- Cryptococcal and Candida endocarditis (in addition to amphotericin B).
- Cryptococcal meningitis (in addition to amphotericin B).
- Cryptococcal and Candida pneumonia (in addition to amphotericin B).
- Cryptococcal and Candida septicemia (in addition to amphotericin B).
- Cryptococcal and Candida urinary tract infections (in addition to amphotericin B).
250 mg 100/caps
500 mg 100/caps
*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).
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
- 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
- GI intolerance: diarrhea, dyspepsia, and abdominal pain
- Marrow suppression: leukopenia or thrombocytopenia (with concentrations >100 mcg/mL)
- Taste perversion
- Hepatitis (hepatic necrosis has been reported)
- Peripheral neuropathy
- Fatal bone marrow aplasia
Flucytosine interferes with protein synthesis by incorporation into fungal RNA after being converted to 5-FU intracellularly.
Metabolism and Excretion
Minimal metabolism; principally excreted unchanged in the urine. Unabsorbed drug excreted in feces.
Cmax, Cmin, and AUC
30-40 mcg/mL after 2 g PO.
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.
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.
- 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.
- 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.
- 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).
- 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.
- 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
- 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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