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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Medication Safety Issues
Sound-alike/look-alike issues:
Flucytosine may be confused with fluorouracil
Ancobon® may be confused with Oncovin®
High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error.
Pronunciation
(floo SYE toe seen)
U.S. Brand Names
Index Terms
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Adjunctive treatment of systemic fungal infections (eg, septicemia, endocarditis, UTI, meningitis, or pulmonary) caused by susceptible strains of Candida or Cryptococcus
Pregnancy Risk Factor
C
Pregnancy Considerations
Teratogenic in some animal studies, however, there are no adequate and well-controlled studies in pregnant women.
Lactation
Excretion in breast milk unknown/not recommended
Contraindications
Hypersensitivity to flucytosine or any component of the formulation
Warnings/Precautions
Boxed warnings:
• Monitoring: See “Other warnings/precautions” below.
• Renal impairment: See “Disease-related concerns” below.
Disease-related concerns:
• Hematologic disease: Use with caution in patients with bone marrow depression, hematologic disease or who have been treated with radiation or drugs that suppress the bone marrow; bone marrow toxicity can be irreversible.
• Hepatic impairment: Use with caution in patients with hepatic impairment; hepatotoxicity may occur.
• Renal impairment: [U.S. Boxed Warning]: Use with extreme caution in patients with renal dysfunction; dosage adjustment required.
Special populations:
• Pediatrics: Safety and efficacy have not been established in children.
Other warnings/precautions:
• Monitoring: [U.S. Boxed Warning]: Closely monitor hematologic, renal, and hepatic status. Hepatotoxicity and bone marrow toxicity appear to be dose related; monitor levels closely and adjust dose accordingly.
• Monotherapy: Avoid use as monotherapy; resistance rapidly develops.
Adverse Reactions
Frequency not defined.
Cardiovascular: Cardiac arrest, myocardial toxicity, ventricular dysfunction, chest pain
Central nervous system: Ataxia, confusion, dizziness, drowsiness, fatigue, hallucinations, headache, parkinsonism, psychosis, pyrexia, sedation, seizure, vertigo
Dermatologic: Rash, photosensitivity, pruritus, toxic epidermal necrolysis, urticaria
Endocrine & metabolic: Hypoglycemia, hypokalemia
Gastrointestinal: Abdominal pain, diarrhea, dry mouth, duodenal ulcer, hemorrhage, loss of appetite, nausea, ulcerative colitis, vomiting
Hematologic: Agranulocytosis, anemia, aplastic anemia, eosinophilia, leukopenia, pancytopenia, thrombocytopenia
Hepatic: Acute hepatic injury, bilirubin increased, hepatic dysfunction, jaundice, liver enzymes increased
Neuromuscular & skeletal: Paresthesia, peripheral neuropathy, weakness
Otic: Hearing loss
Renal: Azotemia, BUN increased, crystalluria, renal failure, serum creatinine increased
Respiratory: Dyspnea, respiratory arrest
Miscellaneous: Allergic reaction
Drug Interactions
Amphotericin B: May enhance the adverse/toxic effect of Flucytosine. This may be related to the adverse effects of amphotericin B on renal function. Risk C: Monitor therapy
Cytarabine: May diminish the therapeutic effect of Flucytosine. Risk D: Consider therapy modification
Saccharomyces boulardii: Antifungal Agents may diminish the therapeutic effect of Saccharomyces boulardii. Risk D: Consider therapy modification
Ethanol/Nutrition/Herb Interactions
Food: Food decreases the rate, but not the extent of absorption.
Storage
Store at room temperature of 15°C to 30°C (59°F to 86°F). Protect from light.
Mechanism of Action
Penetrates fungal cells and is converted to fluorouracil which competes with uracil interfering with fungal RNA and protein synthesis
Pharmacodynamics/Kinetics
Absorption: 76% to 89%
Distribution: Into CSF, aqueous humor, joints, peritoneal fluid, and bronchial secretions; Vd: 0.6 L/kg
Protein binding: 3% to 4%
Metabolism: Minimally hepatic; deaminated, possibly via gut bacteria, to 5-fluorouracil
Half-life elimination:
Normal renal function: 2-5 hours
Anuria: 85 hours (range: 30-250)
End stage renal disease: 75-200 hours
Time to peak, serum: ?1-2 hours
Excretion: Urine (>90% as unchanged drug)
Dosage
Usual dosage ranges: Children (unlabeled use) and Adults: Oral: 50-150 mg/kg/day in divided doses every 6 hours
Indication-specific dosing:
Children (unlabeled use) and Adults: Oral:
Endocarditis: 25-37.5 mg/kg every 6 hours (with amphotericin B) for at least 6 weeks after valve replacement
Meningoencephalitis, cryptococcal: Induction: 25 mg/kg/dose (with amphotericin B) every 6 hours for 2 weeks; if clinical improvement, may discontinue both amphotericin and flucytosine and follow with an extended course of fluconazole (400 mg/day); alternatively, may continue flucytosine for 6-10 weeks (with amphotericin B) without conversion to fluconazole treatment
Dosing interval in renal impairment: Use lower initial dose:
Clcr 20-40 mL/minute: Administer 37.5 mg/kg every 12 hours
Clcr 10-20 mL/minute: Administer 37.5 mg/kg every 24 hours
Clcr <10 mL/minute: Administer 37.5 mg/kg every 24-48 hours, but monitor drug concentrations frequently
Hemodialysis: Dialyzable (50% to 100%); administer dose posthemodialysis
Peritoneal dialysis: Adults: Administer 0.5-1 g every 24 hours
Continuous arteriovenous or venovenous hemodiafiltration effects: Change dosing frequency to every 12-24 hours (monitor serum concentrations and adjust)
Administration: Oral
Administer around-the-clock to promote less variation in peak and trough serum levels. To avoid nausea and vomiting, administer a few capsules at a time over 15 minutes until full dose is taken.
