Flucytosine

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

While using flucytosine, you may need frequent blood tests.

Take each dose with a full glass (8 ounces) of water.

Flucytosine may cause nausea and vomiting. If you take more than one capsule per dose, swallow one capsule at a time over a 15-minute period to help prevent nausea and vomiting.

Use this medicine for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antifungal medicine. Flucytosine will not treat a viral infection such as the flu or a common cold.

Store at room temperature away from moisture and heat.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include nausea, vomiting, diarrhea, upper stomach pain, or unusual bleeding or bruising.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

The adverse reactions which have occurred during treatment with Ancobon are grouped according to organ system affected.

Cardiovascular: Cardiac arrest, myocardial toxicity, ventricular dysfunction.

Respiratory: Respiratory arrest, chest pain, dyspnea.

Dermatologic: Rash, pruritus, urticaria, photosensitivity.

Gastrointestinal: Nausea, emesis, abdominal pain, diarrhea, anorexia, dry mouth, duodenal ulcer, gastrointestinal hemorrhage, acute hepatic injury including hepatic necrosis with possible fatal outcome in debilitated patients, hepatic dysfunction, jaundice, ulcerative colitis, enterocolitis, bilirubin elevation, increased hepatic enzymes.

Genitourinary: Azotemia, creatinine and BUN elevation, crystalluria, renal failure.

Hematologic: Anemia, agranulocytosis, aplastic anemia, eosinophilia, leukopenia, pancytopenia, thrombocytopenia, and fatal cases of bone marrow aplasia.

Neurologic: Ataxia, hearing loss, headache, paresthesia, parkinsonism, peripheral neuropathy, pyrexia, vertigo, sedation, convulsions.

Psychiatric: Confusion, hallucinations, psychosis.

Miscellaneous: Fatigue, hypoglycemia, hypokalemia, weakness, allergic reactions, Lyell's syndrome.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Flucytosine falls into category C:

In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans, though. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

OR

There are no well-controlled studies that have been done in pregnant women. Flucytosine should be used during pregnancy only if the possible benefit outweighs the possible risk to the unborn baby.

OR

No studies have been done in animals, and no well-controlled studies have been done in pregnant women. Flucytosine should be given to a pregnant woman only if clearly needed.

Absorption

Bioavailability

Rapidly and almost completely absorbed from GI tract;120 bioavailability is 78–89%.120

In normal renal function, peak serum flucytosine concentrations reached within 2 hours following a single 2-g oral dose.120

Food

Food decreases rate, but not extent, of absorption.a

Special Populations

In a limited number of neonates receiving oral flucytosine, mean time to peak serum concentrations was 2.5 hours after a dose.120 Considerable interindividual variation in serum concentrations, not correlated with gestational age, reported in neonates.120

Peak serum concentrations are higher, more prolonged, and reached more slowly in impaired renal function.

In anephric patients, peak serum concentrations may be 50% higher than in patients with normal renal function.a

Distribution

Extent

Widely distributed into body tissues and fluids including liver, kidney, spleen, heart, aqueous humor, and bronchial secretions.a

Distributed into CSF;120 concentrations in CSF may be 60–100% of serum concentrations.a

Not known whether distributed into milk.a

Plasma Protein Binding

2–4% bound to serum proteins.a

Elimination

Metabolism

Only minimal amounts are metabolized.a Deaminated (probably by gut bacteria) to fluorouracil.120 AUC ratio of fluorouracil to flucytosine is 4%.120

Elimination Route

>75–90% of an oral dose excreted unchanged in urine.a

Unabsorbed flucytosine excreted unchanged in feces.a

Removed by peritoneal dialysis.a

Removed by hemodialysis.a

Half-life

2.4–6 hours in normal renal function.a

Special Populations

In a limited number of infants, median half-life was 7.4 hours.120

Half-life prolonged in renal impairment.a

Half-life is 6–14 hours in those with Clcr 40 mL/minute, 12–15 hours in those with Clcr 20 mL/minute, 21–27 hours in those with Clcr 10 mL/minute, and 30–250 hours in those with Clcr <10 mL/minute.a Half-lives up to 1160 hours have been reported when Clcr <2 mL/minute.a

Flucytosine belongs to the group of medicines called antifungals. It is used to treat certain fungus infections.

