Ancobon

Generic Name: Flucytosine
Class: Pyrimidines
VA Class: AM700
CAS Number: 2022-85-7

Introduction

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

Uses for Ancobon

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

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}

Ancobon 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 Cl_cr 20–40 mL/minute, every 24 hours in those with Cl_cr 10–20 mL/minute, and every 24–48 hours or longer (as determined by serum drug concentrations) in those with Cl_cr <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 Cl_cr <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 Ancobon

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 Ancobon

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

Ancobon 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 Cl_cr 40 mL/minute, 12–15 hours in those with Cl_cr 20 mL/minute, 21–27 hours in those with Cl_cr 10 mL/minute, and 30–250 hours in those with Cl_cr <10 mL/minute.^a Half-lives up to 1160 hours have been reported when Cl_cr <2 mL/minute.^a

Stability

Storage

Oral

Capsules

25°C; may be exposed to 15–30°C.¹²⁰

Actions and SpectrumActions

• 
  

  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

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions December 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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