FLUCYTOSINE (Generic for ANCOBON)

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

Route-Specific Administration

Oral Administration
-To decrease the incidence and severity of nausea and vomiting, administer the dose over 15 minutes, by giving a few capsules at a time or administering small portions of the dose every few minutes.
Extemporaneous Compounding-Oral
Compounded Oral Suspension (10 mg/ml)
-Empty the contents of four (4) flucytosine 250-mg capsules into a glass mortar. Add 10 ml of vehicle to the powder and triturate well.
-Transfer contents to a calibrated bottle. Rinse mortar with additional vehicle and pour contents into the bottle. Repeat rinsing mortar with vehicle to ensure complete transfer of flucytosine powder into bottle.
-Add enough vehicle to the bottle to bring the total volume of the suspension to 100 ml.
-Vehicle options:-Equal volumes of Ora-Plus and Ora-Sweet (or Ora-Sweet SF)
-Cherry syrup

-Storage: The suspension is stable for 60 days when stored at room temperature or under refrigeration. Protect from light.

Compounded Oral Suspension (50 mg/ml)
-Empty the contents of six (6) flucytosine 500-mg capsules into a glass mortar. Add 15 ml of vehicle to the powder and triturate well.
-Transfer contents to a 2 oz amber bottle. Rinse mortar with another 15 ml of vehicle and pour contents into amber bottle. Repeat rinsing mortar with vehicle to ensure complete transfer of flucytosine powder into amber bottle.
-Add enough vehicle to the amber bottle to bring the total volume of the suspension to 60 ml.
-Vehicle options:-Equal volumes of Ora-Plus and Ora-Sweet SF
-Equal volumes of Ora-Plus and strawberry syrup (prepared by combining 3200 ml Simple Syrup NF with 600 ml strawberry fountain syrup)

-Storage: The suspension is stable for 90 days when stored at room temperature or under refrigeration. Protect from light.

Bone marrow suppression is the most severe adverse reaction associated with flucytosine therapy; obtain a baseline CBC prior to therapy and monitor the hematologic status of flucytosine recipients at frequent intervals during treatment. Rapidly proliferating tissues, such as the bone marrow, are susceptible to flucytosine-associated toxicity. Moderate hypoplasia of the bone marrow that occurs with flucytosine treatment can result in 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 toxicity 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) or renal dysfunction. In a study of adult patients, bone marrow depression occurred in 12 of 20 patients (60%) with serum concentrations greater than 100 mcg/mL and in 8 of 65 (12%) of those with concentrations less than 100 mcg/mL. Bone marrow suppression was noted within the first 2 weeks of therapy in 51% of cases and by 4 weeks in 91%.

Gastrointestinal adverse effects to flucytosine therapy are relatively common (6% of adults, incidence in pediatric patients is unknown). Nausea and diarrhea are thought to be the most common effects, with vomiting and diffuse abdominal pain also occurring occasionally. Other GI adverse effects reported less frequently with flucytosine include anorexia, duodenal ulcer (GI peptic ulcer), GI bleeding, ulcerative colitis, enterocolitis and xerostomia. The risk of developing GI toxicity from flucytosine may be increased with prolonged, high serum flucytosine concentrations (> 100 mcg/ml) or renal dysfunction.

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

Flucytosine can cause significant hepatotoxicity; the true incidence is unclear but has ranged from 0% to 41% of patients. Obtain baseline liver function tests prior to initiating therapy and monitor liver function frequently during therapy. Elevated hepatic enzymes, hyperbilirubinemia, jaundice, and hepatitis may occur. In most cases, hepatotoxicity has been reversible with a dosage reduction or discontinuation, but rarely, cases of acute hepatic injury with fatal hepatic failure have occurred in debilitated patients. The risk of developing hepatic toxicity is increased with prolonged, high serum concentrations (greater than 100 mcg/mL) or renal dysfunction.

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 rarely, toxic epidermal necrolysis (TENS). 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, pyrexia, 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. The following events have been reported in patients receiving flucytosine: chest pain (unspecified), dyspnea, myocardial toxicity, ventricular dysfunction, cardiac arrest, 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. Monitor blood glucose concentrations, especially in patients already at risk for hypoglycemia (e.g. neonates).

Flucytosine is contraindicated in patients with a known hypersensitivity to the drug.

