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Flucytosine

Class: Pyrimidines
VA Class: AM700
CAS Number: 2022-85-7
Brands: Ancobon

Medically reviewed by Drugs.com on May 31, 2021. Written by ASHP.

Introduction

Antifungal; fluorinated pyrimidine analog.

Uses for Flucytosine

Candida Infections

Treatment of serious Candida infections, including urinary tract or pulmonary infections, candidemia, endocarditis, meningitis, and endophthalmitis. Usually used in conjunction with IV amphotericin B. Should not be used alone for systemic candidiasis or severe, life-threatening infections since it may be ineffective or result in emergence of flucytosine resistance.

For treatment of CNS candidiasis in adults, IDSA recommends initial treatment with IV amphotericin B (with or without oral flucytosine) followed by step-down treatment with fluconazole.

Although oral flucytosine has been used in conjunction with IV amphotericin B for treatment of severe invasive candidiasis, including CNS candidiasis, in pediatric patients, this regimen not usually recommended for treatment of candidiasis in children, including HIV-infected children. AAP and others state that routine use of flucytosine for treatment of meningitis in neonates not recommended because of toxicity concerns. IDSA states consider salvage therapy with a regimen of flucytosine and amphotericin B in neonates only if there is no response to amphotericin B alone.

For treatment of endocarditis (native or prosthetic valve) or implantable cardiac device infections caused by Candida, IDSA recommends initial treatment with a lipid formulation of IV amphotericin B (with or without oral flucytosine) or an IV echinocandin (anidulafungin, caspofungin, micafungin) followed by step-down treatment with fluconazole.

For treatment of urinary tract infections caused by Candida, especially fluconazole-resistant strains, oral flucytosine is used alone or in conjunction with IV amphotericin B. IDSA states antifungal treatment not usually indicated in patients with asymptomatic cystitis, unless there is high risk of disseminated candidiasis (e.g., neutropenic patients, low-birthweight infants [<1.5 kg], patients undergoing urologic manipulations). Fluconazole is drug of choice for treatment of symptomatic cystitis, pyelonephritis, or fungus balls likely to be caused by fluconazole-susceptible Candida. When fluconazole-resistant C. glabrata are likely, IV amphotericin B or oral flucytosine recommended for symptomatic cystitis and IV amphotericin B (with or without oral flucytosine) or oral flucytosine alone recommended for pyelonephritis.

For treatment of endophthalmitis caused by fluconazole- and voriconazole-resistant Candida in adults, IDSA states IV amphotericin B liposomal (with or without oral flucytosine) is regimen of choice. Decisions regarding antifungal treatment and surgical intervention should be made jointly by an ophthalmologist and infectious disease clinician.

Cryptococcosis

Treatment of serious cryptococcal infections, including pulmonary infections, septicemia, and meningitis, caused by Cryptococcus neoformans. Should not be used alone for treatment of cryptococcosis.

Usually used in conjunction with IV amphotericin B for initial treatment of cryptococcal infections, especially cryptococcal meningitis in HIV-infected patients. Addition of flucytosine to the amphotericin B regimen for initial treatment may reduce the time required for sterilization of CSF in those with CNS involvement. Has also been used in conjunction with fluconazole for treatment of cryptococcal meningitis in HIV-infected individuals.

For treatment of cryptococcal meningitis in HIV-infected adults, adolescents, and children, CDC, NIH, IDSA, and others state that the preferred regimen is initial (induction) therapy with IV amphotericin B (liposomal or conventional formulation) given in conjunction with oral flucytosine for at least 2 weeks until there is evidence of clinical improvement and negative CSF cultures after repeat lumbar puncture, then follow-up (consolidation) therapy with oral or IV fluconazole given for at least 8 weeks, followed by long-term suppressive or maintenance therapy (secondary prophylaxis) with oral fluconazole to complete ≥1 year of azole therapy.

