Ancobon

Name: Ancobon

Description

Ancobon (flucytosine), an antifungal agent, is available as 250 mg and 500 mg capsules for oral administration. Each capsule also contains corn starch, lactose and talc. Gelatin capsule shells contain parabens (butyl, methyl, propyl) and sodium propionate, with the following dye systems: 250 mg capsules — black iron oxide, FD&C Blue No. 1, FD&C Yellow No. 6, D&C Yellow No. 10 and titanium dioxide; 500 mg capsules — black iron oxide and titanium dioxide. Chemically, flucytosine is 5-fluorocytosine, a fluorinated pyrimidine which is related to fluorouracil and floxuridine. It is a white to off-white crystalline powder with a molecular weight of 129.09 and the following structural formula:

Ancobon Drug Class

Ancobon is part of the drug class:

  • Other antifungals for topical use

Introduction

Antifungal; fluorinated pyrimidine analog structurally related to fluorouracil and floxuridine.120 150

Ancobon Dosage and Administration

Administration

Oral Administration

Administer orally.120

Has been administered IV, but a parenteral preparation not commercially available in the US.150

Nausea or vomiting associated with oral flucytosine may be reduced or avoided if each dose is administered by ingesting the capsules a few at a time over a 15-minute period.120

Dosage

Prolonged serum flucytosine concentrations >100 mcg/mL may be associated with an increased risk of toxicity (e.g., adverse hematologic, GI, and hepatic effects),120 150 169 170 adjust to ensure that serum concentrations remain <100 mcg/mL.133 150 169 170 436 Optimal serum concentrations have not been identified,170 and a variety of target ranges have been recommended.108 150 167 168 169 170 427 440 441

Measure serum flucytosine concentrations after 3–5 days of therapy427 and whenever there is evidence of toxicity or a change in renal function.168 Peak serum concentrations usually are measured using samples taken 2 hours after an oral dose.427 440

AAP, CDC, NIH, IDSA, and others recommend target concentrations of 40–60 mcg/mL.108 150 441 For treatment of cryptococcal infections, IDSA recommends target concentrations of 30–80 mcg/mL.427

Pediatric Patients

General Pediatric Dosage† Oral

50–150 mg/kg daily, administered in 4 equally divided doses at 6-hour intervals.108

Candida Infections Invasive Candidiasis (Including CNS Infections) Oral

HIV-infected infants and children†: 100–150 mg/kg daily given in 4 equally divided doses in conjunction with IV amphotericin B.441 Continue treatment for candidemia 2–3 weeks after clearance of Candida from the bloodstream is documented and neutropenia and symptoms attributable to candidemia resolve.425 441

Cryptococcosis Oral

Children with CNS or disseminated cryptococcosis†: Induction therapy with 100 mg/kg daily in 4 divided doses in conjunction with IV amphotericin B for at least 2 weeks, then consolidation therapy with oral fluconazole alone for at least 8 weeks.427

HIV-infected infants and children with severe pulmonary or disseminated (non-CNS) cryptococcosis†: 100 mg/kg daily in 4 divided doses in conjunction with IV amphotericin B.441 Treatment duration depends on response and site and severity of infection.441

HIV-infected infants, children, and adolescents with cryptococcal meningitis†: Induction therapy with 100 mg/kg daily given in 4 divided doses in conjunction with IV amphotericin B for at least 2 weeks until there is evidence of clinical improvement and negative CSF cultures after repeat lumbar puncture, then consolidation therapy with oral or IV fluconazole alone for at least 8 weeks.427 441

HIV-infected infants and children with cryptococcal meningitis who cannot receive amphotericin B†: Induction therapy with 100 mg/kg daily in 4 divided doses in conjunction with oral or IV fluconazole given for at least 2 weeks, then consolidation therapy with oral or IV fluconazole alone for at least 8 weeks.441

Adults

General Adult Dosage Oral

50–150 mg/kg daily, administered in 4 equally divided doses at 6-hour intervals.120

To reduce risk of toxicity when used in conjunction with IV amphotericin B, a low initial dosage (i.e., 75 mg/kg daily given in 4 divided doses) has been suggested.436 Dosage can then be adjusted based on serum flucytosine concentrations and presence or absence of amphotericin B-associated renal toxicity.436

Candida Infections Treatment of CNS Candidiasis Oral

25 mg/kg 4 times daily in conjunction with IV amphotericin B for several weeks, then follow-up therapy with fluconazole alone.425 Continue antifungal treatment until signs and symptoms, CSF abnormalities, and radiologic abnormalities resolve.425

Treatment of Symptomatic Cystitis Caused by Fluconazole-resistant Candida Oral

25 mg/kg 4 times daily for 7–10 days.425

Treatment of Pyelonephritis or Fungus Balls Caused by Fluconazole-resistant Candida Oral

Pyelonephritis: 25 mg/kg 4 times daily alone or in conjunction with IV amphotericin B for 2 weeks.425

Fungus balls: 25 mg/kg 4 times daily in conjunction with IV amphotericin B continued until symptoms resolve and urine cultures are negative for Candida.425

Treatment of Candida Endophthalmitis Oral

Patients with advancing lesions or lesions threatening the macula: 25 mg/kg 4 times daily in conjunction with IV amphotericin B.425 Duration of treatment is at least 4–6 weeks as determined by repeated examinations to verify resolution.425

