Version May 2024
Use with extreme caution in patients with renal impairment. Close monitoring of hematologic, renal, and hepatic status of all patients is essential.
Usual dosage range: Oral: 50 to 150 mg/kg/day in divided doses every 6 hours.
Candidiasis:
Cardiac infection, native or prosthetic valve endocarditis, or device infection (eg, implantable cardiac defibrillator, pacemaker, ventricular assist device): Oral: 25 mg/kg/dose 4 times daily (in combination with an amphotericin B lipid formulation). For device infection without endocarditis, duration is 4 weeks after device removal for generator pocket infections and ≥6 weeks after device removal for wire infections. For endocarditis, duration is ≥6 weeks after valve replacement surgery, with longer durations for perivalvular abscesses or other complications. Note: May transition to step-down therapy with fluconazole in patients with fluconazole-susceptible isolates who are clinically stable with negative repeat blood cultures (Ref).
Central nervous system (eg, meningitis): Oral: 25 mg/kg/dose 4 times daily (in combination with amphotericin B [liposomal]) until step-down therapy is clinically appropriate (Ref).
Endophthalmitis (with or without vitritis): Fluconazole- or voriconazole-resistant isolates: Oral: 25 mg/kg/dose 4 times daily (in combination with amphotericin B [liposomal]) for ≥4 to 6 weeks until examination indicates resolution; for patients with vitritis or with macular involvement, intravitreal antifungal therapy is also recommended (Ref).
Urinary tract infection:
Cystitis, symptomatic: Oral: Fluconazole-resistant C. glabrata: 25 mg/kg/dose 4 times daily for 7 to 10 days as monotherapy (Ref).
Pyelonephritis: Fluconazole-resistant C. glabrata: Oral: 25 mg/kg/dose 4 times daily in combination with amphotericin B deoxycholate for 1 to 7 days or as monotherapy for 14 days (Ref).
Vulvovaginal, caused by C. glabrata (alternative agent) (off-label use): Intravaginal: 16% extemporaneously compounded cream: 1 applicatorful (~5 g) once daily (at bedtime) for 14 days (Ref). Note: Reserve for patients with no other clear cause of symptoms (Ref). May also be used in combination with intravaginal amphotericin B (Ref).
Cryptococcal meningitis, disseminated disease, or severe pulmonary infection:
Oral: Induction: 25 mg/kg/dose 4 times daily, as part of an appropriate combination regimen. Duration of induction therapy is ≥2 weeks, but should be extended in patients with evidence of neurological complications; for cerebral cryptococcomas, recommended duration is ≥6 weeks. Induction therapy is followed by consolidation and maintenance therapy with fluconazole (Ref).
The manufacturer recommends dose reduction for elevated BUN or serum creatinine (or other signs of renal impairment); however, no specific dosage adjustments are provided. The following adjustments have been recommended (based on a usual dose of 25 mg/kg/dose every 6 hours):
CrCl >40 mL/minute: No dosage adjustment necessary (Ref).
CrCl 21 to 40 mL/minute: 25 mg/kg/dose every 12 hours (Ref).
CrCl 10 to 20 mL/minute: 25 mg/kg/dose every 24 hours (Ref).
CrCl <10 mL/minute: 25 mg/kg/dose every 48 hours (Ref).
End-stage renal disease on intermittent hemodialysis: 25 to 50 mg/kg/dose every 48 to 72 hours; administer dose after hemodialysis (Ref).
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
Refer to adult dosing.
(For additional information see "Flucytosine: Pediatric drug information")
Note: Administer as part of an appropriate combination regimen to avoid development of flucytosine resistance. Doses provided are initial and should be adjusted based on therapeutic drug monitoring.
General dosing: Infants, Children, and Adolescents: Oral: 25 mg/kg/dose every 6 hours as part of an appropriate combination regimen (Ref).
Candidiasis:
Chorioretinitis: Infants, Children, and Adolescents: Oral: 25 mg/kg/dose every 6 hours in combination with amphotericin B (Ref).
CNS disease, treatment: Infants, Children, and Adolescents: Oral: 25 mg/kg/dose every 6 hours in combination with amphotericin B (Ref).
Endocarditis or implanted cardiovascular device:
Infants: Oral: 25 mg/kg/dose every 6 hours in combination with amphotericin B; valve replacement or removal of hardware is strongly recommended (Ref).
Children and Adolescents: Oral: 25 to 37.5 mg/kg/dose every 6 hours in combination with amphotericin B; valve replacement or removal of hardware is strongly recommended (Ref).
Urinary tract infection: Infants, Children, and Adolescents:
Cystitis, symptomatic: Oral: 25 mg/kg/dose every 6 hours for 7 to 10 days (Ref).
Pyelonephritis: Oral: 25 mg/kg/dose every 6 hours for 2 weeks with or without amphotericin B (Ref); if fungal balls present, use in combination with amphotericin B and treatment duration should be until symptom resolution and clear urine culture.
