Flucytosine: Pediatric drug information

(For additional information see "Flucytosine: Drug information" and see "Flucytosine: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)

ALERT: US 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.

Brand Names: US

Ancobon

Therapeutic Category

Antifungal Agent, Systemic

Dosing: Neonatal

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 (Ref): Limited data available:

Preterm and term neonates: Oral:

Body Weight	Postnatal Age	Dose
<1 kg	<14 days	75 mg/kg/day in divided doses every 8 hours
<1 kg	14 to 60 days	100 mg/kg/day in divided doses every 6 hours
1 to ≤2 kg	≤7 days	75 mg/kg/day in divided doses every 8 hours
1 to ≤2 kg	8 to 60 days	100 mg/kg/day in divided doses every 6 hours
>2 kg	≤60 days	100 mg/kg/day in divided doses every 6 hours

Note: Reported dosing range: 25 to 150 mg/kg/day in divided doses every 6 to 24 hours; closely monitor serum concentrations (Ref).

Candidal meningitis

Candidal meningitis: Limited data available: Note: Not routinely recommended; typically reserved for salvage therapy due to toxicity profile and unclear benefit (Ref).

Preterm and term neonates: Oral: 100 mg/kg/day in divided doses every 6 to 8 hours in combination with amphotericin B; usual reported range: 75 to 150 mg/kg/day; dosing based on a retrospective study and case reports including premature neonates (GA: 24 to 28 weeks; PMA at treatment: 26 to 29 weeks); dosing up to 200 mg/kg/day was reported in one preterm neonate (GA 32 weeks); treatment duration in some cases was up to 4 months (Ref).

Dosing: Pediatric

General dosing: Infants, Children, and Adolescents: Oral: 25 mg/kg/dose every 6 hours as part of an appropriate combination regimen (Ref).

Aspergillosis, endocarditis

Aspergillosis, endocarditis: Limited data available: Note: Flucytosine is not included in IDSA guidelines for management of aspergillosis (Ref).

Children and Adolescents: Oral: 37.5 mg/kg/dose every 6 hours in combination with amphotericin B (Ref).

Candidiasis

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; treatment

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).

Dosing: Kidney Impairment: Pediatric

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.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling; however, flucytosine has minimal hepatic metabolism; use caution.

Dosing: Adult

(For additional information see "Flucytosine: Drug information")

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

Candidiasis

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

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).

Dosing: Kidney Impairment: Adult

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).

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

Adverse Reactions

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)

Contraindications

Hypersensitivity to flucytosine or any component of the formulation; known complete dihydropyrimidine dehydrogenase enzyme deficiency.

Warnings/Precautions

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.

Warnings: Additional Pediatric Considerations

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).

Dosage Forms: US

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

Generic Equivalent Available: US

Yes

Pricing: US

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

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Extemporaneous Preparations

50 mg/mL Oral Suspension (ASHP standard concentration) (ASHP 2017)

A 50 mg/mL oral suspension may be made with capsules and OraPlus and OraSweet SF. Mix 30 mL of OraPlus and 30 mL of OraSweet SF 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

10 mg/mL Oral Suspension

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

16% intravaginal cream

A 16% cream may be made with fourteen 500 mg capsules; open into a mortar and reduce to fine powder. Levigate powder with glycerin to form a smooth paste; add to hydrophilic ointment base or cold cream for a total weight of 45 g. Blend until smooth and transfer to two 2-ounce ointment tubes. Instruct patient to insert mixture into 6.4 g vaginal applicator prior to use (Horowitz 1986).

Horowitz BJ. Topical flucytosine therapy for chronic recurrent Candida tropicalis infections. J Reprod Med. 1986;31(9):821-824.3772900

Administration: Pediatric

Oral: To reduce or avoid nausea and vomiting, administer a few capsules at a time over 15 minutes until full dose is taken.

Administration: Adult

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).

Storage/Stability

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

Use

Treatment of serious infections caused by susceptible strains of Candida (eg, candidemia, endocarditis, pulmonary infections, urinary tract infections) and/or Cryptococcus (eg, meningitis, pulmonary infections, cryptococcemia, urinary tract infections) in combination with amphotericin B (FDA approved in adults).