Flucytosine is available only with your doctor's prescription.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Skin rash, redness, or itching
• sore throat and fever
• unusual bleeding or bruising
• unusual tiredness or weakness
• yellow eyes or skin

• Confusion
• hallucinations (seeing, hearing, or feeling things that are not there)
• increased sensitivity of skin to sunlight

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Abdominal pain
• diarrhea
• loss of appetite
• nausea or vomiting

• Dizziness or lightheadedness
• drowsiness
• headache

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

The usual dosage of Flucytosine Capsules is 50 to 150 mg/kg/day administered in divided doses at 6-hour intervals. Nausea or vomiting may be reduced or avoided if the capsules are given a few at a time over a 15-minute period. If the BUN or the serum creatinine is elevated, or if there are other signs of renal impairment, the initial dose should be at the lower level (see WARNINGS).

Flucytosine Capsules should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis because of the emergence of resistance to Flucytosine Capsules (see MICROBIOLOGY).

Amphotericin B: May enhance the adverse/toxic effect of Flucytosine. This may be related to the adverse effects of amphotericin B on renal function. Monitor therapy

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Cytarabine (Conventional): May diminish the therapeutic effect of Flucytosine. Consider therapy modification

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Gimeracil: May increase serum concentrations of the active metabolite(s) of Flucytosine. Specifically, gimeracil may increase concentrations of fluorouracil. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Saccharomyces boulardii: Antifungal Agents (Systemic, Oral) may diminish the therapeutic effect of Saccharomyces boulardii. Avoid combination

Applies to flucytosine: oral capsule

Gastrointestinal

Gastrointestinal side effects have included nausea, emesis, abdominal pain, diarrhea, anorexia, dry mouth, duodenal ulcer, gastrointestinal hemorrhage, enterocolitis, and ulcerative colitis.[Ref]

Nausea is common at high doses, generally occurs in the first two weeks of therapy, and often resolves with time or temporary dose reduction. Diarrhea is often associated with cramps, occurs most frequently in the first two weeks of therapy, and frequently resolves with time or temporary dose reduction. One case has been reported of a patient on long-term therapy who developed diarrhea which did not resolve spontaneously. X-ray of the small bowel revealed ulceration and the ileocecal valve and distal ileum appeared edematous. Flucytosine was discontinued and the patient improved over the next two weeks.[Ref]

Hepatic

Some patients experience significant increases in liver function tests and may develop signs and symptoms of hepatitis. Liver function test abnormalities generally resolve after discontinuation of flucytosine.[Ref]

Hepatic side effects have included jaundice, hepatic dysfunction, bilirubin elevation, increased hepatic enzymes, and acute hepatic injury including hepatic necrosis with possible fatal outcome in debilitated patients.[Ref]

Hematologic

Hematologic side effects have included anemia, agranulocytosis, aplastic anemia, eosinophilia, leukopenia, pancytopenia, thrombocytopenia, and fatal cases of bone marrow suppression.[Ref]

Bone marrow suppression may range from isolated leukopenia or thrombocytopenia to pancytopenia. Often there is just mild leukopenia or thrombocytopenia which does not require discontinuation of the drug. In most cases the suppression is reversible following discontinuation of flucytosine therapy, but at least one case of fatal, irreversible marrow failure has occurred.[Ref]

Hypersensitivity

Photosensitivity has been reported in one case of a patient receiving long-term flucytosine. The photosensitivity persisted for one year after completion of therapy.

