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Drug overview for ANCOBON (flucytosine):
Generic name: flucytosine (flew-SYE-toe-seen)
Drug class: Antifungals-Systemic
Therapeutic class: Anti-Infective Agents
Flucytosine, a fluorinated pyrimidine analog, is a synthetic antifungal agent.
Flucytosine is used for the treatment of serious infections caused by susceptible Candida or Cryptococcus neoformans. Flucytosine usually is used as an adjunct to IV amphotericin B, and should not be used alone in the treatment of systemic candidiasis and cryptococcosis. Use of flucytosine alone may be ineffective and may result in emergence of flucytosine resistance.
Although concomitant use of flucytosine and amphotericin B is based on reported in vitro and in vivo synergistic effects, there is some evidence that combined use of the drugs may be associated with an increased risk of serious adverse effects, especially in immunocompromised patients such as those with human immunodeficiency virus (HIV) infection. To optimize efficacy and reduce the risk of toxicity when flucytosine is used concomitantly with another antifungal, flucytosine dosage should be carefully adjusted based on serum concentrations of the drug and patients receiving such therapy should be monitored closely for adverse effects. (See Dosage and Administration: Dosage.) In addition, because of concerns related to intrinsic resistance or emergence of resistance to flucytosine, it has been recommended that in vitro susceptibility tests be performed prior to and during flucytosine therapy, whenever available.
Generic name: flucytosine (flew-SYE-toe-seen)
Drug class: Antifungals-Systemic
Therapeutic class: Anti-Infective Agents
Flucytosine, a fluorinated pyrimidine analog, is a synthetic antifungal agent.
Flucytosine is used for the treatment of serious infections caused by susceptible Candida or Cryptococcus neoformans. Flucytosine usually is used as an adjunct to IV amphotericin B, and should not be used alone in the treatment of systemic candidiasis and cryptococcosis. Use of flucytosine alone may be ineffective and may result in emergence of flucytosine resistance.
Although concomitant use of flucytosine and amphotericin B is based on reported in vitro and in vivo synergistic effects, there is some evidence that combined use of the drugs may be associated with an increased risk of serious adverse effects, especially in immunocompromised patients such as those with human immunodeficiency virus (HIV) infection. To optimize efficacy and reduce the risk of toxicity when flucytosine is used concomitantly with another antifungal, flucytosine dosage should be carefully adjusted based on serum concentrations of the drug and patients receiving such therapy should be monitored closely for adverse effects. (See Dosage and Administration: Dosage.) In addition, because of concerns related to intrinsic resistance or emergence of resistance to flucytosine, it has been recommended that in vitro susceptibility tests be performed prior to and during flucytosine therapy, whenever available.
DRUG IMAGES
FLUCYTOSINE 500 MG CAPSULE
FLUCYTOSINE 250 MG CAPSULE
The following indications for ANCOBON (flucytosine) have been approved by the FDA:
Indications:
Candidal urinary tract infection
Systemic candidiasis treatment adjunct
Systemic cryptococcosis treatment adjunct
Professional Synonyms:
Disseminated candidiasis treatment adjunct
Urinary candidiasis
Urinary candidosis
Urinary moniliasis
UTI due to Candida albicans
Indications:
Candidal urinary tract infection
Systemic candidiasis treatment adjunct
Systemic cryptococcosis treatment adjunct
Professional Synonyms:
Disseminated candidiasis treatment adjunct
Urinary candidiasis
Urinary candidosis
Urinary moniliasis
UTI due to Candida albicans
The following dosing information is available for ANCOBON (flucytosine):
Because prolonged serum flucytosine concentrations exceeding 100 mcg/mL may be associated with an increased risk of toxicity (e.g., adverse hematologic, GI, and hepatic effects), flucytosine dosage usually should be adjusted to ensure that peak serum concentrations of the drug remain below 100 mcg/mL. However, optimal target serum concentrations have not been identified, and a variety of target ranges have been recommended. The American Academy of Pediatrics (AAP), US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), Infectious Diseases Society of America (IDSA), and others generally recommend target serum flucytosine concentrations of 30-80 mcg/mL.