One alternative regimen for initial (induction) treatment of cryptococcal meningitis in HIV-infected adults, adolescents, and children who cannot receive the preferred regimen is oral or IV fluconazole used in conjunction with oral flucytosine. Alternative regimens may be less effective and are recommended only in patients who cannot tolerate or have not responded to the preferred regimen.

Although data are limited, CDC, NIH, and IDSA state that recommendations for treatment of CNS, pulmonary, or disseminated infections caused by C. gattii and recommendations for long-term suppressive or maintenance therapy (secondary prophylaxis) of C. gattii infections are the same as recommendations for C. neoformans infections. IDSA states that single, small cryptococcoma may be treated with oral fluconazole, but induction therapy with a regimen of conventional IV amphotericin B and oral flucytosine given for 4–6 weeks, followed by consolidation therapy with fluconazole given for 6–18 months should be considered for very large or multiple cryptococcomas caused by C. gattii. Regimens that include IV amphotericin B (conventional or liposomal formulation), flucytosine, and fluconazole have been effective in a few patients with CNS infections known to be caused by C. gattii.

Chromoblastomycosis

Treatment of chromoblastomycosis (chromomycosis) caused by various dematiaceous fungi (e.g., Cladosporium, Exophiala, Phialophora).

Optimum regimens for chromoblastomycosis not identified. Azole antifungals (usually itraconazole) or terbinafine have been effective and may be the preferred antifungals for treatment of chromoblastomycosis; surgery and/or adjunctive use of other therapies (e.g., heat therapy, laser therapy, photodynamic therapy) may be indicated.

Regimen of itraconazole and flucytosine has been effective in some patients; regimen of posaconazole and flucytosine suggested as a possible alternative in refractory cases. Regimen of amphotericin B and flucytosine no longer recommended for such infections.

Aspergillosis

Has been used in conjunction with IV amphotericin B for treatment of invasive aspergillosis or other infections caused by Aspergillus (e.g., osteomyelitis and joint infections). Unclear whether concomitant amphotericin B and flucytosine offers any benefit over amphotericin B alone for treatment of invasive aspergillosis, and there are concerns related to possible increased risk of adverse effects.

Voriconazole is considered drug of choice for initial treatment of invasive aspergillosis in most patients; IV amphotericin B (a lipid formulation) is preferred alternative.

Free-living Ameba Infections

Has been used in conjunction with other anti-infectives in a few patients for treatment of free-living ameba infections, including granulomatous amebic encephalitis or other infections caused by Acanthamoeba or Balamuthia mandrillaris.

CNS infections caused by free-living ameba have high mortality rate, and only very limited number of cases have been successfully treated. Early diagnosis and treatment with a multiple-drug regimen may increase chance of survival.

Although data are limited, most reported cases of Acanthamoeba and B. mandrillaris infection have been treated empirically with regimens that include a variety of anti-infectives (e.g., albendazole, amphotericin B, azole antifungals [fluconazole, itraconazole, ketoconazole], flucytosine, macrolides [azithromycin or clarithromycin], miltefosine, rifampin, pentamidine, sulfonamides [co-trimoxazole or sulfadiazine]).

Contact CDC Emergency Operations Center at 770-488-7100 for assistance with diagnosis or treatment of suspected free-living ameba infections.

Flucytosine Dosage and Administration

Administration

Oral Administration

Administer orally. Nausea or vomiting may be reduced or avoided if each dose is administered by ingesting a few capsules at a time over a 15-minute period.

For patients unable to swallow capsules, oral suspensions containing 10 or 50 mg/mL have been prepared extemporaneously using the commercially available capsules.

Has been administered IV, but a parenteral preparation not commercially available in US.

Has been administered topically as a cream, but topical preparations not commercially available in US.

Dosage

Prolonged serum flucytosine concentrations >100 mcg/mL may be associated with increased risk of toxicity (e.g., adverse hematologic, GI, and hepatic effects). Adjust dosage to ensure that serum concentrations remain <100 mcg/mL. Optimal target serum concentrations not identified, and a variety of target ranges have been recommended.

