Flucytosine

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

Introduction

Antifungal; fluorinated pyrimidine analog structurally related to fluorouracil and floxuridine.120 150

Uses for Flucytosine

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).137 148 157 167 Unclear whether concomitant amphotericin B and flucytosine offers any benefit over amphotericin B alone for treatment of invasive aspergillosis,157 167 and there are concerns related to possible increased risk of adverse effects.137 157

Flucytosine is not included in current IDSA guidelines for treatment of aspergillosis.423 IDSA considers voriconazole the drug of choice for primary treatment of invasive aspergillosis in most patients and IV amphotericin B the preferred alternative.423

Candida Infections

Treatment of serious Candida infections, including urinary tract or pulmonary infections, candidemia, endocarditis, meningitis, and endophthalmitis.108 120 133 146 167 425 441 Usually used in conjunction with IV amphotericin B.108 120 133 146 167 425 441 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.120 167 425

For treatment of CNS candidiasis, IDSA recommends initial treatment with IV amphotericin B (with or without oral flucytosine), then follow-up treatment with fluconazole.425 Although not recommended as a regimen of choice, fluconazole given with flucytosine has been effective in some patients with Candida meningitis.425

IDSA states that oral flucytosine alone is an alternative for treatment of symptomatic candiduria caused by fluconazole-resistant Candida, but is not recommended as primary therapy for uncomplicated Candida cystitis.425 IV amphotericin B (with or without oral flucytosine) or oral flucytosine alone is an alternative for treatment of pyelonephritis; IV amphotericin B (with or without oral flucytosine) is an alternative for fungus balls caused by fluconazole-resistant Candida.425

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Has been used orally or topically for treatment of Candida ophthalmic infections (keratitis, endophthalmitis).140 IDSA states that IV amphotericin B with oral flucytosine is the regimen of choice for treatment of Candida endophthalmitis when lesions are advancing or threaten the macula.425 Efficacy of subconjunctival injection of flucytosine in these infections not established.140

Cryptococcosis

Treatment of serious cryptococcal infections, including pulmonary infections, septicemia, and meningitis.108 109 110 111 112 113 115 116 119 120 128 133 145 147 167 427 436 440 441 Should not be used alone for treatment of cryptococcosis.120 167 427 436 440 441

Usually used in conjunction with IV amphotericin B for initial treatment of cryptococcal infections, especially cryptococcal meningitis in HIV-infected patients.108 123 128 134 135 145 167 427 436 440 441 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.107 110 111 116 118 122 427 440 Has also been used in conjunction with fluconazole for treatment of cryptococcal meningitis in HIV-infected individuals.166 427 441

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 (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 fluconazole administered for at least 8 weeks.108 427 436 440 441 A lipid formulation of amphotericin B (e.g., amphotericin B lipid complex, amphotericin B liposomal) could be substituted for conventional amphotericin B in this preferred regimen in patients who have or are predisposed to renal dysfunction.427 440 441

Alternative regimens for treatment of cryptococcal meningitis in HIV-infected adults, adolescents, and children who cannot receive the preferred regimen are induction and consolidation therapy with IV amphotericin B (conventional or lipid formulation) given for 4–6 weeks; induction therapy with IV amphotericin B (conventional formulation) given in conjunction with oral fluconazole 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 fluconazole administered for at least 8 weeks;108 427 440 441 induction and consolidation therapy with oral fluconazole used in conjunction with oral flucytosine for 4–6 weeks;108 427 440 441 or induction and consolidation therapy with oral fluconazole given for 10–12 weeks.427 These alternative regimens may be less effective and are recommended only in patients who cannot tolerate or have not responded to the preferred regimen.427 440 441

Although data are limited, IDSA states that recommendations for treatment of CNS, pulmonary, or disseminated infections caused by Cryptococcus gattii and recommendations for secondary prophylaxis of C. gattii infections are the same as recommendations for C. neoformans infections.427 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.427 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.163 164 165

Chromomycosis

Treatment of chromomycosis (chromoblastomycosis) caused by various dematiaceous fungi (e.g., Cladosporium, Exophiala, Phialophora).133 138 139 143 161 167