Some clinicians suggest that serum flucytosine concentrations should be measured beginning 3-5 days after initiation of the drug (or beginning after 3-5 doses) and then once or twice weekly during treatment and whenever there is evidence of toxicity or a change in renal function. Peak serum concentrations usually are measured using blood samples taken 2 hours after an oral dose.
The usual adult dosage of oral flucytosine recommended by the manufacturer is 50-150 mg/kg daily given in divided doses at 6-hour intervals. The manufacturer recommends that the lower dosage be used initially in patients with elevated BUN or serum creatinine concentrations.
To reduce the risk of toxicity in patients receiving flucytosine concomitantly with IV amphotericin B, some clinicians suggest that flucytosine therapy be initiated using a low dosage (i.e., 75 mg/kg daily given in 4 divided doses). Dosage can then be adjusted based on serum concentrations of flucytosine and the presence or absence of amphotericin B-associated renal toxicity.
If flucytosine is used in pediatric patients+, AAP recommends a dosage of 100 mg/kg daily given in divided doses every 6 hours.
In patients with impaired renal function, doses and/or frequency of administration of flucytosine must be modified in response to the degree of impairment and serum concentrations of the drug. Several methods of calculating flucytosine dosage for patients with impaired renal function have been proposed; however, for greater accuracy, dosage in these patients should be based on actual serum concentrations of the drug. Precise dosing is limited, since flucytosine is commercially available only as 250- and 500-mg capsules.
Some clinicians recommend that adults with creatinine clearances of 20-40 mL/minute receive 25 mg/kg of flucytosine every 12 hours and that those with creatinine clearances of 10-20 mL/minute receive 25 mg/kg once daily. In those with creatinine clearances less than 10 mL/minute, these clinicians recommend a flucytosine dosage of 25 mg/kg once every 48 hours.
Other clinicians recommend that the usual individual dose of flucytosine (12.5-37.5 mg/kg) be administered every 12 hours in patients with creatinine clearances of 20-40 mL/minute, every 24 hours in those with creatinine clearances of 10-20 mL/minute, and every 24-48 hours or longer (as determined by serum drug concentrations) in those with creatinine clearances less than 10 mL/minute. Alternatively, other clinicians have recommended that flucytosine doses of 12-35 mg/kg be administered at intervals equal to twice the half-life of the drug.
In patients undergoing hemodialysis, some clinicians recommend that flucytosine doses of 20-50 mg/kg be given once every 48-72 hours and that the doses be administered after dialysis.
Some clinicians suggest that serum flucytosine concentrations should be measured beginning 3-5 days after initiation of the drug (or beginning after 3-5 doses) and then once or twice weekly during treatment and whenever there is evidence of toxicity or a change in renal function. Peak serum concentrations usually are measured using blood samples taken 2 hours after an oral dose.
The usual adult dosage of oral flucytosine recommended by the manufacturer is 50-150 mg/kg daily given in divided doses at 6-hour intervals. The manufacturer recommends that the lower dosage be used initially in patients with elevated BUN or serum creatinine concentrations.
To reduce the risk of toxicity in patients receiving flucytosine concomitantly with IV amphotericin B, some clinicians suggest that flucytosine therapy be initiated using a low dosage (i.e., 75 mg/kg daily given in 4 divided doses). Dosage can then be adjusted based on serum concentrations of flucytosine and the presence or absence of amphotericin B-associated renal toxicity.
If flucytosine is used in pediatric patients+, AAP recommends a dosage of 100 mg/kg daily given in divided doses every 6 hours.
In patients with impaired renal function, doses and/or frequency of administration of flucytosine must be modified in response to the degree of impairment and serum concentrations of the drug. Several methods of calculating flucytosine dosage for patients with impaired renal function have been proposed; however, for greater accuracy, dosage in these patients should be based on actual serum concentrations of the drug. Precise dosing is limited, since flucytosine is commercially available only as 250- and 500-mg capsules.