AAP, CDC, NIH, IDSA, and others generally recommend target serum concentrations of 30–80 mcg/mL.

Some clinicians suggest measuring serum flucytosine concentrations beginning 3–5 days after initiation of the drug (or beginning after 3–5 doses) and then once or twice weekly during treatment and whenever there is evidence of toxicity or a change in renal function. Peak serum concentrations usually measured using blood samples taken 2 hours after an oral dose.

Pediatric Patients

General Pediatric Dosage†
Oral

100 mg/kg daily given in 4 divided doses every 6 hours recommended by AAP.

Candida Infections
CNS Candidiasis
Oral

Neonates: If salvage therapy indicated because of nonresponse to initial treatment with IV amphotericin B alone, IDSA states consider adding flucytosine 25 mg/kg 4 times daily to the amphotericin B regimen. After several weeks and when response attained, transition to fluconazole step-down therapy. Continue antifungal treatment until all signs, symptoms, CSF abnormalities, and radiologic abnormalities (if present) have resolved.

Cryptococcosis
Oral

Children with CNS or disseminated cryptococcosis: Induction therapy with 100 mg/kg daily in 4 divided doses in conjunction with IV amphotericin B for at least 2 weeks, then consolidation therapy with oral fluconazole alone for at least 8 weeks.

HIV-infected infants, children, and adolescents with cryptococcal meningitis: Induction therapy with 25 mg/kg 4 times daily in conjunction with IV amphotericin B for at least 2 weeks until there is evidence of clinical improvement and negative CSF cultures after repeat lumbar puncture, then consolidation therapy with oral or IV fluconazole alone.

HIV-infected infants and children with cryptococcal meningitis who cannot receive amphotericin B: Induction therapy with 25 mg/kg 4 times daily in conjunction with oral or IV fluconazole.

HIV-infected infants and children with severe pulmonary or disseminated (non-CNS) cryptococcosis: 25 mg/kg 4 times daily in conjunction with IV amphotericin B. Treatment duration depends on response and site and severity of infection.

Adults

General Adult Dosage
Oral

Manufacturer recommends 50–150 mg/kg daily given in 4 divided doses at 6-hour intervals. In patients with elevated BUN or Scr, use lower dosage initially.

To reduce risk of toxicity when used in conjunction with IV amphotericin B, some clinicians suggest a low initial dosage (i.e., 75 mg/kg daily given in 4 divided doses). Dosage can then be adjusted based on serum flucytosine concentrations and presence or absence of amphotericin B-associated renal toxicity.

Candida Infections
CNS Candidiasis
Oral

25 mg/kg 4 times daily in conjunction with IV amphotericin B for several weeks, then follow-up therapy with fluconazole alone. Continue antifungal treatment until signs and symptoms, CSF abnormalities, and radiologic abnormalities resolve.

Candida Cardiovascular Infections
IV

25 mg/kg 4 times daily in conjunction with IV amphotericin B. If infection caused by fluconazole-susceptible Candida, consider transitioning to oral fluconazole after patient stabilized and Candida cleared from bloodstream.

Symptomatic Cystitis, Pyelonephritis, or Fungus Balls
Oral

Symptomatic cystitis caused by fluconazole-resistant C. glabrata: 25 mg/kg 4 times daily for 7–10 days.

Pyelonephritis caused by fluconazole-resistant C. glabrata: 25 mg/kg 4 times daily in conjunction with IV amphotericin B for up to 7 days. If used without IV amphotericin B, 25 mg/kg 4 times daily for 2 weeks recommended.

Fungus balls: 25 mg/kg 4 times daily in conjunction with IV amphotericin B for up to 7 days. If used without IV amphotericin B, 25 mg/kg 4 times daily for 2 weeks recommended.

Candida Endophthalmitis
Oral

Endophthalmitis caused by fluconazole- and voriconazole-resistant Candida: 25 mg/kg 4 times daily in conjunction with IV amphotericin B liposomal. Duration of treatment is at least 4–6 weeks as determined by repeated examinations to verify resolution.

