INDICATIONS

FDA

FORMS

brand name

preparation

manufacturer

route

form

dosage^

cost*

Ancobon

Flucytosine (5-FC)

ICN Pharmaceuticals

oral

capsule

250 mg 100/caps

$22.64

oral

capsule

500 mg 100/caps

$43.81

*Prices represent cost per unit specified, are representative of "Average Wholesale Price" (AWP).
^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

  • 25 mg/kg PO q6h in combination with amphotericin B products
    • Sole exception: monotherapy can be used for Candida UTI, e.g. azole-resistant candiduria.
    • Obesity: use IBW for dosing
  • Therapeutic drug monitoring recommended with renal insufficiency.
    • Goal peak, 2 hrs post-dose after 3-5 days: 30-80 mcg/mL

ADULT RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

25 mg/kg q6h.

DOSING FOR GLOMERULAR FILTRATION OF 10-50

25 mg/kg q12-24h (monitor CBC and serum levels with appropriate dose adjustments).

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

25 mg/kg q24-48h (monitor CBC serum levels closely with appropriate dose adjustments).

DOSING IN HEMODIALYSIS

25 mg/kg q24-48h. Dose post-dialysis on days of dialysis (monitor CBC and serum levels w/ appropriate dose adjustment).

DOSING IN PERITONEAL DIALYSIS

0.5-1.0 gm q24h (monitor CBC and serum levels w/ appropriate dose adjustments).

DOSING IN HEMOFILTRATION

CVVH and CVVHD: no data. Consider 25 mg/kg q24 for dialysis rate of 1L/hr and 25 mg/kg q12h for dialysis rate > or = 1.5 L/hr (monitor CBC and serum levels with appropriate dose adjustments).

PEDIATRIC DOSING

USUAL PEDIATRIC DOSING

  • 25 mg/kg PO q6h
  • Adjust dose to maintain flucytosine concentrations (2-hour post-dose) between 40-60 mcg/mL.
  • Obtain drug levels after 3-54 days of continuous dosing.

PEDIATRIC RENAL DOSING

  • CrCL
    • 20-40 mL/min: 25 mg/kg q12h
    • 10-20 mL/min: 25mg/kg q24 h
    • < 10 ml/min: 25mg/kg q24-48h
  • Important to adjust dose to maintain 2-hour post-dose between 40-60 mcg/mL.
  • Supplemental dose needed after hemodialysis or peritoneal dialysis.

Pediatric Dosing Author: George K Siberry, MD, MPH

ADVERSE DRUG REACTIONS

OCCASIONAL

  • GI intolerance: diarrhea, dyspepsia, and abdominal pain
  • Marrow suppression: leukopenia or thrombocytopenia (with concentrations >100 mcg/mL)
  • Headache
  • Taste perversion
  • Pruritus

RARE

  • Confusion
  • Rash
  • Hepatitis (hepatic necrosis has been reported)
  • Peripheral neuropathy
  • Enterocolitis
  • Photosensitivity
  • Fatal bone marrow aplasia

DRUG INTERACTIONS

  • Cytarabine: antagonism (avoid co-administration).
  • Drugs that cause bone marrow suppression (e.g., AZT, ganciclovir, and interferon): increased bone marrow suppression.

PHARMACOLOGY

MECHANISM

Flucytosine interferes with protein synthesis by incorporation into fungal RNA after being converted to 5-FU intracellularly.

PHARMACOKINETIC PARAMETERS

Absorption

75-90%.

Metabolism and Excretion

Minimal metabolism; principally excreted unchanged in the urine. Unabsorbed drug excreted in feces.

Protein Binding

2-4%.

Cmax, Cmin, and AUC

30-40 mcg/mL after 2 g PO.

T1/2

2.5-6 hrs.

Distribution

Widely distributed into body tissues and fluids such as liver, kidney, spleen, heart, aqueous humor and bronchial secretion. Good CNS penetration (60-100% of serum concentration attained in the CSF).

DOSING FOR DECREASED HEPATIC FUNCTION

No data. Usual dose likely.

PREGNANCY RISK

Category C: Teratogenicity reported in animal studies. Partially metabolized to 5-fluorouracil, a known human teratogen. Avoid use in first trimester.

BREAST FEEDING COMPATIBILITY

No data. Breast feeding during flucytosine therapy not recommended because of concern for potential adverse effects.

COMMENTS

  • Most often used as part of recommended combination with amphotericin for treatment of cryptococcal meningitis, resulting in more rapid CSF sterilization, but clinical outcome similar with or without flucytosine.
    • Should be used if tolerated, but can treat with amphotericin B alone if toxicity develops.
  • Close monitoring of renal function and serum level critical to prevent bone marrow suppression.
  • 5-FC may be considered in combination with amphotericin (and surgery) in the treatment of candidal endocarditis.
  • Flucytosine should never be used alone due to the rapid development of resistance, with the exception of candiduria.

References

  1. van der Horst CM et al: Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med 337:15, 1997  [PMID:9203426]

    Comment: Addition of 5FC to amphotericin resulted in faster CSF sterilization but did not improve clinical outcome.

  2. Saag MS et al: A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis 28:291, 1999  [PMID:10064246]

    Comment: Fluconazole superior to itraconazole for maintenance therapy of cryptococcal meningitis. Factor best associated with relapse was having not received flucytosine during the initial 2 wks of primary treatment for cryptococcal disease (relative risk = 5.88; 95% confidence interval, 1.27-27.14; p=0.04).

  3. Perfect JR et al: Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis 50:291, 2010  [PMID:20047480]

    Comment: Flucytosine plus AmphoB, liposomal AmB, or AmB lipid complex (for a minimum of 2 weeks) is recommended for the treatment of cryptococcal meningoencephalitis. Without flucytosine, the recommended amphoB treatment duration is 4-6 weeks. Fluconazole 1200 mg/day plus flucytosine x 6 weeks can be considered as an alternative in patients unable to tolerate amphoB.

  4. Vermes A, Guchelaar HJ, Dankert J: Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother 46:171, 2000  [PMID:10933638]

    Comment: Focused review on pharmacological aspects of this antifungal drug, originally developed in 1957 as an antimetabolite

  5. Yao ZW et al: Comparison of flucytosine and fluconazole combined with amphotericin B for the treatment of HIV-associated cryptococcal meningitis: a systematic review and meta-analysis. Eur J Clin Microbiol Infect Dis Feb 20  [PMID:24550039]

    Comment: Group exmained primary outcomes using mortality d14 and d70 with secondary outcome as early fungicidal activity (EFA) at 2 weeks. Four trials were identified. Meta-analysis found lower mortality in patients given AmB + 5-FC at the 2 weeks point--combination group 44% [risk ratio (RR) 0.56, 95% confidence interval (CI) 0.33-0.95, p = 0.03]. EFA was significantly shorter in patients receiving AmB plus 5-FC [mean difference (MD) -0.10 log10 colony-forming units (CFU) per day, 95 % CI -0.11-0.09, p <  0.00001]. Mortality was no different between the 5-FC and fluconazole groups at the 3 months time point (p = 0.15) Adverse events occurred with similar frequency between the two treatment groups. There was no statistically significant difference in the survival rate between AmB in combination with high-dose fluconazole and the current standard of AmB plus 5-FC therapy for HIV-associated cryptococcal meningitis.

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Last updated: January 15, 2016