Some clinicians recommend that adults with creatinine clearances of 20-40 mL/minute receive 25 mg/kg of flucytosine every 12 hours and that those with creatinine clearances of 10-20 mL/minute receive 25 mg/kg once daily. In those with creatinine clearances less than 10 mL/minute, these clinicians recommend a flucytosine dosage of 25 mg/kg once every 48 hours.
Other clinicians recommend that the usual individual dose of flucytosine (12.5-37.5 mg/kg) be administered every 12 hours in patients with creatinine clearances of 20-40 mL/minute, every 24 hours in those with creatinine clearances of 10-20 mL/minute, and every 24-48 hours or longer (as determined by serum drug concentrations) in those with creatinine clearances less than 10 mL/minute. Alternatively, other clinicians have recommended that flucytosine doses of 12-35 mg/kg be administered at intervals equal to twice the half-life of the drug.
In patients undergoing hemodialysis, some clinicians recommend that flucytosine doses of 20-50 mg/kg be given once every 48-72 hours and that the doses be administered after dialysis.
Flucytosine is administered orally. The manufacturer suggests that nausea and 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. Flucytosine has been administered IV; however, a parenteral dosage form of the drug is not commercially available in the US. Flucytosine also has been administered topically as a cream, but topical preparations of the drug are not commercially available in the US.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| ANCOBON 250 MG CAPSULE | Maintenance | Adults take 25 mg/kg by oral route every 6 hours |
| ANCOBON 500 MG CAPSULE | Maintenance | Adults take 25 mg/kg by oral route every 6 hours |
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| FLUCYTOSINE 250 MG CAPSULE | Maintenance | Adults take 25 mg/kg by oral route every 6 hours |
| FLUCYTOSINE 500 MG CAPSULE | Maintenance | Adults take 25 mg/kg by oral route every 6 hours |
The following drug interaction information is available for ANCOBON (flucytosine):
There are 0 contraindications.
There are 3 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Deferiprone/Selected Myelosuppressive Agents SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1) CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal. PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2) PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1) DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3) |
DEFERIPRONE, DEFERIPRONE (3 TIMES A DAY), FERRIPROX, FERRIPROX (2 TIMES A DAY), FERRIPROX (3 TIMES A DAY) |
| Clozapine/Selected Myelosuppressive Agents SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Clozapine and other myelosuppressive agents may be associated with neutropenia or agranulocytosis.(2) CLINICAL EFFECTS: Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal. PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia. PATIENT MANAGEMENT: If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent ANC monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. Clozapine is only available through a restricted distribution system which requires documentation of the absolute neutrophil count (ANC) prior to dispensing.(1-2) For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2) DISCUSSION: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing.(1) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26) |
CLOZAPINE, CLOZAPINE ODT, CLOZARIL, VERSACLOZ |
| Sodium Iodide I 131/Myelosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1) DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1) |
HICON, SODIUM IODIDE I-131 |
There are 0 moderate interactions.
The following contraindication information is available for ANCOBON (flucytosine):
Drug contraindication overview.
No enhanced Contraindications information available for this drug.
No enhanced Contraindications information available for this drug.
There are 1 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Lactation |
There are 7 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Aplastic anemia secondary to drugs |
| Bone marrow depression |
| Granulocytopenic disorder |
| Kidney disease with likely reduction in glomerular filtration rate (GFr) |
| Kidney disease with reduction in glomerular filtration rate (GFr) |
| Leukopenia |
| Thrombocytopenic disorder |
There are 2 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Disease of liver |
| Hypokalemia |
The following adverse reaction information is available for ANCOBON (flucytosine):
Adverse reaction overview.
No enhanced Common Adverse Effects information available for this drug.
No enhanced Common Adverse Effects information available for this drug.
