CONTRAINDICATIONS: Ancobon should not be used in patients with a known

hypersensitivity to the drug.

WARNINGS: Ancobon must be given with extreme caution to patients with impaired

renal function. Since Ancobon is excreted primarily by the kidneys, renal impairment

may lead to accumulation of the drug. Ancobon blood concentrations should be

monitored to determine the adequacy of renal excretion in such patients.1 Dosage

adjustments should be made in patients with renal insufficiency to prevent progressive

accumulation of active drug.

Ancobon must be given with extreme caution to patients with bone marrow depression.

Patients may be more prone to depression of bone marrow function if they: 1) have a

hematologic disease, 2) are being treated with radiation or drugs which depress bone

marrow, or 3) 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 therapy.

PRECAUTIONS: General: Before therapy with Ancobon is instituted, electrolytes

(because of hypokalemia) and the hematologic and renal status of the patient should be

determined (see WARNINGS). Close monitoring of the patient during therapy is

essential.

Laboratory Tests: Since renal impairment can cause progressive accumulation of the

drug, blood concentrations and kidney function should be monitored during therapy.

Hematologic status (leucocyte and thrombocyte count) and liver function (alkaline

phosphatase, SGOT and SGPT) should be determined at frequent intervals during

treatment as indicated.

Drug Interactions: Cytosine arabinoside, a cytostatic agent, has been reported to

inactivate the antifungal activity of Ancobon by competitive inhibition. Drugs which

impair glomerular filtration may prolong the biological half-life of flucytosine.

Drug/Laboratory Test Interactions: Measurement of serum creatinine levels should be

determined by the Jaffé reaction, since Ancobon does not interfere with the determination

of creatinine values by this method. Most automated equipment for measurement of

creatinine makes use of the Jaffé reaction.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Flucytosine has not undergone

adequate animal testing to evaluate carcinogenic potential. The mutagenic potential of

flucytosine was evaluated in Ames-type studies with five different mutants of S.

typhimurium and no mutagenicity was detected in the presence or absence of activating

enzymes. Flucytosine was nonmutagenic in three different repair assay systems (i.e., rec,

uvr and pol).

There have been no adequate trials in animals on the effects of flucytosine on fertility or

reproductive performance. The fertility and reproductive performance of the offspring (F1

generation) of mice treated with 100 mg/kg/day (345 mg/M2/day or 0.059 times the

human dose), 200 mg/kg/day (690 mg/M2/day or 0.118 times the human dose) or 400

mg/kg/day (1380 mg/M2/day or 0.236 times the human dose) of flucytosine on days 7 to

13 of gestation was studied; the in utero treatment had no adverse effect on the fertility or

reproductive performance of the offspring.

Pregnancy: Teratogenic Effects. Pregnancy Category C. Flucytosine was shown to be

teratogenic (vertebral fusions) in the rat at doses of 40 mg/kg/day (298 mg/M2/day or

0.051 times the human dose) administered on days 7 to 13 of gestation. At higher doses

(700 mg/kg/day; 5208 mg/M2/day or 0.89 times the human dose administered on days 9

to 12 of gestation), cleft lip and palate and micrognathia were reported. Flucytosine was

not teratogenic in rabbits up to a dose of 100 mg/kg/day (1423 mg/M2/day or 0.243 times

the human dose) administered on days 6 to 18 of gestation. In mice, 400 mg/kg/day of

flucytosine (1380 mg/M2/day or 0.236 times the human dose) administered on days 7 to

13 of gestation was associated with a low incidence of cleft palate that was not