Cryptococcal disease; disseminated (including CNS disease); treatment (independent of HIV status):
Infants, Children, and Adolescents: Oral: 25 mg/kg/dose every 6 hours as part of an appropriate combination regimen. Duration of induction therapy is ≥2 weeks and is dependent upon multiple factors including immune or HIV status, source of infection and concomitant antifungal therapy; induction therapy should be followed by consolidation and maintenance therapy with fluconazole (Ref).
There are no dosage adjustments provided in the manufacturer's labeling; however, the following guidance has been used by some clinicians:
Infants, Children, and Adolescents without HIV infection:
Note: Dosing adjustment based on a usual initial dose of 25 to 37.5 mg/kg/dose every 6 hours (Ref). Doses should be adjusted based on therapeutic drug monitoring.
GFR >50 mL/minute/1.73 m2: No adjustment recommended.
GFR 30 to 50 mL/minute/1.73 m2: Oral: 25 to 37.5 mg/kg/dose every 8 hours.
GFR 10 to 29 mL/minute/1.73 m2: Oral: 25 to 37.5 mg/kg/dose every 12 hours.
GFR <10 mL/minute/1.73 m2: Oral: 25 to 37.5 mg/kg/dose every 24 hours.
Hemodialysis or peritoneal dialysis: Oral: 25 to 37.5 mg/kg/dose every 24 hours.
Adolescents with HIV:
Note: Dosing adjustment based on a usual dose of 25 mg/kg/dose every 6 hours (Ref); doses should be adjusted based on therapeutic drug monitoring.
CrCl >40 mL/minute: No adjustment recommended.
CrCl >20 to 40 mL/minute: Oral: 25 mg/kg/dose every 12 hours.
CrCl 10 to 20 mL/minute: Oral: 25 mg/kg/dose every 24 hours.
CrCl <10 mL/minute: Oral: 25 mg/kg/dose every 48 hours.
Hemodialysis: Oral: 25 to 50 mg/kg every 48 to 72 hours; administer dose after hemodialysis.
There are no dosage adjustments provided in the manufacturer's labeling; however, flucytosine has minimal hepatic metabolism; use caution.
The following adverse drug reactions are derived from product labeling unless otherwise specified. Frequency not defined.
Frequency not defined:
Cardiovascular: Cardiotoxicity, chest pain, ventricular dysfunction
Dermatologic: Pruritus, skin photosensitivity, skin rash, toxic epidermal necrolysis, urticaria
Endocrine & metabolic: Hypoglycemia, hypokalemia
Gastrointestinal: Abdominal pain, anorexia, diarrhea, duodenal ulcer, enterocolitis, gastrointestinal hemorrhage, nausea, ulcerative colitis, vomiting, xerostomia
Genitourinary: Azotemia, crystalluria
Hematologic & oncologic: Agranulocytosis, anemia, aplastic anemia, bone marrow aplasia, eosinophilia, leukopenia, pancytopenia, thrombocytopenia
Hepatic: Hepatic injury (acute), hepatic necrosis, increased liver enzymes, increased serum bilirubin, jaundice
Hypersensitivity: Hypersensitivity reaction
Nervous system: Asthenia, ataxia, confusion, fatigue, hallucination, headache, paresthesia, parkinsonism, peripheral neuropathy, psychosis, sedated state, seizure, vertigo
Otic: Hearing loss
Renal: Increased blood urea nitrogen, increased serum creatinine, kidney failure
Respiratory: Dyspnea
Miscellaneous: Fever
Postmarketing: Gastrointestinal: Colitis (Sohail 2014)
Hypersensitivity to flucytosine or any component of the formulation; known complete dihydropyrimidine dehydrogenase enzyme deficiency.
Disease-related concerns:
• Hematologic disease: Use with caution in patients with bone marrow depression, hematologic disease, or those who have been treated with radiation or drugs that suppress the bone marrow; bone marrow toxicity may be dose related and irreversible.
• Hepatic impairment: Use with caution in patients with hepatic impairment; hepatotoxicity that appears to be dose related may occur.
• Renal impairment: Dosage adjustment recommended in patients with renal impairment.
Special populations:
• Dihydropyrimidine dehydrogenase enzyme deficiency: Severe toxicity, including diarrhea, mucositis, neurotoxicity, and neutropenia, may be increased in patients with dihydropyrimidine dehydrogenase enzyme deficiency; consider determination of dihydropyrimidine dehydrogenase enzyme deficiency in patients who develop drug toxicity.
Other warnings/precautions:
• Monotherapy: Generally should not be used as monotherapy, as resistance can rapidly develop.
Serum flucytosine concentrations are highly variable in neonates and tend to be higher in children <12 years of age; monitor closely (Baley 1990; Pasqualotto 2007; Soltani 2006).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Ancobon: 250 mg, 500 mg
Generic: 250 mg, 500 mg
Yes
Capsules (Ancobon Oral)
250 mg (per each): $92.21
500 mg (per each): $178.43
Capsules (Flucytosine Oral)
250 mg (per each): $82.07
500 mg (per each): $158.81
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Oral: To reduce or avoid nausea and vomiting, administer a few capsules at a time over 15 minutes until full dose is taken.
