Flucytosine is an oral antifungal agent. It is a fluorinated pyrimidine that is structurally similar to both fluorouracil and floxuridine. Flucytosine is also known as 5-FC. It was approved by the FDA in 1971 and until recently was used mainly in combination with amphotericin B in the treatment of cryptococcal meningitis. Since the release of fluconazole in 1990, flucytosine use has declined significantly.

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Available in only two strengths of capsules.
-To decrease the incidence and severity of nausea and vomiting, administer the dose over 15 minutes.
Oral Liquid Formulations
-For pediatric patients, a suspension may be made. The contents of two 500 mg capsules can be mixed with 100 mL of distilled water to give a 10 mg/mL suspension.
-The suspension is stable for 1 week at room temperature when protected from light. Maintain pH of the suspension between 5-6.5.



Injectable Administration
Intrathecal Administration
NOTE: Flucytosine is not approved by the FDA for intrathecal administration.
-Not indicated due to the excellent CSF:serum distribution after oral administration.

Rapidly proliferating tissues, such as the bone marrow, are susceptible to flucytosine associated toxicity. Moderate hypoplasia of the bone marrow that occurs following treatment with flucytosine, causes anemia, aplastic anemia, eosinophilia, leukopenia, thrombocytopenia, and, rarely, pancytopenia and agranulocytosis. Anemic patients may complain of unusual fatigue or weakness, while leukopenic patients may develop fever. Patients with thrombocytopenia can experience unusual bleeding or bruising. Bone marrow suppression can be irreversible and, in immunosuppressed patients, may result in fatalities. The risk of developing bone marrow toxicity from flucytosine is increased with prolonged, high serum flucytosine concentrations (greater than 100 mcg/mL), renal dysfunction, or concurrent amphotericin B therapy. Health care providers are advised to monitor the hematologic status of flucytosine recipients before initiating therapy and at frequent intervals during treatment as indicated.

Manifestations of flucytosine toxicity on the rapidly proliferating lining of the gastrointestinal (GI) tract include abdominal pain, anorexia, diarrhea, nausea, and vomiting. Nausea/vomiting also may be a result of a central nervous system mechanism as high concentrations of flucytosine are achieved in cerebral spinal fluid. Other GI adverse effects reported with flucytosine include duodenal ulcer (GI peptic ulcer), GI bleeding, ulcerative colitis, and xerostomia. The risk of developing GI toxicity from flucytosine is increased with prolonged, high serum flucytosine concentrations (> 100 mcg/mL), renal dysfunction, or concurrent amphotericin B therapy.

Genitourinary adverse reactions associated with flucytosine have included azotemia, creatinine and BUN elevation, crystalluria, and renal failure (unspecified). Since flucytosine is primarily excreted by the kidneys, health care providers are advised to closely monitor renal function before initiating and during therapy.

During clinical use, recipients of flucytosine have experienced hepatotoxicity including jaundice and hepatitis. Elevated hepatic enzymes (e.g., ALT, AST) and alkaline phosphatase and hyperbilirubinemia have also been reported. Cases of acute hepatic injury with possible fatal hepatic failure have occurred in debilitated patients. The risk of developing hepatic toxicity is increased with prolonged, high serum concentrations (greater than100 mcg/mL), renal dysfunction, or concurrent amphotericin B therapy. Frequently monitor hepatic function in patients receiving flucytosine; consider discontinuation if jaundice develops.

Some patients exhibit a hypersensitivity to flucytosine, which is manifested as rash (unspecified), pruritus, or urticaria. Other dermatologic adverse events associated with flucytosine therapy include photosensitivity and toxic epidermal necrolysis (TENS) (Lyell's disease). Patients who develop hypersensitivity should not be rechallenged with the drug.

Flucytosine has been associated with central nervous system events. These adverse reactions include ataxia, drowsiness (sedation), headache, hearing loss, paresthesias, peripheral neuropathy, pseudoparkinsonism, seizures, and vertigo. Psychiatric adverse reactions have also been reported and include confusion, hallucinations, and psychosis.

Flucytosine has been associated with cardiovascular and respiratory adverse reactions. Cardiovascular adverse reactions to flucytosine include cardiac arrest, myocardial toxicity, and ventricular dysfunction. Respiratory adverse adverse reactions to flucytosine include chest pain (unspecified), dyspnea, and respiratory arrest.