Optimum regimens for chromomycosis have not been identified.133 138 143

Flucytosine may be a drug of choice used alone or in conjunction with another antifungal (e.g., IV amphotericin B, oral itraconazole, oral ketoconazole).133 137 138 139 143

Flucytosine Dosage and Administration

Administration

Oral Administration

Administer orally.120

Has been administered IV, but a parenteral preparation not commercially available in the US.150

Nausea or vomiting associated with oral flucytosine may be reduced or avoided if each dose is administered by ingesting the capsules a few at a time over a 15-minute period.120

Dosage

Prolonged serum flucytosine concentrations >100 mcg/mL may be associated with an increased risk of toxicity (e.g., adverse hematologic, GI, and hepatic effects),120 150 169 170 adjust to ensure that serum concentrations remain <100 mcg/mL.133 150 169 170 436 Optimal serum concentrations have not been identified,170 and a variety of target ranges have been recommended.108 150 167 168 169 170 427 440 441

Measure serum flucytosine concentrations after 3–5 days of therapy427 and whenever there is evidence of toxicity or a change in renal function.168 Peak serum concentrations usually are measured using samples taken 2 hours after an oral dose.427 440

AAP, CDC, NIH, IDSA, and others recommend target concentrations of 40–60 mcg/mL.108 150 441 For treatment of cryptococcal infections, IDSA recommends target concentrations of 30–80 mcg/mL.427

Pediatric Patients

General Pediatric Dosage
Oral

50–150 mg/kg daily, administered in 4 equally divided doses at 6-hour intervals.108

Candida Infections
Invasive Candidiasis (Including CNS Infections)
Oral

HIV-infected infants and children: 100–150 mg/kg daily given in 4 equally divided doses in conjunction with IV amphotericin B.441 Continue treatment for candidemia 2–3 weeks after clearance of Candida from the bloodstream is documented and neutropenia and symptoms attributable to candidemia resolve.425 441

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.427

HIV-infected infants and children with severe pulmonary or disseminated (non-CNS) cryptococcosis: 100 mg/kg daily in 4 divided doses in conjunction with IV amphotericin B.441 Treatment duration depends on response and site and severity of infection.441

HIV-infected infants, children, and adolescents with cryptococcal meningitis: Induction therapy with 100 mg/kg daily given in 4 divided doses 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 for at least 8 weeks.427 441

HIV-infected infants and children with cryptococcal meningitis who cannot receive amphotericin B: Induction therapy with 100 mg/kg daily in 4 divided doses in conjunction with oral or IV fluconazole given for at least 2 weeks, then consolidation therapy with oral or IV fluconazole alone for at least 8 weeks.441

Adults

General Adult Dosage
Oral

50–150 mg/kg daily, administered in 4 equally divided doses at 6-hour intervals.120

To reduce risk of toxicity when used in conjunction with IV amphotericin B, a low initial dosage (i.e., 75 mg/kg daily given in 4 divided doses) has been suggested.436 Dosage can then be adjusted based on serum flucytosine concentrations and presence or absence of amphotericin B-associated renal toxicity.436

Candida Infections
Treatment of 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.425 Continue antifungal treatment until signs and symptoms, CSF abnormalities, and radiologic abnormalities resolve.425

Treatment of Symptomatic Cystitis Caused by Fluconazole-resistant Candida
Oral

25 mg/kg 4 times daily for 7–10 days.425

Treatment of Pyelonephritis or Fungus Balls Caused by Fluconazole-resistant Candida
Oral

Pyelonephritis: 25 mg/kg 4 times daily alone or in conjunction with IV amphotericin B for 2 weeks.425

Fungus balls: 25 mg/kg 4 times daily in conjunction with IV amphotericin B continued until symptoms resolve and urine cultures are negative for Candida.425

Treatment of Candida Endophthalmitis
Oral

Patients with advancing lesions or lesions threatening the macula: 25 mg/kg 4 times daily in conjunction with IV amphotericin B.425 Duration of treatment is at least 4–6 weeks as determined by repeated examinations to verify resolution.425

