Flucytosine

Janessa Smith, Pharm.D., BCPS, Paul A. Pham, Pharm.D.

INDICATIONS

FDA

Cryptococcal and Candida endocarditis (in addition to amphotericin B ).
Cryptococcal meningitis (in addition to amphotericin B or liposomal amphotericin).
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).

FORMS

brand name	preparation	manufacturer	route	form	dosage^	cost*
Ancobon	Flucytosine (5-FC)	ICN Pharmaceuticals	oral	capsule	250 mg	$92.21
			oral	capsule	500 mg	$178.43
	Flucytosine (5-FC)	Generic manufacturer	oral	capsule	250 mg	$82.07
			oral	capsule	500 mg	$158.80

*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 q6h.

Therapeutic monitoring recommended with renal insufficiency to limit toxicity. Goal peak: 70-80 mcg/mL drawn 2 hrs post-dose after 3-5 days. Peak serum concentrations >100 mcg/mL associated with increased toxicity.
Dosing in obesity: Consider IBW for dosing of non-life threatening infections. For severe infections, consider using adjusted body weight and monitor serum concetrations.

RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

25 mg/kg q6h.

DOSING FOR GLOMERULAR FILTRATION OF 10-50

CrCl 20-40 mL/min: 25 mg/kg q12

CrCl 10-19 mL/min: 25 mg/kg q24h (monitor CBC and serum levels with appropriate dose adjustments).

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

25 mg/kg q48h (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: Limited data. Consider 25 mg/kg q24 for dialysis rate of 1L/hr and 25 mg/kg q12h for dialysis rate ≥1.5 L/hr (monitor CBC and serum levels with appropriate dose adjustments).

ADVERSE DRUG REACTIONS

OCCASIONAL

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

RARE

Confusion
Rash
Hepatitis (hepatic necrosis has been reported)
Peripheral neuropathy
Enterocolitis
Photosensitivity

DRUG INTERACTIONS

Drugs that cause bone marrow suppression (i.e. AZT, ganciclovir, and interferon): increased bone marrow suppression.

SPECTRUM

Cryptococcus neoformans and Candida spp.

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

Cmax: 60-80 mcg/mL, Cmin: 20-40 mcg/mL after 37.5 mg/kg/dose.

T1/2

2.5-6 hrs (normal renal function). Half-life may be up to 250 hrs in patients with ESRD.

Distribution

Widely distributed into body tissues and fluids such as liver, kidney, spleen, heart, aqueous humor and bronchial secretion. Good CNS penetration (70-85% of serum concentration attained in the CSF).

DOSING FOR DECREASED HEPATIC FUNCTION

No data. Usual dose likely.

PREGNANCY RISK

Category C. Crosses placental barrier. Teratogenicity reported in animal studies. Three case reports of second and third exposure found no defects in infants.

BREAST FEEDING COMPATIBILITY

No data. Breast feeding during flucytosine therapy not recommended.

COMMENTS

Recommended in combination with amphotericin or liposomal amphotericin for treatment of cryptococcal meningitis for at least 2 weeks. Combination therapy with flucytosine results in more rapid CSF sterilization and improved mortality when compared to amphotericin alone. When compared to amphotericin plus fluconazole, there was no difference in survival outcomes but combination with flucytosine resulted in more rapid CSF sterilization.[4][2]
Levels should be considered for patients with renal insufficiency to minimize toxicity. Levels >100 ng/mL for >2 weeks have been associated with increased risk of toxicity. Levels < 25 ng/mL have been associated with emergence of resistance in vitro.
Close monitoring of renal function and serum level may prevent bone marrow suppression.

Basis for recommendation

Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2010;50(3):291-322. [PMID:20047480]
Comment: 5FC plus amphotericin B, liposomal amphotericin, or amphotericin lipd complex (for ≥2 wks) is recommended for treatment of cryptococcal meningitis. Without 5FC, recommended amphotericinB treatment duration is 4-6 weeks. Fluconazole 1200 mg/day plus 5FC x 6 wks is alternative in pts unable to tolerate amphotericin.

References

Day JN, Chau TT, Wolbers M, et al. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med. 2013;368(14):1291-302. [PMID:23550668]
Comment: Amphotericin B (1 mg/kg/day) plus flucytosine (100 mg/kg/day) was associated with improved survival at day 70 as compared with amphotericin B (1 mg/kg/day) alone. Combination therapy with flucytosine also resulted in more rapid yeast clearance from CSF when compared to amphotericin monotherapy or amphotericin B plus fluconazole (800 mg/kg/day). There was no survival benefit found for those treated with amphotericin B plus fluconazole.
Saag MS, Cloud GA, Graybill JR, 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. 1999;28(2):291-6. [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).
van der Horst CM, Saag MS, Cloud GA, 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. 1997;337(1):15-21. [PMID:9203426]
Comment: Addition of 5FC to amphotericin resulted in faster CSF sterilization but did not improve clinical outcome.
Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf.
Gillum JG, Johnson M, Lavoie S, et al. Flucytosine dosing in an obese patient with extrameningeal cryptococcal infection. Pharmacotherapy. 1995;15(2):251-3. [PMID:7624273]
Comment: A case report of a morbidly obese patient who received 150 mg/kg/day IBW for treatment of extrameningeal cryptococcal infection. Pharmacokinetic parameters were similar as those reported in non-obese patients receiving the same dose.

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