Flucytosine

Indications

Flucytosine is used for: Systemic fungal infections

Adult Dose

Oral Systemic fungal infections Adult: 50-150 mg/kg daily in 4 divided doses. Commonly used w/ amphotericin B or fluconazole in severe infections. Intravenous Systemic fungal infections Adult: 200 mg/kg daily in 4 divided doses via infusion over 20-40 min. Adjust dose to produce trough plasma levels of 25-50 mcg/mL. In severe systemic candidiasis, cryptococcal meningitis, and other severe infections, it is usually given in combination w/ amphotericin B or fluconazole. Treatment duration is individualised based on sensitivity of the organism and patient response (usually ?7 days, except for cryptococcal meningitis when it is continued for at least 4 mth).

Child Dose

Candidiasis/Cryptococcus Infection Child: 50-150 mg/kg/d div q6hr PO Neonates (<28 days old): 80-160 mg/kg/d div q6hr PO

Renal Dose

Renal impairment: CrCl (ml/min) Dosage Recommendation <10 mL/min: 50 mg/kg; further doses should be based on plasma levels (not exceeding 80 mcg/mL). 10-<20 mL/min: 50 mg/kg 24 hrly. 20-40 mL/min: 50 mg/kg 12 hrly.

Administration

May be taken with or without food. Nausea & vomiting may be minimised if the dose is spaced over a 15-min period.

Contra Indications

Hypersensitivity to flucytosine. Co-administration w/ antiviral nucleoside drugs and their analogues. Lactation.

Precautions

Patient w/ blood dyscrasias or bone marrow depression, dihydropyrimidine dehydrogenase (DPD) deficiency, or those receiving radiation therapy. Renal and hepatic impairment. Monitoring Parameters Monitor renal, hepatic, and haematologic functions prior to and during treatment (at least wkly in patients w/ renal impairment or blood dyscrasia).

Pregnancy-Lactation

Pregnancy Category: C Lactation: excretion in milk unknown/not recommended

Interactions

May result in synergistic effect when combined w/ amphotericin B or fluconazole. May increase phenytoin plasma levels. Cytarabine antagonises the antifungal activity of flucytosine by competitive inhibition. Potentially Fatal: Co-administration w/ antiviral nucleoside drugs (e.g. brivudine, sorivudine, and their analogues) may result in severe drug toxicity due to inhibition of DPD, a key enzyme involved in the metabolism of 5-FU.

Side Effects

Side effects of Flucytosine : Frequency Not Defined Confusion Headache Hallucinations Dizziness Drowsiness Psychosis Parkinsonism Ataxia Sedation Rash Photosensitivity Pruritus Urticaria Temporary growth failure Hypoglycemia Hypokalemia Nausea Vomiting Diarrhea Abdominal pain Loss of appetite Bone marrow suppression Anemia Leukopenia Thrombocytopenia Elevated liver enzymes Hepatitis Azotemia Peripheral neuropathy Paresthesia Weakness Hearing loss Elevated BUN and serum creatinine Renal failure Respiratory arrest Anaphylaxis

Mode of Action

Flucytosine is a fluorinated pyrimidine antifungal that is taken up by cytosine permease into the fungal cells. It is rapidly converted to fluorouracil (5-FU) and subsequently into 5-fluorouridine triphosphate (FUTP), which is then incorporated into fungal RNA, resulting to faulty protein biosynthesis. 5-FU is also converted to fluorodeoxyuridine monophosphate which interferes w/ thymidylate synthase, thereby causing disruption of DNA synthesis.