Monitoring Parameters
Pretreatment: Electrolytes (especially potassium), CBC with differential, BUN, renal function, blood culture
During treatment: CBC with differential, and LFTs (eg, alkaline phosphatase, AST/ALT) frequently, serum flucytosine concentration, renal function
Reference Range
Therapeutic: Trough: 25-50 mcg/mL; peak: 50-100 mcg/mL; peak levels should not exceed 100 mcg/mL to avoid toxic bone marrow depressive and hepatic effects
Trough: Draw just prior to dose administration
Peak: Draw 2 hours after an oral dose administration
Test Interactions
Flucytosine causes markedly false elevations in serum creatinine values when the Ektachem® analyzer is used. The Jaffé reaction is recommended for determining serum creatinine.
Patient Education
Do not take any new medication during therapy unless approved by prescriber. Take capsules one at a time over a few minutes with food to reduce GI upset. Take full course of medication as ordered. Do not discontinue without consulting prescriber. Practice good hygiene measures to prevent reinfection. Frequent blood tests may be required. May cause nausea and vomiting (small, frequent meals may help). Report rash; respiratory difficulty; CNS changes (eg, confusion, hallucinations, ataxia, acute headache); yellowing of skin or eyes; changes in color or frequency of stool or urine; unresolved diarrhea or anorexia; or unusual bleeding, fatigue, or weakness. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.
Geriatric Considerations
Adjust for renal function.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May rarely cause drowsiness, confusion, or hallucinations
Mental Health: Effects on Psychiatric Treatment
May cause bone marrow suppression; use caution with clozapine and carbamazepine
Nursing: Physical Assessment/Monitoring
See Warnings/Precautions for use cautions (eg, renal dysfunction, bone marrow depression, hematologic disease). Assess potential for interactions with other pharmacological agents patient may be taking (see Drug Interactions). Assess results of laboratory tests prior to and during treatment. Hematologic, renal, and hepatic status must be closely monitored; dose adjustments may be necessary. Assess therapeutic effectiveness (resolution of fungal infection) and adverse response (eg, cardiac incidents, CNS changes, bone marrow suppression, jaundice, skin reactions, hearing loss) on a regular basis throughout therapy. Teach patient use (full course of therapy may require some time after symptoms resolve), possible side effects/appropriate interventions, and adverse symptoms to report.
Oncology: Emetic Potential
Very low (<10%)
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule: 250 mg, 500 mg
Pricing: U.S. (www.drugstore.com)
Capsules (Ancobon)
250 mg (100): $1324.25
500 mg (30): $1000.98
Extemporaneously Prepared
Flucytosine oral liquid has been prepared by using the contents of ten 500 mg capsules triturated in a mortar and pestle with a small amount of distilled water; the mixture was transferred to a 500 mL volumetric flask; the mortar was rinsed several times with a small amount of distilled water and the fluid added to the flask; sufficient distilled water was added to make a total volume of 500 mL of a 10 mg/mL liquid; oral liquid was stable for 70 days when stored in glass or plastic prescription bottles at 4°C or for up to 14 days at room temperature.
Wintermeyer SM and Nahata MC, “Stability of Flucytosine in an Extemporaneously Compounded Oral Liquid,” Am J Health Syst Pharm, 1996, 53:407-9.
References
Aronoff GR, Berns JS, Brier ME, et al, “Drug Prescribing in Renal Failure: Dosing Guidelines for Adults,” 4th ed. Philadelphia, PA: American College of Physicians; 1999.
Lau AH and Kronfol NO, “Elimination of Flucytosine by Continuous Hemofiltration,” Am J Nephrol, 1995, 15(4):327-31.
Lyman CA and Walsh TJ, “Systemically Administered Antifungal Agents. A Review of Their Clinical Pharmacology and Therapeutic Applications,” Drugs, 1992, 44(1):9-35.
Mofenson LM, Oleske J, Serchuck L, et al, “Treating Opportunistic Infections Among HIV-Exposed and Infected Children: Recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America,” MMWR Recomm Rep, 2004, 53(RR-14):1-92. Available at http://www.cdc.gov/MMWR/preview/MMWRhtml/rr5314a1.htm
Patel R, “Antifungal Agents. Part I. Amphotericin B Preparations and Flucytosine,” Mayo Clin Proc, 1998, 73(12):1205-25.
Saag MS, Graybill RJ, Larsen RA, et al, “Practice Guidelines for the Management of Cryptococcal Disease. Infectious Diseases Society of America,” Clin Infect Dis, 2000, 30(4):710-8.
Vermes A, Guchelaar H, and Dankert J, “Flucytosine: A Review of its Pharmacology, Clinical Indications, Pharmacokinetics, Toxicity and Drug Interactions,” J Antimicrob Chemother, 2000, 46(2):171-9.
International Brand Names
Lexi-Comp.com
Last full review/revision July 2009
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