Hypoglycemia and hypokalemia have been associated with flucytosine therapy. Health care providers are advised to monitor electrolytes concentrations before initiating and during treatment with flucytosine.

Flucytosine is renally eliminated and must be given with extreme caution to patients with renal failure or renal impairment. Flucytosine serum concentrations can accumulate to toxic levels in patients with renal impairment; adverse effects occur more frequently in azotemic patients. In addition, flucytosine is often given in combination with amphotericin B, which is known to adversely affect renal function in many patients. Monitor urine output, renal function, and serum concentrations of flucytosine frequently in patients with renal disease to ensure that recommended serum concentrations are not exceeded (trough 25 to 50 mcg/mL; peak 50 to less than 100 mcg/mL). Significant dose adjustments are necessary for patients with renal impairment or renal failure.

Flucytosine must be given with extreme caution to patients with bone marrow suppression. Patients with hematological disease and patients currently receiving, or who have a history of treatment with, radiation or drugs that depress bone marrow are most susceptible to flucytosine's myelosuppressive effects. Bone marrow toxicity can be irreversible and may lead to death in immunosuppressed patients. Frequently monitor blood counts during flucytosine therapy.

Frequently monitor hepatic function during treatment with flucytosine, as hepatotoxicity (acute hepatic injury including hepatic necrosis, hepatic dysfunction, jaundice, and elevated hepatic enzymes) has been reported with use.

Patients who have previously received either radiation therapy or cytotoxic drug therapy also may be at an increased risk for flucytosine-associated bone marrow suppression because their bone marrow may still be recovering from the previous myelosuppression.

Flucytosine should be used cautiously in patients with electrolyte imbalance (especially hypokalemia). Flucytosine has been associated with hypokalemia. Close monitoring is necessary during flucytosine therapy.

Flucytosine may cause photosensitivity so patients should use caution with sunlight (UV) exposure.

There are no adequate and well-controlled studies in pregnant women; however in animal studies, flucytosine was shown to be teratogenic in rats. The rats were administered doses ranging from 0.051-times to 0.89-times the recommended human dose (RHD) during the first trimester (days 7 to 13 of gestation). Teratogenic effects observed in the offspring included vertebral fusions, cleft lip and palate, and micrognathia. Flucytosine was not teratogenic in rabbits receiving doses of 0.243-times RHD, nor were there any statistically significant increases in adverse events observed in mice receiving doses of 0.236-times RHD. Due to the potential for adverse events, the manufacturer recommends use of flucytosine during pregnancy only if the potential benefits outweigh the potential risk to the fetus.

Limited data are available regarding use of flucytosine in nursing mothers and it is not known if it is excreted in human milk. Due to the potential for serious adverse reactions in a nursing infant, a decision should be made whether to discontinue flucytosine, taking into account the importance of the drug to the mother. Fluconazole and ketoconazole may be potential alternatives to consider during breast-feeding. However, site of infection, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative agent. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested or administered drug, health care providers are encouraged to report the adverse effect to the FDA.

The safe and effective use of flucytosine has not been systematically studied in children or infants. A small number of neonates were treated with 25-200 mg/kg/day, with and without amphotericin B, for systemic candidiasis. No unexpected adverse reactions occurred. However, hypokalemia and acidemia were reported in one patient who received flucytosine with amphotericin B, and anemia was observed in another patient who received flucytosine alone. Transient thrombocytopenia was noted in two other patients, one of whom also received amphotericin B.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Candida sp., Cryptococcus neoformans, Cryptococcus sp.
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

This drug may also have activity against the following microorganisms: Aspergillus sp., Cladosporium sp., Phialophora sp., Sporothrix schenckii
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.

For the treatment of candidemia and disseminated (non-CNS) candidiasis:
NOTE: For candidemia or disseminated candidiasis, an echinocandin or fluconazole is the preferred therapy.
Oral dosage:
Adults: 50 to 150 mg/kg/day PO in divided doses every 6 hours in combination with amphotericin B. Adjust dosage, if necessary, based on serum flucytosine concentrations.
Infants*, Children*, and Adolescents*: 25 mg/kg/dose PO 4 times daily in combination with amphotericin B (conventional or lipid formulation) is the general dosage for most infections. Adjust dosage, if necessary, based on serum flucytosine concentrations.
Neonates*: 50 to 150 mg/kg/day PO divided every 6 hours in combination with amphotericin B (conventional or lipid formulation) is the most commonly reported dosage range ; adjust dosage based on serum flucytosine concentrations. Rarely, up to 200 mg/kg/day PO has been used ; however, based on pharmacokinetic data, that dosage is likely to be excessive for most neonates. Although most cases in the literature were administered flucytosine in 4 divided doses per day, pharmacokinetic data suggest that a longer interval (i.e., 50 to 100 mg/kg/day given every 24 hours) may be sufficient in neonates due to a longer elimination half-life, immature renal function, and the time-dependent pharmacodynamic activity of flucytosine. The addition of flucytosine to amphotericin B therapy is not routinely recommended for neonatal candidiasis by the Infectious Diseases Society of America (IDSA).

