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DRUGS & SUPPLEMENTS
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Ancotyl
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Ancotyl uses
- Warning
- Description
- Clinical pharmacology
- Indications and usage
- Contraindications
- Warnings
- Precautions
- Adverse reactions
- Overdosage
- Dosage and administration
- How suppliedancobon® (flucytosine) capsules are supplied as capsules containing 250 mg and 500 mg flucytosine.
- References
WARNING
Use with extreme caution in patients with impaired renal function. Close monitoring of hematologic, renal and hepatic status of all patients is essential. These instructions should be thoroughly reviewed before administration of Ancotyl.
DESCRIPTION
Ancotyl (flucytosine), an antifungal agent, is available as 250 mg and 500 mg capsules for oral administration. In addition to the active ingredient of Ancotyl, 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, Ancotyl 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:
CLINICAL PHARMACOLOGY
Ancotyl is rapidly and virtually completely absorbed following oral administration. Ancotyl is not metabolized significantly when given orally to man. Bioavailability estimated by comparing the area under the curve of serum concentrations after oral and intravenous administration showed 78% to 89% absorption of the oral dose. Peak serum concentrations of 30 to 40 mcg/mL were reached within 2 hours of administration of a 2 g oral dose to normal subjects. Other studies revealed mean serum concentrations of approximately 70 to 80 mcg/mL 1 to 2 hours after a dose in patients with normal renal function receiving a 6-week regimen of Ancotyl in combination with amphotericin B. The half-life in the majority of healthy subjects ranged between 2.4 and 4.8 hours. Ancotyl is excreted via the kidneys by means of glomerular filtration without significant tubular reabsorption. More than 90% of the total radioactivity after oral administration was recovered in the urine as intact drug. Ancotyl is deaminated (probably by gut bacteria) to 5-fluorouracil. The area under the curve (AUC) ratio of 5-fluorouracil to Ancotyl is 4%. Approximately 1% of the dose is present in the urine as the α-fluoro-β-ureido-propionic acid metabolite. A small portion of the dose is excreted in the feces.
The half-life of Ancotyl is prolonged in patients with renal insufficiency; the average half-life in nephrectomized or anuric patients was 85 hours (range: 29.9 to 250 hours). A linear correlation was found between the elimination rate constant of Ancotyl and creatinine clearance.
In vitro studies have shown that 2.9% to 4% of Ancotyl is protein-bound over the range of therapeutic concentrations found in the blood. Ancotyl readily penetrates the blood-brain barrier, achieving clinically significant concentrations in cerebrospinal fluid.
Pharmacokinetics in Pediatric Patients
Limited data are available regarding the pharmacokinetics of Ancotyl administered to neonatal patients being treated for systemic candidiasis. After five days of continuous therapy, median peak levels in infants were 19.6 mcg/mL, 27.7 mcg/mL, and 83.9 mcg/mL at doses of 25 mg/kg (N=3), 50 mg/kg (N=4), and 100 mg/kg (N=3), respectively. Mean time to peak serum levels was of 2.5 ± 1.3 hours, similar to that observed in adult patients. A good deal of interindividual variability was noted, which did not correlate with gestational age. Some patients had serum levels > 100 mcg/mL, suggesting a need for drug level monitoring during therapy. In another study, serum concentrations were determined during Ancotyl therapy in two patients (total assays performed =10). Median serum Ancotyl concentrations at steady state were calculated to be 57 ± 10 mcg/mL (doses of 50 to 125 mg/kg/day, normalized to 25 mg/kg per dose for comparison). In three infants receiving Ancotyl 25 mg/kg/day (four divided doses), a median Ancotyl half-life of 7.4 hours was observed, approximately double that seen in adult patients. The concentration of Ancotyl in the cerebrospinal fluid of one infant was 43 mcg/mL 3 hours after a 25 mg oral dose, and ranged from 20 to 67 mg/L in another neonate receiving oral doses of 120 to 150 mg/kg/day.
