FLUCYTOSINE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for FLUCYTOSINE (FLUCYTOSINE).
Flucytosine is a prodrug that is converted intracellularly to 5-fluorouracil (5-FU) by cytosine deaminase, an enzyme present in susceptible fungi. 5-FU is further metabolized to 5-fluorouridine triphosphate, which inhibits fungal RNA and DNA synthesis by incorporating into RNA and inhibiting thymidylate synthase.
| Metabolism | Flucytosine is minimally metabolized, with about 80-90% excreted unchanged in the urine. Small amounts are converted to 5-fluorouracil by gut bacteria, and further metabolism follows the pyrimidine pathway. |
| Excretion | Approximately 80-90% of a dose is excreted unchanged in the urine via glomerular filtration. Less than 10% is metabolized to 5-fluorouracil. Fecal excretion is minimal (<4%). No significant biliary excretion. |
| Half-life | Terminal elimination half-life is 3-6 hours in patients with normal renal function. In renal impairment (CrCl <40 mL/min), half-life extends to 50-100 hours, requiring dose adjustment. |
| Protein binding | Plasma protein binding is 2-4%, bound primarily to albumin. Binding is negligible and does not affect distribution. |
| Volume of Distribution | Volume of distribution is approximately 0.6-0.9 L/kg, indicating distribution into total body water. Penetrates well into most tissues, including CSF (50-100% of serum levels). |
| Bioavailability | Oral bioavailability is 78-90% (mean ~85%). Food does not significantly affect absorption. Intravenous: 100%. |
| Onset of Action | Oral: Therapeutic serum concentrations reached within 2-6 hours after first dose. Antifungal effect begins as drug accumulates in fungal cells; clinical response typically seen within 24-48 hours. |
| Duration of Action | Duration of antifungal activity correlates with serum levels above MIC. Dosing every 6 hours in normal renal function maintains continuous exposure. After discontinuation, drug cleared within 1-2 days. |
50-150 mg/kg/day orally divided every 6 hours. For cryptococcosis, 100 mg/kg/day in 4 divided doses.
| Dosage form | CAPSULE |
| Renal impairment | GFR 20-50 mL/min: 50-100 mg/kg/day every 12 hours. GFR 10-20 mL/min: 50-100 mg/kg/day every 24 hours. GFR <10 mL/min: 25-50 mg/kg/day every 24-48 hours. |
| Liver impairment | No dosage adjustment recommended for Child-Pugh A or B. For Child-Pugh C, monitor levels and consider reduction based on bilirubin and albumin. |
| Pediatric use | 50-100 mg/kg/day orally divided every 6 hours. For severe infections, up to 150 mg/kg/day in 4 divided doses. |
| Geriatric use | Start at lower end of dosing range (50 mg/kg/day) and adjust based on renal function (creatinine clearance), as elderly often have reduced GFR. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for FLUCYTOSINE (FLUCYTOSINE).
| Breastfeeding | Flucytosine is excreted into human breast milk; M/P ratio not established. Concentrations may approach therapeutic levels. Potential for serious adverse reactions in nursing infants (bone marrow suppression, hepatic toxicity). Recommend discontinuing breastfeeding or the drug, considering importance of drug to mother. |
| Teratogenic Risk | Flucytosine is teratogenic in animal studies (rats: cleft palate, skeletal anomalies; mice: cleft palate, encephalocoele). Human data limited; avoid first trimester unless benefit outweighs risk. Second/third trimester: use only if clearly needed, as fetal risk cannot be excluded. |
■ FDA Black Box Warning
None.
| Serious Effects |
["Hypersensitivity to flucytosine or any component of the formulation.","Pregnancy (category C; risk of teratogenicity)."]
| Precautions | ["Bone marrow suppression: leukopenia, thrombocytopenia, anemia; monitor blood counts.","Hepatotoxicity: elevated liver enzymes, hepatitis; monitor liver function.","Renal impairment: dose adjustment required; monitor renal function.","Gastrointestinal toxicity: nausea, vomiting, diarrhea, severe enterocolitis.","Teratogenicity: avoid in pregnancy unless benefits outweigh risks.","Hypersensitivity reactions: rash, eosinophilia."] |
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| Fetal Monitoring | Monitor maternal CBC with differential, liver function tests (LFTs), renal function (serum creatinine, BUN) weekly during therapy. Monitor fetal growth and well-being via serial ultrasound if used in pregnancy. In neonates of treated mothers, monitor for bone marrow suppression and hepatic dysfunction. |
| Fertility Effects | No human data. In animal studies, no adverse effects on fertility reported. However, high doses may cause testicular atrophy in rats; relevance human unknown. |