For the treatment of Candida infections of the cardiovascular system, including endocarditis and infected pacemaker*, implantable cardiac defibrillator (ICD)*, or ventricular assist devices (VAD)*:
Oral dosage:
Adults: 50 to 150 mg/kg/day PO in divided doses every 6 hours , or alternately, the Infectious Diseases Society of America (IDSA) recommends 25 mg/kg/dose PO 4 times daily in combination with a lipid amphotericin B product. However, surgical management is the primary recommendation. Adjust dosage, if necessary, based on serum flucytosine concentrations. For endocarditis, treat for at least 6 weeks after valve replacement. For infected cardiac hardware, treat for at least 4 to 6 weeks after hardware removal. When valve replacement or hardware removal is not possible, chronic suppressive therapy with fluconazole is recommended after initial treatment.
Infants*, Children*, and Adolescents*: 25 mg/kg/dose PO 4 times daily in combination with a lipid amphotericin B product is recommended by the Infectious Diseases Society of America (IDSA); however, surgical management is the primary recommendation. Adjust dosage, if necessary, based on serum flucytosine concentrations. For endocarditis, treat for at least 6 weeks after valve replacement. For infected cardiac hardware, treat for at least 4 to 6 weeks after hardware removal. When valve replacement or hardware removal is not possible, chronic suppressive therapy with fluconazole is recommended after initial treatment.
Neonates*: 50 to 150 mg/kg/day PO divided every 6 hours in combination with amphotericin B (conventional or lipid formulation) is the most commonly reported dosage range ; adjust dosage based on serum flucytosine concentrations. Rarely, up to 200 mg/kg/day PO has been used ; however, based on pharmacokinetic data, that dosage is likely to be excessive for most neonates. Although most cases in the literature were administered flucytosine in 4 divided doses per day, pharmacokinetic data suggest that a longer interval (i.e., 50 to 100 mg/kg/day given every 24 hours) may be sufficient in neonates due to a longer elimination half-life, immature renal function, and the time-dependent pharmacodynamic activity of flucytosine. For endocarditis, treat for at least 6 weeks after valve replacement. For infected cardiac hardware, treat for at least 4 to 6 weeks after hardware removal. When valve replacement or hardware removal is not possible, chronic suppressive therapy with fluconazole is recommended after initial treatment. The addition of flucytosine to amphotericin B therapy is not routinely recommended for neonatal candidiasis by the Infectious Diseases Society of America (IDSA).

For the treatment of Candida meningitis*:
Oral dosage:
Adults: 50 to 150 mg/kg/day PO in divided doses every 6 hours , or alternately, the Infectious Diseases Society of America (IDSA) recommends 25 mg/kg/dose PO 4 times daily in combination with liposomal amphotericin B. Adjust dosage, if necessary, based on serum flucytosine concentrations. Treatment should continue until all signs and symptoms and CSF and radiologic abnormalities have resolved. Intraventricular devices should be removed.
Infants, Children, and Adolescents: 25 mg/kg/dose PO 4 times daily in combination with liposomal amphotericin B is recommended by the Infectious Diseases Society of America (IDSA) ; however, 37.5 mg/kg/dose PO every 6 hours has also been used in children with Candida meningitis. Adjust dosage, if necessary, based on serum flucytosine concentrations. Treatment should continue until all signs and symptoms and CSF and radiologic abnormalities have resolved. Intraventricular devices should be removed.
Neonates: 50 to 150 mg/kg/day PO divided every 6 hours in combination with amphotericin B (conventional or lipid formulation) is the most commonly reported dosage range ; adjust dosage based on serum flucytosine concentrations. Rarely, up to 200 mg/kg/day PO has been used ; however, based on pharmacokinetic data, that dosage is likely to be excessive for most neonates. Although most cases in the literature were administered flucytosine in 4 divided doses per day, pharmacokinetic data suggest that a longer interval (i.e., 50 to 100 mg/kg/day given every 24 hours) may be sufficient in neonates due to a longer elimination half-life, immature renal function, and the time-dependent pharmacodynamic activity of flucytosine. Treatment should continue until all signs and symptoms and CSF and radiologic abnormalities have resolved. Intraventricular devices should be removed. The addition of flucytosine to amphotericin B therapy is not routinely recommended for neonatal candidiasis by the Infectious Diseases Society of America (IDSA). Treatment outcomes of combination therapy with amphotericin B and flucytosine for candidiasis in neonates have been conflicting. An early study revealed improvement in 15 patients (n = 7 neonates) on combination therapy. In a study of extremely low birth weight neonates with candidiasis (total n = 320; with positive culture for Candida in CSF, n = 27), clearance of CSF was longer in neonates who received combination therapy compared with amphotericin B alone.

