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Flucytosine

Pronunciation

(floo SYE toe seen)

Index Terms

  • 5-FC
  • 5-Fluorocytosine
  • 5-Flurocytosine

Dosage Forms

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

Brand Names: U.S.

  • Ancobon

Pharmacologic Category

  • Antifungal Agent, Oral

Pharmacology

Penetrates fungal cells and is converted to fluorouracil which competes with uracil interfering with fungal RNA and protein synthesis

Absorption

Rapid; serum concentrations are highly variable in neonates; monitor closely (Pasqualotte, 2007); serum concentrations tended to be higher in children <12 years of age; monitor closely (Soltani, 2006)

Distribution

Into CSF, aqueous humor, joints, peritoneal fluid; Vd: 0.6 L/kg

Metabolism

Minimally hepatic; deaminated both in yeasts and possibly via gut bacteria to 5-fluorouracil

Excretion

Urine (>90% as unchanged drug)

Time to Peak

Serum: ~1 to 2 hours

Half-Life Elimination

Neonates: 4-34 hours (Baley, 1990); Adults: 2 to 5 hours; Anuria: 85 hours (range: 30 to 250); End-stage renal disease (ESRD): 75 to 200 hours

Protein Binding

3% to 4%

Special Populations: Renal Function Impairment

Prolonged half-life (29.9 to 250 hours in anuric or nephrectomized patients).

Use: Labeled Indications

Adjunctive treatment of systemic fungal infections (eg, septicemia, endocarditis, UTI, meningitis, or pulmonary) caused by susceptible strains of Candida or Cryptococcus

Contraindications

Hypersensitivity to flucytosine or any component of the formulation

Dosing: Adult

Usual dosage ranges: Oral: 50 to 150 mg/kg/day in divided doses every 6 hours

Cryptococcal meningitis, treatment: Oral:

Non–HIV-infected: Induction: 25 mg/kg/dose (with amphotericin B) every 6 hours for at least 4 weeks; if clinical improvement, may discontinue both amphotericin and flucytosine and follow with an extended course of fluconazole (Perfect 2010).

HIV-infected: Oral: Induction: 25 mg/kg/dose (with an amphotericin B formulation [liposomal amphotericin B is preferred]) every 6 hours for at least 2 weeks (HHS [OI adult 2015]).

Endocarditis (off-label use): Oral: 100 mg/kg daily in 3 or 4 divided doses (with amphotericin B) for at least 4 to 6 weeks after valve replacement (Gould 2012; Pappas 2009)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Cryptococcal meningitis, treatment:

Non–HIV-infected: Children (off-label population): Oral: Induction: 25 mg/kg/dose (with amphotericin B) every 6 hours for at least 4 weeks; if clinical improvement, may discontinue both amphotericin and flucytosine and follow with an extended course of fluconazole (Perfect 2010).

HIV-infected: Adolescents (off-label population): Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment provided in manufacturer’s labeling (Note: Manufacturer recommends dose reduction); however, the following adjustments have been recommended:

Adults (based upon dosing of 25 mg/kg every 6 hours):

CrCl >40 mL/minute: No dosage adjustment recommended (Perfect 2010)

CrCl 20 to 40 mL/minute: 50% of standard dose every 6 hours (Perfect 2010)

CrCl 10 to 20 mL/minute: 25% of standard dose every 6 hours (Perfect 2010)

ESRD on intermittent hemodialysis (IHD): 25 to 50 mg/kg every 48 to 72 hours; administer dose after hemodialysis (Drew 1999; HHS [OI adult 2015])

Adults and Adolescents (HIV-infected patients) (based upon dosing of 25 mg/kg every 6 hours) (HHS [OI adult 2015]):

CrCl >40 mL/minute: No dosage adjustment recommended

CrCl 20 to 40 mL/minute: 25 mg/kg every 12 hours

CrCl 10 to ≤20 mL/minute: 25 mg/kg every 24 hours

CrCl <10 mL/minute: 25 mg/kg every 48 hours

ESRD on intermittent hemodialysis (IHD): 25 to 50 mg/kg every 48 to 72 hours; administer dose after hemodialysis

Infants, Children, and non-HIV positive Adolescents (based upon dosing of 100 to 150 mg/kg/day divided every 6 hours) (Aronoff 2007): Note: Flucytosine should be avoided in children with severe renal impairment (DHHS [pediatric] 2013):

CrCl 30 to 50 mL/minute: 25 to 37.5 mg/kg every 8 hours

CrCl 10 to 29 mL/minute: 25 to 37.5 mg/kg every 12 hours

CrCl <10 mL/minute: 25 to 37.5 mg/kg every 24 hours

Hemodialysis: 25 to 37.5 mg/kg every 24 hours

Peritoneal dialysis: 25 to 37.5 mg/kg every 24 hours

Continuous renal replacement therapy: 25 to 37.5 mg/kg every 8 hours (monitor serum concentrations)

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer's labeling; use with caution.

Extemporaneously Prepared

Oral suspension (10 mg/mL): A 10 mg/mL oral suspension may be made with capsules and distilled water. Empty the contents of ten 500 mg capsules in a mortar; add small portions of distilled water and mix to a uniform paste. Mix while adding distilled water in incremental proportions to almost 500 mL; transfer to a 500 mL volumetric flask, rinse mortar several times with distilled water, and add sufficient quantity of distilled water to make 500 mL. Store in glass or plastic prescription bottles and label "shake well". Stable for 70 days refrigerated and 14 days at room temperature.