Use flucytosine with extreme caution in patients with renal impairment. Since flucytosine is excreted primarily by the kidneys, renal impairment may lead to accumulation of the drug. Monitor kidney function and flucytosine serum concentrations during therapy to determine the adequacy of renal excretion in patients with renal disease. Adjust the flucytosine dose in patients with renal impairment or renal failure to prevent progressive accumulation of active drug. Measurement of serum creatinine should be determined by the Jaffe reaction due to laboratory test interference with flucytosine; flucytosine does not interfere with the determination of creatinine values by this method.

Use flucytosine with extreme caution in patients with bone marrow suppression. Patients may be more prone to depression of bone marrow function if they have a hematological disease, are being treated with radiation therapy or drugs which depress bone marrow, or have a history of treatment with such drugs or radiation. Bone marrow toxicity can be irreversible and may lead to death in immunosuppressed patients. Frequent monitoring of hepatic function and of the hematopoietic system is indicated during flucytosine therapy.

Use flucytosine with caution in patients with hepatic disease or jaundice; also use with caution in neonates with hyperbilirubinemia. Flucytosine can cause hepatotoxicity (i.e., hepatitis and jaundice), and worsening of previously existing hepatic dysfunction. Monitor liver function tests (AST, ALT, and alkaline phosphatase) frequently throughout therapy.

Use flucytosine with caution in patients with electrolyte imbalance. Flucytosine can cause hypokalemia. Measure baseline electrolyte concentrations prior to initiating therapy and monitor closely during therapy.

Flucytosine is contraindicated in patients with known complete dihydropyrimidine dehydrogenase (DPD) deficiency. Dihydropyrimidine dehydrogenase is a key enzyme involved in the metabolism and elimination of 5-fluorouracil, a metabolite of flucytosine. Therefore, the risk of severe drug toxicity, including mucositis, diarrhea, neutropenia, and neurotoxicity, is increased when flucytosine is used in individuals with deficiency in DPD. In the event of suspected drug toxicity, consider stopping flucytosine treatment. Determination of DPD activity may be considered where drug toxicity is confirmed or suspected.

Description: Flucytosine, also known as 5-FC, is an oral antifungal agent. It is a fluorinated pyrimidine that is structurally similar to both fluorouracil and floxuridine. Flucytosine is used mainly in combination with amphotericin B in the treatment of cryptococcal meningitis and for certain infections caused by Candida sp. It is also used in combination with azole antifungal agents. Monotherapy with flucytosine is used rarely due to the rapid development of resistance. In patients with renal failure, significant dose adjustments are necessary. Bone-marrow toxicity and hepatotoxicity are the major toxicities of flucytosine, with toxicity more common with serum concentrations > 100 mcg/ml. Therapeutic drug monitoring is recommended in children, particularly neonates and those with renal impairment. Flucytosine use has declined significantly due to the availability of newer antifungals that are less toxic and may not develop resistance as rapidly. Although not FDA approved in children, flucytosine is used off-label in pediatric patients as young as neonates for cryptococcosis and invasive candidal infections.

General dosing information:
-Due to immature and changing renal function in premature neonates, the Infectious Diseases Society of America (IDSA) recommends using flucytosine in this population only when serum concentrations can be monitored.

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*:
Oral dosage:
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 may be considered as part of salvage therapy.
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 dose, if necessary, based on serum flucytosine concentrations.

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:
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).
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 dose, 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.

For the treatment of Candida meningitis*:
Oral dosage:
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.
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 dose, 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.

For the treatment of endophthalmitis* caused by Candida sp.:
Oral dosage:
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).
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) for fluconazole/voriconazole-resistant infections. Adjust dosage based on serum flucytosine concentrations. Treat for at least 4 to 6 weeks with final duration depending on resolution of lesions.

For the treatment of Candida urinary tract infection (UTI)*, including cystitis* and pyelonephritis*:
-for the treatment of cystitis*:
Oral dosage:
Infants, Children, and Adolescents: 25 mg/kg/dose PO 4 times daily for 7 to 10 days. Guidelines suggest flucytosine for C. glabrata. Adjust dosage, if necessary, based on serum flucytosine concentrations.
-for the treatment of ascending pyelonephritis*:
Oral dosage:
Infants, Children, and Adolescents: 25 mg/kg/dose PO 4 times daily for 14 days. Guidelines suggest flucytosine for C. glabrata as monotherapy or in combination with amphotericin B. Adjust dosage, if necessary, based on serum flucytosine concentrations.
-for the treatment of urinary fungal balls*:
Oral dosage:
Infants, Children, and Adolescents: 25 mg/kg/dose PO 4 times daily for 7 to 14 days. Adjust dosage, if necessary, based on serum flucytosine concentrations.