MICROBIOLOGY
Mechanism of Action
Ancotyl is taken up by fungal organisms via the enzyme cytosine permease. Inside the fungal cell, Ancotyl is rapidly converted to fluorouracil by the enzyme cytosine deaminase. Fluorouracil exerts its antifungal activity through the subsequent conversion into several active metabolites, which inhibit protein synthesis by being falsely incorporated into fungal RNA or interfere with the biosynthesis of fungal DNA through the inhibition of the enzyme thymidylate synthetase.
Activity In Vitro
Ancotyl has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections.
Candida albicans
Cryptococcus neoformans
The following in vitro data are available, but their clinical significance is unknown.
Ancotyl exhibits in vitro minimum inhibitory concentrations of 4 mcg/mL, or less against most (≥90%) strains of the following microorganisms, however, the safety and effectiveness of Ancotyl in treating clinical infections due to these microorganisms have not been established in adequate and well control trials.
Candida dubliniensis
Candida glabrata
Candida guilliermondii
Candida lusitaniae
Candida parapsilosis
Candida tropicalis
Candida krusei should be considered to be resistant to Ancotyl.
In vitro activity of Ancotyl is affected by the test conditions. It is essential to follow the approved standard method guidelines.1
Susceptibility Testing Methods
Cryptococcus neoformans:
No interpretive criteria have been established for Cryptococcus neoformans.
Candida species:
Broth Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida spp. to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth)1 with standardized inoculum concentrations and standardized concentrations of Ancotyl powder. The MIC values should be interpreted according to the criteria in Table 1.
| Broth Dilution at 48 hours (MIC in mcg/mL) | |||
| Antifungal Agent | Susceptible (S) | Intermediate (I) | Resistant (R) |
| Ancotyl | ≤4.0 | 8.0-16 | >32 |
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable; other therapy should be selected. Because of other significant host factors, in vitro susceptibility may not correlate with clinical outcomes.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard Ancotyl powder should provide the range of MIC values noted in Table 2. NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant.
| QC Strain | Macrodilution (MIC in mcg/mL) at 48 hours | Microdilution (MIC in mcg/mL) at 48 hours |
|---|---|---|
| Candida parapsilosis ATCC 22019 | 0.12-0.5 | 0.12-0.5 |
| Candida krusei ATCC 6258 | 4.0-16 | 8.0-32 |
Drug Resistance
Ancotyl resistance may arise from a mutation of an enzyme necessary for the cellular uptake or metabolism of Ancotyl or from an increased synthesis of pyrimidines, which compete with the active metabolites of Ancotyl (fluorinated antimetabolites). Resistance to Ancotyl has been shown to develop during monotherapy after prolonged exposure to the drug.
Candida krusei should be considered to be resistant to Ancotyl.
Drug Combination
Antifungal synergism between Ancotyl and polyene antibiotics, particularly amphotericin B has been reported in vitro. Ancotyl is usually administered in combination with amphotericin B due to lack of cross-resistance and reported synergistic activity of both drugs.
INDICATIONS AND USAGE
Ancotyl is indicated only in the treatment of serious infections caused by susceptible strains of Candida and/or Cryptococcus.
Candida: Septicemia, endocarditis and urinary system infections have been effectively treated with Ancotyl. Limited trials in pulmonary infections justify the use of Ancotyl
Cryptococcus: Meningitis and pulmonary infections have been treated effectively. Studies in septicemias and urinary tract infections are limited, but good responses have been reported.
Ancotyl should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis because of the emergence of resistance to Ancotyl (see MICROBIOLOGY ).
CONTRAINDICATIONS
Ancotyl should not be used in patients with a known hypersensitivity to the drug.
WARNINGS
Ancotyl must be given with extreme caution to patients with impaired renal function. Since Ancotyl is excreted primarily by the kidneys, renal impairment may lead to accumulation of the drug. Ancotyl serum concentrations should be monitored to determine the adequacy of renal excretion in such patients. Dosage adjustments should be made in patients with renal insufficiency to prevent progressive accumulation of active drug.