Wintermeyer SM and Nahata MC. Stability of Flucytosine in an Extemporaneously Compounded Oral Liquid. Am J Health Syst Pharm. 1996;53(4):407-409.8673661

Oral suspension (50 mg/mL): A 50 mg/mL oral suspension may be made with capsules and OraPlus and OraSweet. Mix 30 mL of OraPlus and 30 mL of OraSweet together in a separate container. Empty the contents of six 500 mg capsules in a mortar; add 15 mL portion of the vehicle mixture and triturate. Transfer mixture to a 60 mL (2 ounce) amber prescription bottle. Rinse the mortar with an additional 15 mL of vehicle mixture and pour into the amber bottle. Repeat rinsing procedure until a final bottle volume of 60 mL is achieved. Label the bottle "shake well". Stable for 90 days at 3°C to 5°C (37°F to 41°F) or 23°C to 25 °C (73°F to 77°F).

VandenBussche HL, Johnson CE, Yun J, et al. Stability of flucytosine 50 mg/mL in extemporaneous oral liquid formulations. Am J Health Syst Pharm. 2002;93(19):1853-1855.12374070

Administration

Administer around-the-clock to promote less variation in peak and trough serum levels. To avoid nausea and vomiting, administer a few capsules at a time over 15 minutes until full dose is taken.

Storage

Store at room temperature of 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Amphotericin B: May enhance the adverse/toxic effect of Flucytosine. This may be related to the adverse effects of amphotericin B on renal function. Monitor therapy

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Cytarabine (Conventional): May diminish the therapeutic effect of Flucytosine. Consider therapy modification

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Gimeracil: May increase serum concentrations of the active metabolite(s) of Flucytosine. Specifically, gimeracil may increase concentrations of fluorouracil. Avoid combination

Saccharomyces boulardii: Antifungal Agents (Systemic, Oral) may diminish the therapeutic effect of Saccharomyces boulardii. Avoid combination

Test Interactions

Flucytosine causes markedly false elevations in serum creatinine values when the Ektachem® analyzer is used. The Jaffé reaction is recommended for determining serum creatinine.

Adverse Reactions

Frequency not defined.

Cardiovascular: Cardiotoxicity, chest pain, ventricular dysfunction

Central nervous system: Ataxia, confusion, fatigue, hallucination, headache, paresthesia, parkinsonian-like syndrome, peripheral neuropathy, psychosis, sedation, seizure, vertigo

Dermatologic: Pruritus, skin photosensitivity, skin rash, toxic epidermal necrolysis, urticaria

Endocrine & metabolic: Hypoglycemia, hypokalemia

Gastrointestinal: Abdominal pain, anorexia, diarrhea, duodenal ulcer, enterocolitis, nausea, ulcerative colitis, vomiting, xerostomia

Genitourinary: Azotemia, crystalluria

Hematologic & oncologic: Agranulocytosis, anemia, aplastic anemia, bone marrow aplasia, eosinophilia, hemorrhage, leukopenia, pancytopenia, thrombocytopenia

Hepatic: Hepatic injury (acute), hepatic insufficiency, increased liver enzymes, increased serum bilirubin, jaundice

Hypersensitivity: Hypersensitivity reaction

Neuromuscular & skeletal: Weakness

Otic: Auditory impairment

Renal: Increased blood urea nitrogen, increased serum creatinine, renal failure

Respiratory: Dyspnea

Miscellaneous: Fever

ALERT: U.S. Boxed Warning

Monitoring:

Use with extreme caution in patients with renal impairment. Close monitoring of hematologic, renal, and hepatic status of all patients is essential.

Warnings/Precautions

Disease-related concerns:

• Hematologic disease: Use with caution in patients with bone marrow depression, hematologic disease or who have been treated with radiation or drugs that suppress the bone marrow; bone marrow toxicity may be irreversible.

• Hepatic impairment: Use with caution in patients with hepatic impairment; hepatotoxicity may occur.

• Renal impairment: [US Boxed Warning]: Use with extreme caution in patients with renal dysfunction; dosage adjustment required.

Other warnings/precautions:

• Monitoring: [US Boxed Warning]: Closely monitor hematologic, renal, and hepatic status. Hepatotoxicity and bone marrow toxicity appear to be dose related; monitor levels closely and adjust dose accordingly.

• Monotherapy: Avoid use as monotherapy; resistance rapidly develops.

Monitoring Parameters

Pretreatment: Electrolytes (especially potassium), CBC with differential, BUN, renal function, blood culture

During treatment: CBC with differential, and LFTs (eg, alkaline phosphatase, AST/ALT) frequently, serum flucytosine concentration, renal function

Pregnancy Risk Factor

C

Pregnancy Considerations

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.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, dry mouth, abdominal pain, nausea, vomiting, diarrhea, or lack of appetite. Have patient report immediately to prescriber signs of infection, signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), angina, tachycardia, illogical thinking, seizures, mood changes, hearing impairment, change in balance, burning or numbness feeling, shortness of breath, or hallucinations (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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