For the treatment of endophthalmitis* caused by Candida sp.:
Oral dosage:
Adults, Adolescents, Children, and Infants: 25 mg/kg/dose PO 4 times daily in combination with liposomal amphotericin B is recommended by the Infectious Diseases Society of America (IDSA) for fluconazole/voriconazole-resistant infections. Adjust dosage, if necessary, based on serum flucytosine concentrations. Treat for at least 4 to 6 weeks with final duration depending on resolution of lesions.
Neonates: 50 to 150 mg/kg/day PO divided every 6 hours in combination with amphotericin B (conventional or lipid formulation) is the most commonly reported dosage range ; adjust dosage based on serum flucytosine concentrations. Rarely, up to 200 mg/kg/day PO has been used ; however, based on pharmacokinetic data, that dosage is likely to be excessive for most neonates. Although most cases in the literature were administered flucytosine in 4 divided doses per day, pharmacokinetic data suggest that a longer interval (i.e., 50 to 100 mg/kg/day given every 24 hours) may be sufficient in neonates due to a longer elimination half-life, immature renal function, and the time-dependent pharmacodynamic activity of flucytosine. Treat for at least 4 to 6 weeks with final duration depending on resolution of lesions. The addition of flucytosine to amphotericin B therapy is not routinely recommended for neonatal candidiasis by the Infectious Diseases Society of America (IDSA).

For the treatment of urinary tract infection (UTI), including symptomatic cystitis, caused by Candida sp. (e.g. candiduria):
Oral dosage:
Adults, Adolescents*, Children*, and Infants*: 25 mg/kg/dose PO 4 times daily, with or without amphotericin B (conventional), is recommended by the Infectious Diseases Society of America (IDSA) for fluconazole-resistant C. glabrata when treatment is necessary. Adjust dosage, if necessary, based on serum flucytosine concentrations. Routine treatment for asymptomatic candiduria is not recommended for most patients. However, candiduria may be the only microbiological documentation of disseminated candidiasis in high-risk patients (e.g., neutropenic), and therefore, candiduria should be treated as disseminated candidiasis in these patients. Treatment is also appropriate for those undergoing urologic procedures, but fluconazole or amphotericin B is the preferred agent. For symptomatic cystitis, treat for 7 to 10 days. For urinary fungal balls, surgical removal in addition to antifungal therapy is recommended. Antifungal therapy can include amphotericin B with or without flucytosine.
Neonates*: 50 to 150 mg/kg/day PO divided every 6 hours in combination with amphotericin B (conventional or lipid) is the most commonly reported dosage range ; adjust dosage based on serum flucytosine concentrations. Rarely, up to 200 mg/kg/day PO has been used ; however, based on pharmacokinetic data, that dosage is likely to be excessive for most neonates. Although most cases in the literature were administered flucytosine in 4 divided doses per day, pharmacokinetic data suggest that a longer interval (i.e., 50 to 100 mg/kg/day given every 24 hours) may be sufficient in neonates due to a longer elimination half-life, immature renal function, and the time-dependent pharmacodynamic activity of flucytosine. Neonates are a high risk population; therefore, candiduria should be treated as disseminated candidiasis. Amphotericin B (conventional) or fluconazole is the preferred therapy. The addition of flucytosine to amphotericin B therapy is not routinely recommended for neonatal candidiasis by the Infectious Diseases Society of America (IDSA).

