Flucytosine (Systemic)


VA CLASSIFICATION
Primary: AM700

Other commonly used names are
5-fluorocytosine and 5-FC .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antifungal (systemic)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Endocarditis, fungal (treatment)—Flucytosine is indicated in the treatment of endocarditis caused by Candida species.{01} {06}

Meningitis, fungal (treatment)—Flucytosine is indicated in the treatment of meningitis caused by Cryptococcus species.{01} {06}

Pneumonia, fungal (treatment)
Septicemia, fungal (treatment) or
Urinary tract infections, fungal (treatment)—Flucytosine is indicated in the treatment of pneumonia, septicemia, and urinary tract infections caused by Candida and Cryptococcus species.{01} {06}

Candidiasis (treatment){01}
[Chromomycosis (treatment)]{27} or
Cryptococcosis (treatment){01}— Flucytosine is used in the treatment of disseminated candidiasis, chromomycosis, and cryptococcosis.

—In the treatment of disseminated fungal disease, flucytosine is usually administered concurrently with parenteral amphotericin B because of rapid development of resistance when flucytosine is administered alone. {11}

—Not all species or strains of a particular organism may be susceptible to flucytosine.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Fluorinated pyrimidine derivative; chemically related to fluorouracil and floxuridine {01}
Molecular weight—
    129.09{01}

Mechanism of action/Effect:

Flucytosine penetrates into fungal cells and is converted to fluorouracil, an antimetabolite. By interfering with purine and pyrimidine uptake and by deaminated to 5-fluorouracil (5-FU) and then converted to 5-fluorodeoxyuridylic acid monophosphate, a noncompetitive inhibitor of thymidylate synthetase which interferes with DNA synthesis. , flucytosine interrupts nucleic acid and protein synthesis. The cells of the host do not convert large quantities of flucytosine to fluorouracil, accounting for the selective toxicity of the compound against fungi. {01}{21}

Absorption:

Rapidly and well absorbed from the gastrointestinal tract. {15}

Bioavailability—78 to 90%.{01}

Distribution:

Flucytosine is distributed widely throughout the body. The exact distribution in body fluids and organs is not known. However, cerebrospinal fluid (CSF) concentrations may range from about 60 to 90% of those achieved in the serum. Concentrations in the liver, kidneys, spleen, heart, and lungs appear to equal those in the serum. {13}

Protein binding:

Very low (2.9–4%).{01}

Biotransformation:

Flucytosine is not significantly metabolized.{01}

Half-life:

Elimination—2.5 to 6 hours in patients with normal renal function.{01}{12}

12 to 250 hours in patients with impaired renal function.{01}{12}

Time to peak serum concentration

1 to 2 hours.{01}{15}

Peak serum concentration:

30 to 40 mcg/mL 2 to 4 hours after a 2-gram dose in adults.{01}{13}

Elimination:
    Renal; more than 90% excreted by glomerular filtration as unchanged drug.{01}


Precautions to Consider

Carcinogenicity/Mutagenicity

Adequate studies in animals have not been performed to evaluate the carcinogenic potential of flucytosine. No mutagenicity was detected in Ames-type studies in the presence or absence of activating enzymes. {01}

Pregnancy/Reproduction

Pregnancy—
Flucytosine crosses the placenta. Problems in humans have not been documented.

However, studies in rats have shown that flucytosine, which is metabolized in rats to fluorouracil, is teratogenic. {01}

FDA Pregnancy Category C.

Breast-feeding

It is not known whether flucytosine is excreted into breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, based on the importance of the drug to the mother. {01}

Pediatrics

Appropriate studies on the relationship of age to the effects of flucytosine have not been performed in the pediatric population. However, no pediatrics-specific problems have been documented to date. {01}


Geriatrics


No information is available on the relationship of age to the effects of flucytosine in geriatric patients. However, elderly patients are more likely to have an age-related decrease in renal function, which may require an adjustment of dosage in patients receiving flucytosine.


Dental

The bone marrow-depressant effects of flucytosine may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Amphotericin B, parenteral    (concurrent use of amphotericin B and flucytosine may have additive or slightly synergistic effects; amphotericin B-induced renal dysfunction may increase the bone marrow toxicity of flucytosine. However, 2-drug therapy may allow the total daily dose of amphotericin B to be lowered, decreasing its risk of nephrotoxicity {01}{16}{17}{18})


Blood dyscrasia-causing medications (See Appendix II ) or
» Bone marrow depressants, other, (See Appendix II ) or
» Radiation therapy    (concurrent use with flucytosine may increase the bone marrow–depressant effects of these medications and radiation therapy; dosage reduction may be required {06})


Cytarabine    (cytarabine has been reported to antagonize the antifungal activity of flucytosine by competitive inhibition {01})


Glomerular filtration-reduction medication    (drugs that impair glomerular filtration may prolong the half-life of flucytosine {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Allergy to flucytosine {19}
Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression or
Hematologic disease    (flucytosine may cause bone marrow depression, resulting in anemia, leukopenia, and thrombocytopenia {01}))


