrata (Candida glabrata).
Pharmacokinetics: Absorption: Flucytosine is absorbed rapidly and almost completely from the gastrointestinal tract (GI). Bioavailability is 78-89% following oral administration.
Distribution: Flucytosine is widely distributed into body tissues and fluids including liver, kidney, spleen, heart, aqueous humor and bronchial secretions. Flucytosine is distributed into cerebrospinal fluid (CSF) following oral administration. CSF concentrations are approximately 65-90% of serum levels. About 2-4% of Flucytosine is protein bound.
Metabolism: A small amount of Flucytosine may be metabolized to fluorouracil.
Elimination: More than 90% of the dose is excreted unchanged in the urine by glomerular filtration. The small amount of an oral dose of Flucytosine not absorbed from the gastrointestinal tract is eliminated unchanged in the feces. The elimination half-life is 2.5-6 hours in the patients with normal renal function but increases with decreasing renal function. Flucytosine is readily removed by peritoneal dialysis or hemodialysis.

Adjunctive treatment of severe systemic fungal infection caused by susceptible strains of Candida or Cryptococcus.
Flucytosine is used for the treatment of chromoblastomycosis caused by susceptible fungi.
Flucytosine should be used in combination with amphotericin B for the treatment of candidiasis and cryptococcosis because of rapid emergence of resistance to Flucytosine in Candida and Cryptococcus isolated in patients receiving Flucytosine alone.
Combination with amphotericin B is often synergistic.

Flucytosine is administered orally.
The usual dosage of Flucytosine is 50-150 mg/kg daily, administered in 4 equally divided doses at 6-hour intervals. Nausea and vomiting associated with oral Flucytosine may be reduced or avoided if each dose is administered by ingesting the capsules a few at a time over a 15-minute period.
To reduce the risk of toxicity when Flucytosine is used concomitantly with another antifungal, Flucytosine dosage should be carefully adjusted based on serum concentrations of the drug and patients receiving such therapy should be monitored closely for adverse effects. In addition, intrinsic resistance or emergence of resistance to Flucytosine may develop during therapy, it has been recommended that in vitro susceptibility tests be performed prior to and during Flucytosine therapy, whenever available.
Serum Flucytosine concentrations should be measured after 3-5 days of therapy and whenever there is evidence of toxicity or a change in renal function. Peak serum concentrations usually are measured using samples taken 2 hours after an oral dose.
Concomitant use of amphotericin B and Flucytosine for initial treatment of cryptococcosis may reduce the time required for sterilization of CSF in patients with CNS involvement.
Antifungal synergism between Flucytosine and polyene antibiotics, particularly amphotericin B has been reported in vitro. Flucytosine is usually administered in combination with amphotericin B due to lack of cross-resistance and reported synergistic activity of both drugs.
Use in patients with renal impairment: The following adjustments have been recommended (based on a usual dose of 25 mg/kg/dose every 6 hours): see Table.

Click on icon to see table/diagram/image

End-stage renal disease on intermittent hemodialysis: 25 to 50 mg/kg every 48-72 hours, administer dose after hemodialysis.
Use in patients with hepatic impairment: There are no dosage adjustments provided. Use with cautions.

Limited information is available on the acute overdosage of Flucytosine. Although there have been no reports to date of intentional overdosage of Flucytosine, the signs and symptoms of overdosage can be expected to produce pronounced manifestations of the known adverse effects of the drug. Prolonged serum Flucytosine concentrations greater than 100 mcg/mL may be associated with an increased incidence of toxicity, especially GI effects (diarrhea, nausea, vomiting), hematologic effects (leukopenia, thrombocytopenia), and hepatic effects (hepatitis). In the event of Flucytosine overdosage, the stomach should be emptied immediately by gastric lavage or an emetic. Adequate fluid intake should be maintained and IV fluid given if necessary. Hematologic parameters should be assessed frequently and liver and kidney function carefully monitored.

This drug is contraindicated in patients with known hypersensitivity to Flucytosine or any ingredient in the formulation.

This drug is contraindicated in patients with known hypersensitivity to Flucytosine.
This drug may be harmful to the kidneys, liver and bone marrow.

Bone marrow depression: Give with extreme caution to patients with bone marrow depression. Patients may be more prone to bone marrow depression if they have a hematologic disease, are being treated with radiation or marrow suppressant drugs, or have a history of treatment with such drugs or radiation. Bone marrow toxicity can be irreversible and may lead to death in immunosuppressed patients. Frequently monitor hepatic function and hematopoietic system during therapy.
Renal function impairment: Give with extreme caution; drug accumulation may occur. Monitor blood levels to determine the adequacy of renal excretion in such patients. Adjust dosage to prevent progressive accumulation of the drug and to maintain the blood levels at less than 100 mcg/mL.
Monitoring: Before therapy is initiated, determine electrolytes and hematological and renal status of the patient. Because renal impairment can cause accumulation of the drug, monitor blood concentrations and renal function during therapy. Monitor hematologic status (white blood cell count and platelet count) and liver function (alkaline phosphatase, ALT and AST) at frequent intervals during treatment.

Pregnancy: Pregnancy category C.
Flucytosine was shown to be teratogenic in rats. There are no adequate or controlled studies to date using Flucytosine in pregnant women and the drug should be used during pregnancy only when potential benefits justify the potential risks to the fetus.
Lactation: It is not known whether Flucytosine is excreted into human breast milk. Because of the potential for serious adverse effects in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother.

Cardiovascular: cardiac arrest, myocardial toxicity, ventricular dysfunction.
Central nervous system: ataxia, confusion, seizure, fatigue, hallucination, headache, hearing loss, paresthesia, parkinsonism, peripheral neuropathy, psychosis, pyrexia, sedation, vertigo, weakness.
Gastrointestinal: abdominal pain, anorexia, bilirubin elevation, diarrhea, dry mouth, duodenal ulcer, emesis, gastrointestinal hemorrhage, hepatic dysfunction, elevation of hepatic enzymes, acute hepatic injury with possible fatal outcome in debilitated patients, jaundice, nausea, ulcerative colitis.
Hematologic: myelosuppression, agranulocytosis, aplastic anemia, anemia, eosinophilia, leukopenia, pancytopenia, thrombocytopenia.
Dermatologic: photosensitivity, pruritus, rash, toxic epidermal necrolysis, urticaria.
Genitourinary: azotemia, creatinine elevation, BUN elevation, crystalluria, renal failure.
Respiratory: chest pain, dyspnea, respiratory arrest.
Miscellaneous: allergic reactions, hypoglycemia, hypokalemia.

Amphotericin B: amphotericin B may enhance the adverse/toxic effect of Flucytosine, possibly by increasing cellular uptake and/or by decreasing renal excretion of Flucytosine. This may be related to the adverse effects of amphotericin B on renal function. If Flucytosine is used in conjunction with amphotericin B, serum Flucytosine concentrations and blood cell counts should be carefully monitored.
Cytarabine: cytarabine (cytosine arabinoside) may diminish the therapeutic effect of Flucytosine. Concomitant use of the drugs is not recommended.
Zidovudine: zidovudine may increase the risk of hematologic toxicity, possibly by additive or synergistic bone marrow suppression.
Laboratory test interferences: Determine measurement of serum creatinine levels by Jaffe reaction, because Flucytosine does not interfere with the determination of creatinine values by this method.

Storage below 30°C.

Antifungals

J02AX01 - flucytosine ; Belongs to the class of other systemic antimycotics.

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