For the treatment of pyelonephritis caused by Candida sp.:
Oral dosage:
Adults, Adolescents*, Children*, and Infants*: 25 mg/kg/dose PO 4 times daily for 2 weeks, with or without amphotericin B (conventional), is recommended by the Infectious Diseases Society of America (IDSA) for fluconazole-resistant C. glabrata. Adjust dosage, if necessary, based on serum flucytosine concentrations. If disseminated candidiasis is suspected, treat as candidemia.
Neonates*: 50 to 150 mg/kg/day PO divided every 6 hours in combination with amphotericin B (conventional or lipid formulation) is the most commonly reported dosage range ; adjust dosage based on serum flucytosine concentrations. Rarely, up to 200 mg/kg/day PO has been used ; however, based on pharmacokinetic data, that dosage is likely to be excessive for most neonates. Although most cases in the literature were administered flucytosine in 4 divided doses per day, pharmacokinetic data suggest that a longer interval (i.e., 50 to 100 mg/kg/day given every 24 hours) may be sufficient in neonates due to a longer elimination half-life, immature renal function, and the time-dependent pharmacodynamic activity of flucytosine. Neonates are a high risk population; therefore, pyelonephritis should be treated as disseminated candidiasis. Amphotericin B (conventional) or fluconazole is the preferred therapy. The addition of flucytosine to amphotericin B therapy is not routinely recommended for neonatal candidiasis by the Infectious Diseases Society of America (IDSA).

For the treatment of cryptococcosis, including disseminated disease, CNS disease (e.g., cryptococcal meningitis) and severe pulmonary infection:
NOTE: Flucytosine in combination with amphotericin B is the preferred induction therapy for cryptococcal meningitis, severe pulmonary cryptococcosis, and cryptococcemia.
Oral dosage:
Adults: 50 to 150 mg/kg/day PO in divided doses every 6 hours , or alternately, an initial dosage of 25 mg/kg/dose PO 4 times daily in combination with amphotericin B (conventional or lipid formulation) or fluconazole (alternative for HIV-infected patients who cannot tolerate amphotericin B) is recommended by clinical practice guidelines as induction therapy. Adjust dosage, if necessary, based on serum flucytosine concentrations. Induction therapy is usually for 2 weeks; however, the duration of initial therapy depends on site and severity of infection, clinical response, and underlying risk factors. For cerebral cryptococcomas, give induction therapy for at least 6 weeks. For persistence or relapse of cryptococcosis, reinstate induction therapy for 4 to 10 weeks. Consolidation and maintenance therapy with fluconazole should follow acute treatment.
Neonates*, Infants*, Children*, and Adolescents*: 25 mg/kg/dose PO 4 times daily in combination with amphotericin B (conventional or lipid formulation) or fluconazole (alternative for HIV-infected patients who cannot tolerate amphotericin B) is recommended by clinical practice guidelines as induction therapy. Adjust dosage, if necessary, based on serum flucytosine concentrations. Induction therapy is usually for 2 weeks; however, the duration of initial therapy depends on site and severity of infection, clinical response, and underlying risk factors. Consolidation and maintenance therapy with fluconazole should follow acute treatment.

For the treatment of chromomycosis* in combination with amphotericin B:
Oral dosage:
Adults: 150 mg/kg/day PO in divided doses every 6 hours. Flucytosine is usually administered concurrently with parenteral amphotericin B for disseminated fungal disease due to rapid development of resistance to flucytosine alone.

Therapeutic Drug Monitoring:
Peak steady state serum flucytosine concentrations (obtained 2 hours post-dose after 3 to 5 doses) of 50 to 100 mcg/mL are often targeted to prevent both development of resistant strains and toxicity. Lower serum drug concentrations (i.e., 25 to 60 mcg/mL) have been recommended for immunocompromised patients who are receiving flucytosine in combination with conventional amphotericin B. Clinical practice guidelines for the management of candidiasis suggest maintaining peak concentrations less than 100 mcg/mL in order to minimize concentration-associated toxicities, such as hepatic and bone marrow effects. The HIV opportunistic infection guidelines recommend peak drug concentrations of 25 to 100 mcg/mL.