Vaginal (off-label route): Gently insert full applicator of cream and press plunger to release the medication (Ref).
Oral: To reduce or avoid nausea and vomiting, administer a few capsules at a time over 15 minutes until full dose is taken.
Candida/Cryptococcus infections: Treatment of systemic fungal infections (eg, bloodstream infection, endocarditis, urinary tract infection, meningitis, pulmonary) caused by susceptible strains of Candida or Cryptococcus, in combination with other antifungal agents.
Candidiasis, vulvovaginal, caused by Candida glabrata
Flucytosine may be confused with fludarabine, fluorouracil
Ancobon may be confused with Oncovin
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Amphotericin B: May enhance the adverse/toxic effect of Flucytosine. Amphotericin B may increase the serum concentration of Flucytosine. Risk C: Monitor therapy
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
Brivudine: May enhance the adverse/toxic effect of Flucytosine. Risk X: Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Chloramphenicol (Systemic): Myelosuppressive Agents may enhance the myelosuppressive effect of Chloramphenicol (Systemic). Risk X: Avoid combination
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Cytarabine (Conventional): May diminish the therapeutic effect of Flucytosine. Risk C: Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Gimeracil: May increase serum concentrations of the active metabolite(s) of Flucytosine. Specifically, gimeracil may increase concentrations of fluorouracil. Risk X: Avoid combination
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Saccharomyces boulardii: Antifungal Agents (Systemic and Oral [Non-Absorbable]) may diminish the therapeutic effect of Saccharomyces boulardii. Risk X: Avoid combination
Food decreases the rate, but not the extent of absorption.
Adverse events have been observed in some animal reproduction studies. Flucytosine is metabolized to fluorouracil which may cause adverse events if administered during pregnancy; refer to the Fluorouracil (Systemic) monograph for additional information.
It is not known if flucytosine is present in breast milk. Due to the potential for serious adverse reactions in the breastfeeding infant, a decision should be made whether to discontinue breastfeeding or the drug, taking into account the importance of treatment to the mother.
Pretreatment: Electrolytes (especially potassium), CBC with differential, BUN, renal function.
During treatment: CBC with differential and LFTs (eg, alkaline phosphatase, AST/ALT) frequently; renal function; serum flucytosine concentrations (2 hours after administration of a dose) after 3 to 5 doses and as clinically indicated (eg, following dosage adjustment, change in renal function, bone marrow toxicity) (BSMM [Ashbee 2014]; HHS [OI adult 2022]); if serum flucytosine concentrations cannot be monitored, monitor CBC at least twice weekly (HHS [OI adult 2022]).
Target serum concentration: 30 to 80 mcg/mL (2 hours post dose); obtain level after 3 to 5 doses. Serum concentrations should not exceed 100 mcg/mL to avoid bone marrow toxicity and hepatotoxicity (AST-IDCOP [Baddley 2019]; HHS [OI adult] 2022; IDSA [Perfect 2010]). Repeat serum concentrations should be obtained following dosage adjustment, change in renal function, or if bone marrow toxicity occurs (BSMM [Ashbee 2014]).
In some areas, trough monitoring may be utilized; target troughs of 25 to 50 mcg/mL or >20 to 40 mcg/mL have been suggested to minimize resistance development (BSMM [Ashbee 2014]; Gómez-López 2020; Vermes 2000).
Penetrates fungal cells and is converted to fluorouracil; after further bioconversion, it competes with uridylic acid, interfering with fungal RNA and protein synthesis, and inhibits thymidylate synthetase, inhibiting fungal DNA synthesis (Vermes 2000).
Absorption: Rapid.
Distribution: Into CSF, aqueous humor, joints, peritoneal fluid; Vd: 0.6 L/kg.
Protein binding: 3% to 4%.
Metabolism: Minimally hepatic; deaminated both in yeasts and possibly via gut bacteria to 5-fluorouracil.
Bioavailability: 78% to 89%; decreased in neonates.
Half-life elimination:
Neonates: 4 to 34 hours (Baley 1990).
Infants: 7.4 hours.
Adults: 2 to 5 hours.
Anuria: 85 hours (range: 30 to 250).
End-stage renal disease (ESRD): 75 to 200 hours.
Time to peak, serum: ~1 to 2 hours.
Neonates: 2.5 ± 1.3 hours.
Adults: ~1 to 2 hours.
Excretion: Urine (>90% as unchanged drug).
Altered kidney function: Prolonged half-life (29.9 to 250 hours in anuric or nephrectomized patients).
Pediatric: Serum flucytosine concentrations are highly variable in neonates and tend to be higher in children <12 years of age; monitor closely (Baley 1990; Pasqualotto 2007; Soltani 2006).
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