Treatment of Candida Endocarditis
IV

25 mg/kg 4 times daily in conjunction with IV amphotericin B.425 If infection is caused by fluconazole-susceptible strains, consider changing to follow-up therapy with oral fluconazole after patient is clinically stable and Candida have been cleared from the bloodstream.425

Cryptococcosis
Treatment of Cryptococcal Meningitis
Oral

HIV-infected adults: 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 fluconazole alone for at least 8 weeks.427 440

HIV-infected adults who cannot receive amphotericin B: Induction therapy with 25 mg/kg 4 times daily in conjunction with oral fluconazole for 4–6 weeks, then consolidation therapy with oral fluconazole alone for at least 8 weeks.427 440

Special Populations

Renal Impairment

Use with extreme caution and reduce dosage.120

Several methods of calculating flucytosine dosage for impaired renal function have been proposed.a For greater accuracy, dosage should be based on actual serum flucytosine concentrations.a Precise dosing is limited since flucytosine is commercially available only as 250- and 500-mg capsules.a

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.a

Alternatively, consider 12–35 mg/kg at intervals equal to twice the half-life of the drug.a In patients with Clcr <10 mL/minute, an initial loading dose (the usual individual dose) followed by 6–17.5 mg/kg administered at intervals equal to the half-life may be of particular value.a

In patients undergoing hemodialysis every 48–72 hours, 20–50 mg/kg administered immediately after dialysis generally produces therapeutically effective and nontoxic peak and postdialysis serum drug concentrations.a

Cautions for Flucytosine

Contraindications

  • Hypersensitivity to flucytosine.120

Warnings/Precautions

Warnings

Bone Marrow Toxicity

Moderate hypoplasia of bone marrow, resulting in anemia, leukopenia, pancytopenia, thrombocytopenia, or agranulocytosis may occur.120 a Eosinophilia and aplastic anemia also reported.120

Bone marrow toxicity can be irreversible and may be fatal in immunosuppressed patients.120

Risk of bone marrow toxicity is increased with prolonged, high serum flucytosine concentrations (i.e., ≥100 mcg/mL), particularly in renal dysfunction or during concomitant therapy with amphotericin B.a

Use with extreme caution in bone marrow depression, including patients with hematologic disease and those who currently or previously received treatment with radiation or drugs associated with bone marrow depression.120

Monitor hematologic function frequently during therapy.120

Sensitivity Reactions

Hypersensitivity Reactions

Allergic reactions (including anaphylaxis) reported rarely.103 120

General Precautions

Laboratory Monitoring

Prior to initiation of therapy, determine serum electrolytes (hypokalemia) and hematologic and renal status of the patient.120

During therapy, frequently monitor hematologic, renal, and hepatic function.120

Whenever possible, monitor serum flucytosine concentrations to minimize risk of toxicity, especially in patients with renal impairment.133 150 (See Dosage under Dosage and Administration.)

Specific Populations

Pregnancy

Category C.120

Lactation

Not know whether distributed into human milk.120 Discontinue nursing or the drug.120

Pediatric Use

Safety and efficacy not systematically studied in children.120

Has been used in some neonates (with or without concomitant amphotericin B) without unusual adverse effects.120 Hypokalemia, acidemia, anemia, and thrombocytopenia have been reported.120

Renal Impairment

Use with extreme caution in impaired renal function because of increased risk of adverse effects.120

Substantially eliminated by the kidneys; renal impairment may lead to drug accumulation.120

Dosage adjustments necessary in renal impairment.120 (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); renal effects; hepatic effects; CNS effects (confusion, hallucinations, psychosis).120 167 a

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 drug124

In vitro evidence of synergistic antifungal effects against Candida and Cryptococcus neoformans120 a

When used concomitantly, especially in HIV-infected patients, carefully monitor serum flucytosine concentrations and hematologic function109 115 116 118 122

Consider initiating flucytosine at a low dosage (i.e., 75 mg/kg daily) and adjust subsequent dosage based on serum flucytosine concentrations436