There are 34 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Allergic dermatitis Anemia Hepatitis Jaundice Leukopenia Pruritus of skin Skin rash Thrombocytopenic disorder |
Acute cognitive impairment Hallucinations |
| Rare/Very Rare |
|---|
|
Abnormal hepatic function tests Acute myocardial infarction Acute respiratory distress syndrome Agranulocytosis Chest pain Duodenal ulcer Dyspnea Enterocolitis Eosinophilia Gastrointestinal hemorrhage Hepatic necrosis Hyperbilirubinemia Hypokalemia Hypoplastic anemia Neutropenic disorder Pancytopenia Parkinsonism Pure red cell aplasia Renal failure Seizure disorder Toxic epidermal necrolysis Ulcerative colitis Urticaria Ventricular arrhythmias |
There are 20 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Acute abdominal pain Anorexia Diarrhea Headache disorder Nausea Vomiting |
Fatigue Fever Sedation Skin photosensitivity |
| Rare/Very Rare |
|---|
|
Ataxia Crystalluria Drug-induced psychosis Hearing loss Hypoglycemic disorder Paresthesia Peripheral neuropathy Stomatitis Vertigo Xerostomia |
The following precautions are available for ANCOBON (flucytosine):
No enhanced Pediatric Use information available for this drug.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
Flucytosine was shown to be teratogenic in rats. When flucytosine was given to rats in a dosage of 40 mg/kg daily (0.051 times the human dosage) on days 7-13 of gestation, vertebral fusions occurred; at a dosage of 700 mg/kg daily (0.89 times the human dosage) on days 9-12 of gestation, cleft lip and palate and micrognathia were reported. In mice, flucytosine dosage of 400 mg/kg daily (0.236 times the human dosage) on days 7-13 of gestation was associated with a low incidence of cleft palate that was not statistically significant.
Flucytosine was not teratogenic in rabbits when given in dosages up to 100 mg/kg daily (0.243 times the human dosage) on days 6-18 of gestation. There are no adequate or controlled studies to date using flucytosine in pregnant women, and the drug should be used during pregnancy only when potential benefits justify possible risks to the fetus.
Flucytosine was not teratogenic in rabbits when given in dosages up to 100 mg/kg daily (0.243 times the human dosage) on days 6-18 of gestation. There are no adequate or controlled studies to date using flucytosine in pregnant women, and the drug should be used during pregnancy only when potential benefits justify possible risks to the fetus.
It is not known whether flucytosine is distributed into human milk. Because many drugs are distributed into human milk and because of the potential for serious adverse effects in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother.
No enhanced Geriatric Use information available for this drug.
The following prioritized warning is available for ANCOBON (flucytosine):
WARNING: This medication should be used with increased caution if you have kidney problems. Flucytosine may cause decreased kidney function and liver problems. In addition, this medication may decrease bone marrow function.
This serious, possibly life-threatening side effect may lead to a low number of blood cells such as red cells, white cells, and platelets. This effect can cause anemia, decrease your body's ability to fight an infection, and cause bleeding problems. Your doctor will check the results of your kidney, liver, and blood tests and adjust your treatment to reduce your risk for these side effects. See also Side Effects section.
WARNING: This medication should be used with increased caution if you have kidney problems. Flucytosine may cause decreased kidney function and liver problems. In addition, this medication may decrease bone marrow function.
This serious, possibly life-threatening side effect may lead to a low number of blood cells such as red cells, white cells, and platelets. This effect can cause anemia, decrease your body's ability to fight an infection, and cause bleeding problems. Your doctor will check the results of your kidney, liver, and blood tests and adjust your treatment to reduce your risk for these side effects. See also Side Effects section.
The following icd codes are available for ANCOBON (flucytosine)'s list of indications:
| Candidal urinary tract infection | |
| B37.41 | Candidal cystitis and urethritis |
| B37.49 | Other urogenital candidiasis |
| Systemic candidiasis treatment adjunct | |
| B37.7 | Candidal sepsis |
| Systemic cryptococcosis treatment adjunct | |
| B45.7 | Disseminated cryptococcosis |
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