Ancotyl 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 Ancotyl is instituted, electrolytes 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 Ancotyl by competitive inhibition. Drugs which impair glomerular filtration may prolong the biological half-life of Ancotyl.
Drug/Laboratory Test Interactions
Measurement of serum creatinine levels should be determined by the Jaffé reaction, since Ancotyl 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
Ancotyl has not undergone adequate animal testing to evaluate carcinogenic potential. The mutagenic potential of Ancotyl 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. Ancotyl was nonmutagenic in three different repair assay systems.
There have been no adequate trials in animals on the effects of Ancotyl 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 Ancotyl 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
Ancotyl 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. Ancotyl 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 Ancotyl (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 Ancotyl injected intraperitoneally crosses the placental barrier. There are no adequate and well-controlled studies in pregnant women. Ancotyl 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 Ancotyl, 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 Ancotyl have not been systematically studied in pediatric patients. A small number of neonates have been treated with 25 to 200 mg/kg/day of Ancotyl, 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 Ancotyl in combination with amphotericin B, and anemia was observed in a second patient who received Ancotyl alone. Transient thrombocytopenia was noted in two additional patients, one of whom also received amphotericin B.
ADVERSE REACTIONS
The adverse reactions which have occurred during treatment with Ancotyl 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.
To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda,.gov/medwatch.
OVERDOSAGE
There is no experience with intentional overdosage. It is reasonable to expect that overdosage may produce pronounced manifestations of the known clinical adverse reactions. Prolonged serum concentrations in excess of 100 mcg/mL may be associated with an increased incidence of toxicity, especially gastrointestinal (diarrhea, nausea, vomiting), hematologic (leukopenia, thrombocytopenia) and hepatic (hepatitis).
In the management of overdosage, prompt gastric lavage or the use of an emetic is recommended. Adequate fluid intake should be maintained, by the intravenous route if necessary, since Ancotyl is excreted unchanged via the renal tract. The hematologic parameters should be monitored frequently; liver and kidney function should be carefully monitored. Should any abnormalities appear in any of these parameters, appropriate therapeutic measures should be instituted.
Since hemodialysis has been shown to rapidly reduce serum concentrations in anuric patients, this method may be considered in the management of overdosage.
DOSAGE AND ADMINISTRATION
The usual dosage of Ancotyl 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 ).
Ancotyl should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis because of the emergence of resistance to Ancotyl (see MICROBIOLOGY ).
HOW SUPPLIED
ANCOBON® Capsules are supplied as capsules containing 250 mg and 500 mg Ancotyl.
- 250 mg Capsules (gray and green), imprinted Ancotyl® 250 ICN, available in bottles of 100 (NDC 0187-3554-10).
- 500 mg Capsules (gray and white), imprinted Ancotyl® 500 ICN, available in bottles of 100 (NDC 0187-3555-10).
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F).
KEEP OUT OF REACH OF CHILDREN
REFERENCES
- Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard-Third Edition. NCCLS Document M27-A3, 2008 Volume 28, No. 15, NCLLS, Wayne, PA, April 2008.
Manufactured for:
Valeant Pharmaceuticals North America LLC
Bridgewater, NJ 08807 USA
Manufactured by:
Valeant Pharmaceuticals International, Inc.
Steinbach, MB R5G 1Z7, Canada
Ancotyl is a trademark of Valeant Pharmaceuticals International, Inc. or its affiliates.
©Valeant Pharmaceuticals North America LLC
- 9578600 20001815
Rev. 04/2017
LB0096-00
Rev. 02/13
NDC 0187-3554-10
Rx only
Ancotyl ®
(flucytosine)
250 mg
Each capsule
contains 250
mg Ancotyl
100 Capsules
VALEANT
NDC 0187-3555-10
Rx only
Ancotyl ®
(flucytosine)
500 mg
Each capsule
contains 500
mg Ancotyl
100 Capsules
VALEANT
Ancotyl pharmaceutical active ingredients containing related brand and generic drugs:
Ancotyl available forms, composition, doses:
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.