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:
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.

Therapeutic Drug Monitoring:
Usual target trough concentration: 20-50 mcg/ml (some experts prefer 20-40 mcg/ml to minimize risk of toxicity)
Usual target peak concentration: 50-100 mcg/ml (some experts prefer 50-80 mcg/ml to minimize risk of toxicity)
Target peak for patients with HIV: 40-60 mcg/ml
-Measure peak concentration 2 hours after an oral dose and trough concentration just before a dose.
-Toxicity is more common when serum concentrations are > 100 mcg/ml.
-Therapeutic drug monitoring is recommended in children, especially neonates and those with renal impairment.

Maximum Dosage Limits:
-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.
-Infants
Safety and efficacy have not been established; however, doses up to 150 mg/kg/day PO have been used off-label.
-Children
Safety and efficacy have not been established; however, doses up to 150 mg/kg/day PO have been used off-label.
-Adolescents
Safety and efficacy have not been established; however, doses up to 150 mg/kg/day PO have been used off-label.

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
The following initial dosage adjustments are based on the usual recommended dose in children of 25-37.5 mg/kg/dose PO every 6 hours. Monitor serum flucytosine concentrations carefully, and adjust dosage as needed.
CrCl 30-50 ml/min/1.73 m2: 25-37.5 mg/kg/dose PO every 8 hours.
CrCl 10-29 ml/min/1.73 m2: 25-37.5 mg/kg/dose PO every 12 hours.
CrCl < 10 ml/min/1.73 m2: 25-37.5 mg/kg/dose PO every 24 hours.

Intermittent hemodialysis
25-37.5 mg/kg/dose PO every 24 hours. Adjust dosage based on flucytosine serum concentrations.

Peritoneal dialysis
25-37.5 mg/kg/dose PO every 24 hours. Adjust dosage based on flucytosine serum concentrations.

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

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Flucytosine is taken up by fungal organisms via the enzyme cytosine permease. Once inside the fungal cell, it is rapidly deaminated to 5-fluorouracil (5-FU) by the fungal enzyme cytosine deaminase. Mammalian cells do not convert flucytosine to 5-fluorouracil. Acting as an antimetabolite, 5-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. Resistance develops rapidly 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 most Candida species (except for Candida krusei) and Cryptococcus neoformans.

Pharmacokinetics: Flucytosine is administered orally. It is a small molecule with limited protein binding (2-4%); therefore, it has a large volume of distribution (approaching that of total body water) and is widely distributed throughout the body. Flucytosine penetrates the blood-brain barrier, achieving therapeutic concentrations in cerebrospinal fluid. 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% of a dose is excreted by glomerular filtration as unchanged drug. The elimination half-life is a function of creatinine clearance; in most adults with normal renal function, it is around 2.5-4 hours.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Oral Route
Flucytosine is rapidly and almost completely absorbed with a bioavailability between 78-89%. Peak concentrations are achieved approximately 1-2 hours after administration. After a single 2 g dose in normal adults, peak serum concentrations were 30-40 mcg/ml; however, mean concentrations of 70-80 mcg/ml were measured in adults receiving flucytosine 150 mg/kg/day in combination with amphotericin for 6 weeks.


-Special Populations
Pediatrics
Neonates
The clearance of flucytosine is prolonged and highly variable in neonatal patients due to immature renal function. In a pharmacokinetic study in 13 neonates (mean gestational age, 27.4 weeks [range, 24-40 weeks]; mean weight, 1.2 kg [range, 580-3320 g]), the median elimination half-life of flucytosine was 7.4 hours, which is approximately twice that of adults; however, clearance was found to be significantly variable with half-lives ranging from 3.4 to 34.1 hours. Median volume of distribution was 1.1 L/kg (range, 0.4-2 L/kg), and the time to peak serum concentration was 2.5 +/- 1.3 hours. In this study, neonates received flucytosine 50-100 mg/kg/day PO once daily and amphotericin B IV (usual dose = 0.5 mg/kg/day infused over 4-6 hours).

Renal Impairment
Pharmacokinetic data in pediatric patients with renal impairment are unavailable. However, flucytosine is substantially excreted in the kidneys and the elimination half-life in adult patients with severe renal impairment has been shown to be prolonged to approximately 85 hours (range, 30-250 hours).