Medication Safety Issues

Sound-alike/look-alike issues:

Flucytosine may be confused with fludarabine, fluorouracil

Ancobon may be confused with Oncovin

High alert medication:

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.

Metabolism/Transport Effects

None known.

Drug Interactions

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 Interactions

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

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.

Monitoring Parameters

Prior to therapy: Serum electrolytes (especially potassium), CBC with differential, BUN, and SCr.

During therapy: Serum electrolytes, SCr, BUN, alkaline phosphatase, AST, ALT, CBC with differential, and serum flucytosine concentrations. If serum flucytosine concentrations cannot be monitored, monitor CBC at least twice weekly (HHS [OI adult] 2022). Monitor for GI upset and rash.

Reference Range

Timing: Peak serum concentrations are routinely recommended; obtain at steady-state after initiation of a new regimen (eg, within 3 to 5 days of therapy), following dosage adjustments, and as clinically indicated (eg, change in kidney function, bone marrow toxicity). Trough concentrations may also be monitored for avoidance of resistance development or to allow pharmacokinetic calculations (AST-ID COP [Baddley 2019]; BSMM [Ashbee 2014]; Downes 2020; IDSA [Pappas 2016]; IDSA [Perfect 2010]; HHS [OI adult] 2022; HHS [OI pediatric] 2022; Red Book [AAP 2021].

Peak: Collect sample 2 hours after oral dose administration.

Trough: If obtained, collect sample at the end of the dosing interval (ie, 6 hours after oral dose administration), just prior to next dose.

Target:

Peak (2-hour): ≤100 mg/L (to avoid bone marrow toxicity and hepatotoxicity); a target of 30 to 80 mg/L has also been suggested (AST-ID COP [Baddley 2019]; Bradley 2022; Gómez-López 2020; IDSA [Pappas 2016]; IDSA [Perfect 2010]; Red Book [AAP 2021]). Peak concentrations of 40 to 60 mg/L have also been recommended for pediatric patients with HIV and cryptococcal disease (HHS [OI pediatric] 2022).

Trough: Recommendations are variable; targets of 25 to 50 mg/L or >20 to 40 mg/L have been suggested; see institutional protocol (BSMM [Ashbee 2014]; Downes 2020; Gómez-López 2020; Vermes 2000). Trough concentrations <25 mg/L may be associated with development of resistance, though data are limited and study evaluated flucytosine monotherapy (Normark 1972). For treatment of candidiasis in neonates, time above MIC of >40% (with trough concentration of 5 to 10 mg/L) has also been recommended (Bradley 2022).

Mechanism of Action

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).

Pharmacokinetics (Adult Data Unless Noted)

Absorption: Rapid.

Distribution: Into CSF, aqueous humor, joints, peritoneal fluid; V_d: 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).

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

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).

Brand Names: International

International Brand Names by Country

For country code abbreviations (show table)

(AR) Argentina: Ancotil;
(AT) Austria: Ancotil;
(AU) Australia: Ancobon | Ancotil;
(CH) Switzerland: Ancotil;
(CO) Colombia: Ancobon;
(CZ) Czech Republic: Ancotil;
(FI) Finland: Ancotil;
(FR) France: Ancotil;
(GB) United Kingdom: Alcobon;
(GR) Greece: Ancotil;
(HK) Hong Kong: Ancotil;
(HU) Hungary: Ancotil;
(IT) Italy: Ancotil;
(LT) Lithuania: Ancotil;
(LV) Latvia: Ancotil;
(MA) Morocco: Ancotil;
(NL) Netherlands: Ancotil;
(NZ) New Zealand: Alcobon | Ancobon;
(PL) Poland: Ancotil | Ancotil Roche;
(PR) Puerto Rico: Ancobon;
(PT) Portugal: Ancobon;
(SE) Sweden: Ancotil;
(SG) Singapore: Ancotil;
(SI) Slovenia: Ancotil;
(SK) Slovakia: Ancotil

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Topic 13304 Version 228.0

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Flucytosine: Pediatric drug information