Maximum Dosage Limits:
-Adults
150 mg/kg/day PO.
-Geriatric
150 mg/kg/day PO.
-Adolescents
Safety and efficacy have not been established; however, doses of 150 mg/kg/day PO have been used off-label.
-Children
Safety and efficacy have not been established; however, doses of 150 mg/kg/day PO have been used off-label.
-Infants
Safety and efficacy have not been established; however, doses of 150 mg/kg/day PO have been used off-label.
-Neonates
Safety and efficacy have not been established. Doses up to 150 mg/kg/day PO are the most commonly reported maximum doses; however, up to 200 mg/kg/day PO has been used.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Initial dosage adjustment for adult patients is as follows:
CrCl more than 40 mL/minute: No dosage adjustment needed.
CrCl 20 to 40 mL/minute: Extend initial dosing interval to every 12 hours. Adjust dosage, if necessary, based on serum flucytosine concentrations.
CrCl 10 to 19 mL/minute: Extend initial dosing interval to every 24 hours. Adjust dosage, if necessary, based on serum flucytosine concentrations.
CrCl less than 10 mL/minute: Extend initial dosing interval to every 48 hours. Adjust dosage, if necessary, based on serum flucytosine concentrations.

The following initial dosage adjustments are based on the usual recommended dose in children of 25 to 37.5 mg/kg/dose PO every 6 hours:
CrCl 30 to 50 mL/minute/1.73 m2: Extend initial dosing interval to every 8 hours. Adjust dosage, if necessary, based on serum flucytosine concentrations.
CrCl 10 to 29 mL/minute/1.73 m2: Extend initial dosing interval to every 12 hours. Adjust dosage, if necessary, based on serum flucytosine concentrations.
CrCl less than 10 mL/minute/1.73 m2: Extend initial dosing interval to every 24 hours. Adjust dosage, if necessary, based on serum flucytosine concentrations.

Intermittent hemodialysis
For adult patients, 25 to 50 mg/kg PO every 48 to 72 hours, given immediately after dialysis. Adjust dosage, if necessary, based on serum flucytosine concentrations. For pediatric patients, 25 to 37.5 mg/kg/dose PO every 24 hours. Adjust dosage based on flucytosine serum concentrations.

Peritoneal dialysis
For pediatric patients, 25 to 37.5 mg/kg/dose PO every 24 hours. Adjust dosage based on flucytosine serum concentrations.

Continuous renal replacement therapy (CRRT)
For pediatric patients, 25 to 37.5 mg/kg/dose PO every 8 hours. Adjust dosage based on flucytosine serum concentrations.

*non-FDA-approved indication

Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Zidovudine, ZDV should be used cautiously with other drugs that can cause bone marrow suppression, such as flucytosine, because of the increased risk of hematologic toxicity. In some cases, a reduction in the dosage of zidovudine may be warranted.

Alkylating agents: (Minor) Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression.

Amphotericin B cholesteryl sulfate complex (ABCD): (Minor) Amphotericin B may increase the toxicity of flucytosine by possibly increasing flucytosine cellular uptake and/or impairing flucytosine renal excretion. However, flucytosine can have synergistic effects when used with amphotericin B, and these two drugs frequently are used together to treat cryptococcal infections. This combination may allow for a reduction in the total daily dose of amphotericin B. However, amphotericin B-induced reductions in renal function can increase bone marrow toxicity from flucytosine.

Amphotericin B lipid complex (ABLC): (Minor) Amphotericin B may increase the toxicity of flucytosine by possibly increasing flucytosine cellular uptake and/or impairing flucytosine renal excretion. However, flucytosine can have synergistic effects when used with amphotericin B, and these two drugs frequently are used together to treat cryptococcal infections. This combination may allow for a reduction in the total daily dose of amphotericin B. However, amphotericin B-induced reductions in renal function can increase bone marrow toxicity from flucytosine.

Amphotericin B liposomal (LAmB): (Minor) Amphotericin B may increase the toxicity of flucytosine by possibly increasing flucytosine cellular uptake and/or impairing flucytosine renal excretion. However, flucytosine can have synergistic effects when used with amphotericin B, and these two drugs frequently are used together to treat cryptococcal infections. This combination may allow for a reduction in the total daily dose of amphotericin B. However, amphotericin B-induced reductions in renal function can increase bone marrow toxicity from flucytosine.

Amphotericin B: (Minor) Amphotericin B may increase the toxicity of flucytosine by possibly increasing flucytosine cellular uptake and/or impairing flucytosine renal excretion. However, flucytosine can have synergistic effects when used with amphotericin B, and these two drugs frequently are used together to treat cryptococcal infections. This combination may allow for a reduction in the total daily dose of amphotericin B. However, amphotericin B-induced reductions in renal function can increase bone marrow toxicity from flucytosine.