Cryptococcosis
Oral

Severe cryptococcal infections: 100–150 mg/kg daily in conjunction with another antifungal (e.g., IV amphotericin B, fluconazole).

HIV-infected adults with cryptococcal meningitis: Induction therapy with 25 mg/kg 4 times daily in conjunction with IV amphotericin B given for at least 2 weeks until there is evidence of clinical improvement and negative CSF cultures after repeat lumbar puncture, then consolidation therapy with oral or IV fluconazole alone.

HIV-infected adults with cryptococcal meningitis who cannot receive amphotericin B: Induction therapy with 25 mg/kg 4 times daily in conjunction with oral or IV fluconazole.

Free-living Ameba Infections†
Oral

Granulomatous amebic encephalitis or other infections caused by Acanthamoeba or Balamuthia mandrillaris: Some clinicians recommend 37.5 mg/kg every 6 hours (up to 150 mg/kg daily); higher dosage has been used in some patients. Use in conjunction with other anti-infectives. (See Free-living Ameba Infections under Uses.)

Special Populations

Renal Impairment

Use with extreme caution and reduce dosage.

Several methods proposed for calculating flucytosine dosage for patients with impaired renal function. For greater accuracy, base dosage on actual serum flucytosine concentrations. Precise dosing is limited since flucytosine is commercially available only as 250- and 500-mg capsules.

Some clinicians recommend 25 mg/kg every 12 hours in adults with Clcr of 20–40 mL/minute, 25 mg/kg once daily in those with Clcr of 10–20 mL/minute, and 25 mg/kg once every 48 hours in those with Clcr <10 mL/minute.

Others state that usual individual dose (12.5–37.5 mg/kg) can be administered every 12 hours in patients with Clcr 20–40 mL/minute, every 24 hours in those with Clcr 10–20 mL/minute, and every 24–48 hours or longer (as determined by serum drug concentrations) in those with Clcr <10 mL/minute.

Alternatively, other clinicians recommend that doses of 12–35 mg/kg be given at intervals equal to twice the half-life of the drug.

In patients undergoing hemodialysis, some clinicians recommend that doses of 20–50 mg/kg be given every 48–72 hours and that doses be administered after dialysis.

Geriatric Patients

Select dosage with caution because of age-related decreases in renal function; adjust dosage based on renal function.

Cautions for Flucytosine

Contraindications

  • Hypersensitivity to flucytosine.

Warnings/Precautions

Warnings

Hematologic Effects

Anemia, leukopenia, pancytopenia, thrombocytopenia, eosinophilia, agranulocytosis, and aplastic anemia reported.

Fatal bone marrow aplasia reported in some patients. Bone marrow toxicity can be irreversible and may be fatal in immunosuppressed patients.

Risk of bone marrow toxicity is increased in patients who have hematologic disease and in those who are receiving or previously received radiation or drug therapy that depresses the bone marrow. Risk of adverse hematologic effects also may be increased in patients who have prolonged, high serum flucytosine concentrations (i.e., >100 mcg/mL), particularly in those with renal dysfunction or during concomitant therapy with amphotericin B.

Use with extreme caution in patients with bone marrow depression.

Monitor hematologic function frequently during therapy. (See Laboratory Monitoring under Cautions.)

Sensitivity Reactions

Hypersensitivity Reactions

Rash, pruritus, urticaria, toxic epidermal necrolysis (Lyell syndrome), and photosensitivity reported.

Anaphylaxis reported rarely.

General Precautions

Laboratory Monitoring

Hematologic, renal, and hepatic status must be monitored closely during flucytosine therapy.

Prior to initiation of therapy, determine hematologic status (leucocyte and thrombocyte count), renal function, hepatic function (serum alkaline phosphatase, AST, ALT), and serum electrolytes (hypokalemia).

During therapy, frequently monitor hematologic, renal, and hepatic function.