Hepatic function impairment {01}    (flucytosine may cause jaundice or hepatic dysfunction, worsening any pre-existing hepatic function impairment {01} )


» Renal function impairment    (because flucytosine is excreted renally, it is recommended that this medication be administered in a reduced dosage to patients with impaired renal function {01})


» Risk-benefit should be considered in patients who have had previous cytotoxic drug therapy or radiation therapy also. {01}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Alanine aminotransferase (ALT [SGPT]), serum and
» Alkaline phosphatase, serum and
» Aspartate aminotransferase (AST [SGOT]), serum and
» Bilirubin, serum    (concentrations are recommended prior to initiation of therapy and at frequent intervals during therapy)


» Blood urea nitrogen (BUN) and
» Creatinine, serum    (recommended prior to initiation of therapy and at periodic intervals during therapy since flucytosine may cause azotemia or an increase in these values; dosage must be reduced in renal function impairment)

    (flucytosine may interfere with serum creatinine determinations that are measured by the Kodak Ektachem-700 analyzer, falsely elevating creatinine values; an analyzer that uses the Jaffe procedure should be used to measure serum creatinine{01} {20})


Flucytosine concentrations, serum    (serum flucytosine concentrations are recommended in patients with renal function impairment [e.g., creatinine clearance <40 mL per min or 0.67 mL per sec], to assess the adequacy of renal excretion and to prevent flucytosine accumulation in the serum; side effects are more common with serum concentrations >100 mcg/mL {16} {18})


» Hematocrit or hemoglobin and
» Leukocyte count, total and, if appropriate, differential and
» Platelet count    (determinations recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently {01})


Potassium concentrations, serum    (because of hypokalemia, serum potassium concentration are recommended before and during therapy with flucytosine {01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent {01} {12}
    
Anemia (unusual tiredness or weakness)
    
hepatitis or jaundice (yellow eyes or skin)
    
hypersensitivity (skin rash, redness, or itching)
    
leukopenia or (sore throat and fever), thrombocytopenia (unusual bleeding or bruising)— occur more frequently in patients whose blood levels exceed 100 to 125 micrograms/mL {01}{22}{23}

Incidence less frequent {01}
    
Confusion
    
hallucinations
    
photosensitivity (increased sensitivity of skin to sunlight)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent {01}
    
Gastrointestinal disturbances (abdominal pain; diarrhea; loss of appetite; nausea ; vomiting)— occur more frequently in patients whose blood levels exceed 100 to 125 micrograms/mL {01}{22}{23}

Incidence less frequent {01}
    
CNS effects (dizziness or lightheadedness; drowsiness; headache)





Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing ).

Clinical effects of overdose
Chronic—Prolonged serum concentration above 100 mcg/mL may be associated with an increase in the incidence of gastrointestinal (diarrhea, nausea, vomiting), hematologic (leukopenia, thrombocytopenia) and hepatic (hepatitis) adverse effects. {01}

Treatment of overdose
Although there is not experience with acute overdosage of flucytosine, treatment may involve:

To decrease absorption—Gastric lavage or emesis are recommended. {01}{03}

To increase elimination—Adequate fluid intake, by the intravenous route if necessary and increase diuresis. {01}{03}

Hemodialysis rapidly reduces serum concentration of flucytosine in anuric patients and may be considered. {01}{03}

Monitoring—Hematologic parameters, liver and kidney function should be carefully monitored. {01}{03}

Supportive care—Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Flucytosine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Allergy to flucytosine

Pregnancy—Flucytosine crosses the placenta; studies in rats have shown this medication to be teratogenic





Breast-feeding—It is not known whether flucytosine is distributed in the breast milk. However, flucytosine has the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug.





Dental—Bone marrow depression effects of flucytosine may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding
Other medication, especially bone marrow depressants or radiation therapy
Other medical problems, especially bone marrow depression or renal function impairment

Previous cytotoxic drug therapy or radiation therapy

Proper use of this medication
Taking multiple dosage units, prescribed as a single dose, over a period of 15 minutes to minimize nausea or vomiting

» Compliance with full course of therapy

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress during therapy

Using caution in use of regular toothbrushes, dental floss, and toothpicks; completing dental work prior to initiation of therapy or delaying it until blood counts have returned to normal; checking with physician or dentist concerning proper oral hygiene

» Possible photosensitivity reactions

» Caution if dizziness, lightheadedness, or drowsiness occurs


Side/adverse effects
Signs of potential side effects, especially anemia, confusion, hallucinations, hepatitis, hypersensitivity, jaundice, leukopenia, photosensitivity and thrombocytopenia


General Dosing Information
If multiple dosage units are prescribed as a single dose, administration may be spaced over a period of 15 minutes to prevent or reduce nausea or vomiting. {01}

Since fungal resistance may develop rapidly when flucytosine is administered alone, it is usually administered concurrently with parenteral amphotericin B.