Antimetabolites: (Minor) Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression.

Busulfan: (Minor) Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression.

Carbamazepine: (Minor) Because of flucytosine's ability to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants, including carbamazepine.

Chlorpromazine: (Minor) Because of flucytosine's ability to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants. These include: carbamazepine, clozapine, phenothiazines, zidovudine, ZDV and other blood dyscrasia-causing medications.

Clozapine: (Moderate) Because of the ability of flucytosine to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants, including clozapine.

Codeine; Phenylephrine; Promethazine: (Minor) Because of flucytosine's ability to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants. These include: carbamazepine, clozapine, phenothiazines, zidovudine, ZDV and other blood dyscrasia-causing medications.

Codeine; Promethazine: (Minor) Because of flucytosine's ability to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants. These include: carbamazepine, clozapine, phenothiazines, zidovudine, ZDV and other blood dyscrasia-causing medications.

Cytarabine, ARA-C: (Major) Cytarabine, ARA-C can competitively inhibit flucytosine, antagonizing its antifungal activity.

Dacarbazine, DTIC: (Minor) Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression.

Dextromethorphan; Promethazine: (Minor) Because of flucytosine's ability to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants. These include: carbamazepine, clozapine, phenothiazines, zidovudine, ZDV and other blood dyscrasia-causing medications.

Dichlorphenamide: (Moderate) Use dichlorphenamide and flucytosine together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including antifungals. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dichlorphenamide dose or discontinuing dichlorphenamide therapy.

Fluphenazine: (Minor) Because of flucytosine's ability to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants. These include: carbamazepine, clozapine, phenothiazines, zidovudine, ZDV and other blood dyscrasia-causing medications.

Ganciclovir: (Moderate) Use ganciclovir and flucytosine together only if the potential benefits outweigh the risks; bone marrow suppression, spermatogenesis inhibition, skin toxicity, and gastrointestinal toxicity may be additive as both drugs inhibit rapidly dividing cells.

Hydroxyurea: (Minor) Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression.

Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Zidovudine, ZDV should be used cautiously with other drugs that can cause bone marrow suppression, such as flucytosine, because of the increased risk of hematologic toxicity. In some cases, a reduction in the dosage of zidovudine may be warranted.

Mechlorethamine, Nitrogen Mustard: (Minor) Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression.

Meperidine; Promethazine: (Minor) Because of flucytosine's ability to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants. These include: carbamazepine, clozapine, phenothiazines, zidovudine, ZDV and other blood dyscrasia-causing medications.

Mesoridazine: (Minor) Because of flucytosine's ability to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants. These include: carbamazepine, clozapine, phenothiazines, zidovudine, ZDV and other blood dyscrasia-causing medications.

Perphenazine: (Minor) Because of flucytosine's ability to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants. These include: carbamazepine, clozapine, phenothiazines, zidovudine, ZDV and other blood dyscrasia-causing medications.

Perphenazine; Amitriptyline: (Minor) Because of flucytosine's ability to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants. These include: carbamazepine, clozapine, phenothiazines, zidovudine, ZDV and other blood dyscrasia-causing medications.

Phenothiazines: (Minor) Because of flucytosine's ability to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants. These include: carbamazepine, clozapine, phenothiazines, zidovudine, ZDV and other blood dyscrasia-causing medications.

Phenylephrine; Promethazine: (Minor) Because of flucytosine's ability to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants. These include: carbamazepine, clozapine, phenothiazines, zidovudine, ZDV and other blood dyscrasia-causing medications.

Porfimer: (Major) Avoid coadministration of porfimer with flucytosine due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like flucytosine may increase the risk of a photosensitivity reaction.

Procarbazine: (Minor) Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression.

Prochlorperazine: (Minor) Because of flucytosine's ability to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants. These include: carbamazepine, clozapine, phenothiazines, zidovudine, ZDV and other blood dyscrasia-causing medications.

Promethazine: (Minor) Because of flucytosine's ability to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants. These include: carbamazepine, clozapine, phenothiazines, zidovudine, ZDV and other blood dyscrasia-causing medications.

Saccharomyces boulardii: (Major) Because Saccharomyces boulardii is an active yeast, it would be expected to be inactivated by any antifungals. The manufacturer does not recommend taking in conjunction with any antifungal agents. Patients should avoid use of this probiotic yeast until the fungal or yeast infection is completely treated.