Monitor serum flucytosine concentrations to minimize risk of toxicity, especially in patients with renal impairment. (See Dosage under Dosage and Administration.)

Specific Populations

Pregnancy

Teratogenic in rats. When given to pregnant rats in a dosage of 0.051 times the human dosage, vertebral fusions occurred; at a dosage of 0.89 times the human dosage, cleft lip and palate and micrognathia reported.

No adequate or controlled studies to date using flucytosine in pregnant women.

Use during pregnancy only when potential benefits justify possible risks to the fetus.

Lactation

Not know whether distributed into human milk.

Discontinue nursing or the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and efficacy not systematically studied in children.

If used in neonates and infants, closely monitor serum concentrations of the drug. Limited data regarding flucytosine pharmacokinetics in neonates indicate considerable interindividual variation in plasma concentrations attained. High plasma concentrations of the drug may accumulate in very low-birthweight infants because of immature renal function.

Some clinicians state avoid flucytosine in children with severe renal impairment.

Has been used in some neonates (with or without concomitant amphotericin B) without unusual adverse effects. Hypokalemia, acidemia, anemia, and thrombocytopenia have been reported.

Geriatric Use

Dosage adjustment may be required in geriatric patients based on renal function. (See Renal Impairment under Dosage and Administration.)

Hepatic Impairment

Pharmacokinetics not affected by hepatic impairment.

Renal Impairment

Use with extreme caution in patients with impaired renal function.

Eliminated mainly by the kidneys; renal impairment may lead to drug accumulation and increased risk of toxicity.

Adjust dosage in patients with renal impairment. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Bone marrow suppression; GI effects (anorexia, abdominal bloating or pain, diarrhea, dry mouth, duodenal ulcer, GI hemorrhage, nausea, vomiting, ulcerative colitis, enterocolitis); hepatic effects; renal effects; CNS effects (confusion, hallucinations, psychosis).

Interactions for Flucytosine

Specific Drugs

Drug

Interaction

Comments

Amphotericin B

Possible increased risk of flucytosine toxicity; may be related to increased cellular uptake and/or decreased renal excretion of the drug

In vitro evidence of synergistic antifungal effects against Candida and C. neoformans

When used concomitantly, especially in HIV-infected patients, carefully monitor serum flucytosine concentrations and hematologic function and adjust dosage if needed

Consider initiating flucytosine at a low dosage; carefully monitor flucytosine concentrations and adjust flucytosine dosage if needed

Azole antifungals (fluconazole, itraconazole)

In vitro evidence of synergistic, additive, or indifferent antifungal effects with fluconazole or itraconazole against C. neoformans; no evidence of antagonism

Cytarabine

May antagonize antifungal activity of flucytosine

Concomitant use not recommended

Myelosuppressive agents (e.g., zidovudine)

Possible increased risk of bone marrow toxicity

Caution advised

Nephrotoxic drugs

Drugs that impair glomerular filtration: Possible prolonged flucytosine elimination half-life and increased risk of toxicity

Drugs that impair glomerular filtration: Closely monitor flucytosine serum concentrations

Flucytosine Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely absorbed from GI tract; bioavailability is 78–90%.

In normal renal function, peak serum flucytosine concentrations reached within 2 hours following a single 2-g oral dose.

Food

Food decreases rate, but not extent, of absorption.

Special Populations

In a limited number of neonates receiving oral flucytosine, mean time to peak serum concentrations was 2.5 hours after a dose. Considerable interindividual variation in serum concentrations that is not correlated with gestational age.

Peak serum concentrations are higher, more prolonged, and reached more slowly in patients with impaired renal function.

In anephric patients, peak serum concentrations may be 50% higher than in patients with normal renal function.

Distribution

Extent

Widely distributed into body tissues and fluids including liver, kidney, spleen, heart, bronchial secretions, joints, peritoneal fluid, brain, bile, bone, and aqueous humor.

Distributed into CSF; concentrations in CSF may be 60–100% of serum concentrations.

Crosses placenta after intraperitoneal administration in pregnant rats.