Dosing intervals may be adjusted according to creatinine clearance as follows {06}:

Creatinine Clearance
(mL/min)/(mL/sec)
Dosing Interval
(hr)
>40/0.67
6
20–40/0.33–0.67
12
10–20/0.17–0.33
24
<10/0.17
>24



Oral Dosage Forms

FLUCYTOSINE CAPSULES USP

Usual adult and adolescent dose
Antifungal
Oral, 12.5 to 37.5 mg per kg of body weight every six hours. {01}


Note: Dosage should be reduced or dosage intervals lengthened in patients with renal impairment as shown in the table {24}:

Creatinine clearance
(mL/min) 
Dose  Dosage interval  
20–40   0.5 times the usual adult and adolescent dose   Usual dosage interval 
10–20  0.25 times the usual adult and adolescent dose  Usual dosage interval 
See Usual adult and adolescent dose  Every 24 hours  



Usual pediatric dose
Antifungal
Oral, 12.5 to 37.5 mg per kg of body weight {14} or 375 to 562.5 mg per square meter of body surface every six hours.
In neonates a dose of 20 to 40 mg/kg/dose orally every 6 hours has been recommended. {25}{26}


Strength(s) usually available
U.S.—


250 mg (Rx) [Ancobon (lactose) (corn starch)]


500 mg (Rx) [Ancobon (lactose) (corn starch)]

Canada—


500 mg (Rx) [Ancotil]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.

Auxiliary labeling:
   • Continue medicine for full time of treatment.



Revised: 03/08/2000



References
  1. Product Information: Ancobon® (flucytosine), ICN, Costa Mesa, CA, rev. 12/96, reviewed 2/2000.
  1. Panel comments, Flucytosine (Systemic), 12/2/86.
  1. Manufacturer comments, Flucytosine (Systemic), 1/13/87.
  1. USP DI 1989, VA Medication Classification System: 2472.
  1. Not used.
  1. Ancotil (Roche). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 23rd ed. Ottawa: Canadian Pharmaceutical Association, 1988: 50.
  1. Fleeger CA, editor. USAN 1989. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1988: 242.
  1. USP Description and Solubility, 4/3/89.
  1. USP Requirements, USP DI 1989: IV/37.
  1. Panel comment, 5/21/84.
  1. Panel comment, 5/18/84.
  1. Gilman AG, Goodman LS, Rall TW, Murad F, editors. Goodman and Gilman's the pharmocological basis of therapeutics. 7th ed. New York: Macmillan, 1985: 1223-4.
  1. Baley JE, et al. Pharmacokinetics, outcome of treatment, and toxic effects of amphotericin B and 5-fluorocytosine in neonates. J Pediatr 1990; 116(5): 791-797.
  1. Benitz WE, Tatro DS. The pediatric drug handbook. 2nd ed. Chicago: Year Book Medical Publishers, Inc., 1988: 624.
  1. Ancotil (Roche). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 24th ed. Ottawa: Canadian Pharmaceutical Association, 1989: 58.
  1. Shindo K, et al. Granulocytopenia and thrombocytopenia associated with combination therapy of amphotericin B and low-dose flucytosine in a patient with cryptococcal meningitis. Drug Intell Clin Pharm 1989; 23: 672-3.
  1. Smego RA, Perfect JR, Druack DT. Combined therapy with amphotericin B and 5-fluorocytosine for Candida meningitis. Rev Inf Dis 1984; 6(6): 791-801.
  1. Stamm AM, et al. Toxicity of amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis. Am J Med 1987; 83: 236-42.
  1. Kotani S, et al. Anaphylaxis to flucytosine in a patient with AIDS. JAMA 1988; 260(22): 3275-6.
  1. Santeiro ML, Thompson DF, Sagraves R. Flucytosine interference with serum creatinine determinations. Drug Intell Clin Pharm 1988; 22: 879-80.
  1. Diasio RB, Bennett JE & Myers CE: Mode of action of 5-fluorocytosine. Biochem Pharmacol 1978; 27:703.
  1. Kauffman C & Frame PT: Bone marrow toxicity associated with 5-fluorocytosine therapy. Antimicrob Agents Chemother 1977; 11:244.
  1. Stamm AM, Diasio RB, Dismukes WE et al: Toxicity of Amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis. Am J Med 1987; 83:236-242.
  1. Kerkering TM: Present status of flucytosine therapy. Drug Ther 1982; 12:75-79.
  1. Greene MG (Ed): The Harriet Lane Handbook, 12th ed. Mosby Year Book Inc, St Louis, 1991.
  1. Batagol R (ed): Drugs in Pregnancy. The Royal Women's Hospital, CSL Limited, Victoria, Australia, 1993.
  1. Product Information: Ancotil®, flucytosine, ICN Canada, Montreal, PQ, Canada, rev. 12/77, reviewed 2/2000.
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