Cytarabine

May antagonize antifungal activity of flucytosine120 167

Concomitant use not recommended167

Fluconazole or itraconazole

In vitro evidence of synergistic, additive, or indifferent antifungal effects with fluconazole or itraconazole against C. neoformans; no evidence of antagonism129 130 153

Flucytosine Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely absorbed from GI tract;120 bioavailability is 78–89%.120

In normal renal function, peak serum flucytosine concentrations reached within 2 hours following a single 2-g oral dose.120

Food

Food decreases rate, but not extent, of absorption.a

Special Populations

In a limited number of neonates receiving oral flucytosine, mean time to peak serum concentrations was 2.5 hours after a dose.120 Considerable interindividual variation in serum concentrations, not correlated with gestational age, reported in neonates.120

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

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

Distribution

Extent

Widely distributed into body tissues and fluids including liver, kidney, spleen, heart, aqueous humor, and bronchial secretions.a

Distributed into CSF;120 concentrations in CSF may be 60–100% of serum concentrations.a

Not known whether distributed into milk.a

Plasma Protein Binding

2–4% bound to serum proteins.a

Elimination

Metabolism

Only minimal amounts are metabolized.a Deaminated (probably by gut bacteria) to fluorouracil.120 AUC ratio of fluorouracil to flucytosine is 4%.120

Elimination Route

>75–90% of an oral dose excreted unchanged in urine.a

Unabsorbed flucytosine excreted unchanged in feces.a

Removed by peritoneal dialysis.a

Removed by hemodialysis.a

Half-life

2.4–6 hours in normal renal function.a

Special Populations

In a limited number of infants, median half-life was 7.4 hours.120

Half-life prolonged in renal impairment.a

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.a Half-lives up to 1160 hours have been reported when Clcr <2 mL/minute.a

Stability

Storage

Oral

Capsules

25°C; may be exposed to 15–30°C.120

Actions and Spectrum

  • May be fungistatic or fungicidal in action, depending on concentration of the drug.151

  • Appears to enter fungal cells via the action of fungal-specific cytosine permease.120 150 167 Inside the cell, flucytosine is converted into fluorouracil (5-FU) by cytosine deaminase and then converted into 5-fluorouridine triphosphate (FUTP).150 151 167 FUTP is incorporated into fungal RNA and interferes with protein synthesis.150 151 167

  • Flucytosine also appears to be converted to 5-fluorodeoxyuridine monophosphate, which noncompetitively inhibits thymidylate synthetase and interferes with DNA synthesis.150 151 167

  • Does not appear to have antineoplastic activity.a

  • Active against Candida,120 152 162 Cryptococcus neoformans,120 152 153 162 C. gattii,158 162 and some other fungi.a Inactive against bacteria.a

  • Candida: Active in vitro and in vivo against C. albicans,152 162 C. glabrata,152 162 C. guilliermondii,162 C. krusei,162 C. parapsilosis,152 162 and C. tropicalis.152 162 Some strains of C. lusitaniae may be susceptible,154 155 162 but others are resistant.154 155 C. kefyr usually resistant.162

  • Other fungi: Has some in vitro activity against Sporothrix schenckii,a Aspergillus,a Cladosporium,a Exophiala,143 and Phialophora.a Active against some strains of Penicillium marneffei.159 Has little or no activity against Coccidioides immitis, Paracoccidioides brasiliensis, Histoplasma capsulatum, Blastomyces dermatitidis, Madurella species, phycomycetes, or dermatophytes.a

  • Resistance has been reported in some strains of Candida or Cryptococcus;150 151 resistant strains of Candida, C. neoformans, or Cladosporium have emerged in patients receiving oral flucytosine alone or in conjunction with IV amphotericin B.137 150 151

  • Resistance can develop during prolonged monotherapy.120 No cross-resistance between flucytosine and amphotericin B.120

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.120

  • Importance of informing clinician of existing or contemplated therapy, including prescription and OTC drugs, or any concomitant illness.120

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.120

  • Importance of advising patients of other important precautionary information.120 (See Cautions.)

Preparations

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

Flucytosine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

250 mg

Ancobon

Valeant

500 mg

Ancobon

Valeant

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions December 1, 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

Only references cited for selected revisions after 1984 are available electronically.

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