Treatment of Candida Endocarditis IV

25 mg/kg 4 times daily in conjunction with IV amphotericin B.425 If infection is caused by fluconazole-susceptible strains, consider changing to follow-up therapy with oral fluconazole after patient is clinically stable and Candida have been cleared from the bloodstream.425

Cryptococcosis Treatment of Cryptococcal Meningitis Oral

HIV-infected adults: Induction therapy with 25 mg/kg 4 times daily in conjunction with IV amphotericin B given for at least 2 weeks until there is evidence of clinical improvement and negative CSF cultures after repeat lumbar puncture, then consolidation therapy with oral fluconazole alone for at least 8 weeks.427 440

HIV-infected adults who cannot receive amphotericin B: Induction therapy with 25 mg/kg 4 times daily in conjunction with oral fluconazole for 4–6 weeks, then consolidation therapy with oral fluconazole alone for at least 8 weeks.427 440

Special Populations

Renal Impairment

Use with extreme caution and reduce dosage.120

Several methods of calculating flucytosine dosage for impaired renal function have been proposed.a For greater accuracy, dosage should be based on actual serum flucytosine concentrations.a Precise dosing is limited since flucytosine is commercially available only as 250- and 500-mg capsules.a

Usual individual dose (12.5–37.5 mg/kg) can be administered every 12 hours in patients with Clcr 20–40 mL/minute, every 24 hours in those with Clcr 10–20 mL/minute, and every 24–48 hours or longer (as determined by serum drug concentrations) in those with Clcr <10 mL/minute.a

Alternatively, consider 12–35 mg/kg at intervals equal to twice the half-life of the drug.a In patients with Clcr <10 mL/minute, an initial loading dose (the usual individual dose) followed by 6–17.5 mg/kg administered at intervals equal to the half-life may be of particular value.a

In patients undergoing hemodialysis every 48–72 hours, 20–50 mg/kg administered immediately after dialysis generally produces therapeutically effective and nontoxic peak and postdialysis serum drug concentrations.a

Ancobon Pharmacokinetics

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

How is this medicine (Ancobon) best taken?

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • Take with or without food.
  • To lower or avoid upset stomach or throwing up, take a few capsules at a time over 15 minutes.
  • To gain the most benefit, do not miss doses.
  • Keep taking Ancobon as you have been told by your doctor or other health care provider, even if you feel well.

What do I do if I miss a dose?

  • Take a missed dose as soon as you think about it.
  • If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
  • Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
  • Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
  • Signs of low potassium levels like muscle pain or weakness, muscle cramps, or a heartbeat that does not feel normal.
  • Signs of low blood sugar like dizziness, headache, feeling sleepy, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating.
  • Feeling very tired or weak.
  • Chest pain or pressure.
  • Shortness of breath, a big weight gain, or swelling in the arms or legs.
  • Very bad belly pain.
  • Feeling confused.
  • Seizures.
  • Mood changes.
  • Hearing loss.
  • Change in balance.
  • A burning, numbness, or tingling feeling that is not normal.
  • Shakiness, trouble moving around, or stiffness.
  • Hallucinations (seeing or hearing things that are not there).
  • Very bad and sometimes deadly liver problems have happened with this medicine. Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.

Ancobon Description

Ancobon (flucytosine), an antifungal agent, is available as 250 mg and 500 mg capsules for oral administration. In addition to the active ingredient of flucytosine, each capsule contains corn starch, lactose and talc. The 250 mg capsule shell contains black iron oxide, D&C Yellow No. 10, FD&C Blue No. 1, FD&C Yellow No. 6, gelatin and titanium dioxide. The 500 mg capsule shell contains black iron oxide, gelatin and titanium dioxide.

Chemically, flucytosine is 5-fluorocytosine, a fluorinated pyrimidine which is related to fluorouracil and floxuridine. It is a white to off-white crystalline powder with a molecular weight of 129.09 and the following structural formula:

Contraindications

Ancobon should not be used in patients with a known hypersensitivity to the drug.

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

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 statistically significant. Studies in pregnant rats have shown that flucytosine injected intraperitoneally crosses the placental barrier. There are no adequate and well-controlled studies in pregnant women. Ancobon should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Ancobon, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The efficacy and safety of Ancobon 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, for systemic candidiasis. No unexpected adverse reactions were reported in these patients. It should be noted, however, that hypokalemia and acidemia were reported 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 noted in two additional patients, one of whom also received amphotericin B.

PRINCIPAL DISPLAY PANEL - 250 mg Capsule Bottle Label

NDC 0187-3554-10
Rx only

Ancobon®
(flucytosine)

250 mg

Each capsule
contains 250
mg flucytosine

100 Capsules

VALEANT

What happens if i miss a dose (ancobon)?

Take the missed dose as soon as you remember. However, if it is almost time for the next regularly scheduled dose, skip the missed dose and take the next one as directed. Do not take a double dose of this medication.

For the Consumer

Applies to flucytosine: oral capsule, oral tablet

Along with its needed effects, flucytosine (the active ingredient contained in Ancobon) 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 while taking flucytosine:

More common
  • Skin rash, redness, or itching
  • sore throat and fever
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • yellow eyes or skin
Less common
  • Confusion
  • hallucinations (seeing, hearing, or feeling things that are not there)
  • increased sensitivity of skin to sunlight

Some side effects of flucytosine 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:

More common
  • Abdominal pain
  • diarrhea
  • loss of appetite
  • nausea or vomiting
Less common
  • Dizziness or lightheadedness
  • drowsiness
  • headache

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