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. |
| Molecular Weight | 129.09 |
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 | Avoid; teratogenic in animal studies. Use only if benefit outweighs risk. |
| 2nd trimester | Use cautiously; potential for fetal toxicity. Monitor closely. |
| 3rd trimester | Use cautiously; avoid near term due to risk of neonatal hypoglycemia (hypothetical). |
Clinical note
Comprehensive clinical and safety monograph for FLUCYTOSINE (FLUCYTOSINE).
| Placental transfer | Crosses placenta; fetal concentrations similar to maternal. |
| Breastfeeding | Excreted into breast milk in low levels; consider risk of infant neutropenia. Monitor infant for diarrhea, rash, or hepatic effects. |
| Lactation Rating |
■ FDA Black Box Warning
None.
| Serious Effects |
Hypersensitivity to flucytosine
| 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. |
| Food/Dietary | No significant food interactions. Avoid grapefruit juice as it may theoretically affect metabolism (though not well-studied). Take with or without food; if gastrointestinal upset occurs, take with food. |
Loading safety data…
| L3 (Moderately Safe) |
| 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. |
| 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. |
| Clinical Pearls | Flucystosine is a pyrimidine analog antifungal used primarily in combination with amphotericin B for severe systemic mycoses (e.g., cryptococcal meningitis, candidiasis). Monitor serum levels (target peak 50-100 mcg/mL) to avoid hepatotoxicity and myelosuppression. Dose adjustment required for renal impairment (CrCl < 50 mL/min). Avoid monotherapy due to rapid resistance development. May cause rash, diarrhea, or central nervous system effects. |
| Patient Advice | Take this medication exactly as prescribed, even if you feel well. · Monitor for signs of liver problems: yellow skin/eyes, dark urine, severe fatigue, abdominal pain. · Report any unusual bleeding, bruising, or signs of infection (fever, sore throat) immediately. · Use effective contraception during treatment if applicable. · Complete the full course of therapy unless directed otherwise by your doctor. |