Not known whether distributed into milk.

Plasma Protein Binding

2.9–4% bound to serum proteins.

Elimination

Metabolism

Only minimal amounts are metabolized. Deaminated (probably by gut bacteria) to fluorouracil. AUC ratio of fluorouracil to flucytosine is 4%.

Elimination Route

Eliminated by kidneys, principally by glomerular filtration without substantial tubular reabsorption. Unabsorbed flucytosine excreted unchanged in feces.

>90% of an oral dose excreted unchanged in urine.

Removed by peritoneal dialysis.

Removed by hemodialysis.

Half-life

2.4–4.8 hours in normal renal function.

Special Populations

In a limited number of neonates and infants, median half-life was 7.4 hours.

Half-life prolonged in renal impairment.

Half-life is 6–14 hours in those with Clcr 40 mL/minute, 12–15 hours in those with Clcr 20 mL/minute, 21–27 hours in those with Clcr 10 mL/minute, and 30–250 hours in those with Clcr <10 mL/minute. Half-lives up to 1160 hours have been reported when Clcr <2 mL/minute.

Stability

Storage

Oral

Capsules

25°C; may be exposed to 15–30°C.

Actions and Spectrum

  • Fluorinated pyrimidine antifungal.

  • May be fungistatic or fungicidal in action, depending on concentration of the drug.

  • Appears to enter fungal cells via the action of fungal-specific cytosine permease. Inside the cell, flucytosine is converted into fluorouracil (5-FU) by cytosine deaminase and then converted into 5-fluorouridine triphosphate (FUTP). FUTP is incorporated into fungal RNA and interferes with protein synthesis.

  • Flucytosine also appears to be converted to 5-fluorodeoxyuridine monophosphate, which noncompetitively inhibits thymidylate synthetase and interferes with DNA synthesis.

  • Does not appear to have antineoplastic activity.

  • Candida: Active in vitro and in clinical infections against C. albicans. Also active in vitro against C. glabrata, C. guilliermondii, C. parapsilosis, and C. tropicalis. Some strains of C. krusei and C. lusitaniae may be susceptible, but others are resistant. Some clinical isolates of C. auris (often misidentified as C. haemulonii, C. famata, or Rhodotorula glutinis) have been susceptible to flucytosine in vitro; however, wide range of MICs reported and reduced susceptibility or resistance to flucytosine occurs. C. kefyr usually resistant.

  • Cryptococcus: Active in vitro and in clinical infections against C. neoformans. Also active in vitro against C. gattii.

  • Causative agents of chromoblastomycosis and phaeohyphomycosis: Some in vitro evidence of activity against some strains of Cladophialophora, Phialophora verrucosa, Exophiala (E. castellanii, E. dermatitidis, E. spinifera), and Cladosporium. Although some strains of Fonsecaea are susceptible in vitro, flucytosine reportedly has limited or no activity against this organism.

  • Other fungi: Has some in vitro activity against Aspergillus and Sporothrix schenckii, but these fungi generally considered resistant to flucytosine. Inactive against Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, Madurella, dermatophytes (Microsporum, Trichophyton, Epidermophyton), and bacteria.

  • Resistance to flucytosine can be readily induced in vitro in Candida and C. neoformans. Resistant strains of Candida and C. neoformans have emerged in patients receiving oral flucytosine alone or in conjunction with IV amphotericin B.

  • No cross-resistance between flucytosine and amphotericin B.

Advice to Patients

  • Advise patients that incidence and severity of nausea or vomiting may be decreased or eliminated if each dose is administered by ingesting the capsules a few at a time over a 15-minute period.

  • Importance of informing clinician of existing or contemplated therapy, including prescription and OTC drugs, or any concomitant illness.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Flucytosine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

250 mg*

Ancobon

Valeant

Flucytosine Capsules

500 mg*

Ancobon

Valeant

Flucytosine Capsules

AHFS DI Essentials™. © Copyright 2022, Selected Revisions June 10, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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