Streptozocin: (Minor) Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression.

Temozolomide: (Minor) Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression.

Thiethylperazine: (Minor) Because of flucytosine's ability to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants. These include: carbamazepine, clozapine, phenothiazines, zidovudine, ZDV and other blood dyscrasia-causing medications.

Thioridazine: (Minor) Because of flucytosine's ability to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants. These include: carbamazepine, clozapine, phenothiazines, zidovudine, ZDV and other blood dyscrasia-causing medications.

Thiotepa: (Minor) Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression.

Trifluoperazine: (Minor) Because of flucytosine's ability to cause significant hematologic toxicity, it should be used cautiously with all bone marrow depressants. These include: carbamazepine, clozapine, phenothiazines, zidovudine, ZDV and other blood dyscrasia-causing medications.

Valganciclovir: (Moderate) Use valganciclovir and flucytosine together only if the potential benefits outweigh the risks; bone marrow suppression, spermatogenesis inhibition, skin toxicity, and gastrointestinal toxicity may be additive as both drugs inhibit rapidly dividing cells.

Verteporfin: (Moderate) Use caution if coadministration of verteporfin with flucytosine is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like flucytosine may increase the risk of a photosensitivity reaction.

Zidovudine, ZDV: (Moderate) Zidovudine, ZDV should be used cautiously with other drugs that can cause bone marrow suppression, such as flucytosine, because of the increased risk of hematologic toxicity. In some cases, a reduction in the dosage of zidovudine may be warranted.

Flucytosine penetrates fungal cells, where it is deaminated to fluorouracil by the fungal enzyme cytosine deaminase. Mammalian cells do not convert flucytosine to fluorouracil. Acting as an antimetabolite, fluorouracil competes with uracil, interfering with pyrimidine metabolism and eventually disrupting both RNA and protein synthesis. Flucytosine may also be converted to fluorodeoxyuridylic acid, which inhibits the enzyme thymidylate synthase and disrupts DNA synthesis. Although flucytosine is metabolized to 5-fluorouracil, flucytosine itself does not possess antineoplastic activity.

Susceptible fungi readily deaminate flucytosine to its active component, 5-fluorouracil. Resistance develops rapidly, however, if flucytosine is used as a single agent. The mechanism of resistance can be loss of the permease necessary for cytosine transport or decreased activity of uridine monophosphate pyrophosphorylase or cytosine deaminase. Fungi that usually are susceptible include: Candida species, Cryptococcus neoformans, and Candida glabrata.

Flucytosine is administered orally. Because flucytosine is a small molecule with limited protein binding (2-4%), it is widely distributed throughout the body. Concentrations in liver, kidneys, spleen, heart, and lungs are equal to serum concentration, while CSF concentrations are 60-90% of that in the serum. The volume of distribution is 0.68 L/kg in patients with normal renal function, and is decreased to as little as 0.4 L/kg in patients with renal impairment.

Flucytosine is not metabolized. While fungal cells convert flucytosine to fluorouracil intracellularly, only trace amounts of fluorouracil can be detected in the serum. Elimination is primarily renal. Over 90% is excreted by glomerular filtration as unchanged drug. Elimination half-life is a function of creatinine clearance; in patients with normal renal function, it varies from 2.5-6 hours, and can be as long as 11-60 hours if creatinine clearance is less than 2 mL/minute.


-Route-Specific Pharmacokinetics
Oral Route
Oral absorption of flucytosine ranges from 75-90%. Food decreases the rate of absorption, while the extent of absorption remains unchanged. Peak serum concentrations of 30-45 mcg/mL are reached within 6 hours after a 2 g oral dose in patients with normal renal function. After prolonged dosing, peaks are reached 1-2 hours post-dose. Peaks are higher, more prolonged, and reached more slowly in patients with renal impairment. Steady-state serum flucytosine concentrations should range from 50-100 mcg/mL to prevent development of resistant strains and toxicity.


-Special Populations
Renal Impairment
Pharmacokinetic properties of flucytosine are altered in patients with renal impairment. These patients experience higher and more prolonged peak serum concentrations that are reached more slowly than in patients with normal renal function. The volume of distribution is decreased in this population to as little as 0.4 L/kg. The elimination half-life is also a function of creatinine clearance; in patients with normal renal function, it varies from 2.5-6 hours, and can be as long as 11-60 hours if creatinine clearance is less than 2 ml/minute.