A case of anaphylaxis has been reported. In that case, a patient who had hemophilia and AIDS was receiving flucytosine for oral candidiasis. Flucytosine therapy was started following 10 days of miconazole and the patient developed a fever, erythema, pruritus, tachycardia and hypotension requiring volume support. Rechallenge was attempted one week later with one tablet. The rechallenge resulted in the same signs and symptoms and ran a similar course.[Ref]

Hypersensitivity side effects have included allergic reactions. Rashes have been reported rarely. At least one case of photosensitivity has been reported, in addition to a case of anaphylaxis.[Ref]

Cardiovascular

Cardiovascular side effects have included cardiac arrest, myocardial toxicity, and ventricular dysfunction. Cardiac toxicity with ST elevation has been reported in a 34-year-old woman, with no previous history of heart disease, the day after completing a 2-day flucytosine therapy.[Ref]

A 34-year-old woman reported severe chest pain the day after completing a 2-day flucytosine therapy. Cardiac echography indicated septo-apico-lateral severe hypokinesia, with left ventricular ejection fraction less than 15%. Aggressive cardiac intensive care with positive inotropic agents, placement of an intra-aortic balloon pump counterpulsation, and milrinone along with continuous veno-venous hemodiafiltration were needed over the 2 weeks of hospitalization before restoration of her cardiovascular status. Patient has not shown further signs of heart problems during the 2 years since this event.[Ref]

Respiratory

Respiratory side effects have included dyspnea, chest pain, and respiratory arrest.[Ref]

Dermatologic

Dermatologic side effects have included rash, pruritus, urticaria, photosensitivity, and Lyell's syndrome.[Ref]

Genitourinary

Genitourinary side effects have included crystalluria.[Ref]

Renal

Renal side effects have included azotemia, creatinine and BUN elevation, and renal failure.[Ref]

Nervous system

Nervous system side effects have included ataxia, hearing loss, headache, paresthesia, parkinsonism, peripheral neuropathy, pyrexia, vertigo, sedation, and convulsions.[Ref]

Psychiatric

Psychiatric side effects have included confusion, hallucinations, and psychosis.[Ref]

Metabolic

Metabolic side effects have included hypoglycemia.

Other

Other side effects have included fatigue and weakness.[Ref]

Some side effects of flucytosine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Serious infections due to susceptible strains of Candida and/or Cryptococcus (including septicemia, endocarditis, urinary system infections, meningitis, and pulmonary infections): 50 to 150 mg/kg/day orally in divided doses every 6 hours (in conjunction with amphotericin B)

Alternatively, the Infectious Diseases Society of America (IDSA) recommends a dosage of 100 mg/kg/day orally in 4 divided doses (in conjunction with amphotericin B or fluconazole).

Serious infections due to susceptible strains of Candida and/or Cryptococcus (including septicemia, endocarditis, urinary system infections, meningitis, and pulmonary infections): 50 to 150 mg/kg/day orally in divided doses every 6 hours (in conjunction with amphotericin B)

Alternatively, the Infectious Diseases Society of America (IDSA) recommends a dosage of 100 mg/kg/day orally in 4 divided doses (in conjunction with amphotericin B or fluconazole).

Use flucytosine with extreme caution in patients with impaired renal function. Since flucytosine is excreted primarily by the kidneys, renal impairment may lead to accumulation of the drug. Flucytosine levels should be monitored to determine the adequacy of renal excretion in such patients. Dosage adjustments should be made in patients with renal impairment to prevent progressive accumulation of active drug. Close monitoring of renal status of all patients is essential.

Flucytosine must be given with extreme caution in patients with bone marrow depression. Patients may be more prone to bone marrow suppression if they have a hematologic disease, are being treated with radiation or other 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. Close monitoring of hematologic status of all patients is essential.

Peak blood concentrations of flucytosine should not exceed 100 mcg/mL. Prolonged serum levels in excess of 100 mcg/mL may be associated with an increased risk of toxicity, especially gastrointestinal (diarrhea, nausea, vomiting), hematologic (leukopenia, thrombocytopenia), and hepatic (hepatitis).

Close monitoring of hepatic (alkaline phosphatase, SGOT, and SGPT) and electrolytes status of all patients is essential.

The safety and efficacy of flucytosine have not been systematically studied in pediatric patients. A small number of neonates have been treated with 25 to 200 mg/kg/day of flucytosine, with and without the addition of amphotericin B therapy, for systemic candidiasis. No unexpected side effects were reported in these patients. It should be noted, however, that hypokalemia and acidemia were observed in one patient who received flucytosine in combination with amphotericin B, and anemia was observed in a second patient who received flucytosine alone. Transient thrombocytopenia was observed in two additional patients, one of whom also received amphotericin B therapy.