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FLUCYTOSINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Flucytosine is a fluorinated pyrimidine used as a systemic antimycotic agent.
    B) Chemically, flucytosine is 5-fluorocytosine and is related to fluorouracil and floxuridine.
    C) It is chemically active against the following species: Candida, Cryptococcus neoformans, Cladosporium, Fonsecaea and some forms of Aspergillus. Flucytosine acts synergistically with amphotericin to treat Candida and Cryptococcus neoformans infections.

Specific Substances

    1) 5-FC
    2) Cytosine, 5-fluoro-
    3) Flucytosinum
    4) Ro-2-9915
    5) 5-Fluorocystosine
    6) 5-Fluorocytosine
    7) 4-Amino-5-fluoro-2(1H)-pyrimidinone
    8) Molecular Formula: C4-H4-F-N3-O
    9) CAS 2022-85-7

Available Forms Sources

    A) SOURCES
    1) Flucytosine is available as 250 mg and 500 mg oral capsules (Prod Info ANCOBON(R) oral capsules, 2013).
    B) USES
    1) Flucytosine is used to treat serious systemic fungal infections, caused by susceptible strains of candida and cryptococcus (Prod Info ANCOBON(R) oral capsules, 2013).
    a) Septicemia, endocarditis and urinary tract infections due to Candida have been effectively treated with flucytosine. Cryptococcal meningitis and pulmonary infections have also been successfully treated (Prod Info ANCOBON(R) oral capsules, 2013).
    2) Flucytosine has also been used in combination with amphotericin B in the treatment of systemic candidiasis and cryptococcosis because of emergence of resistance with flucytosine (Prod Info ANCOBON(R) oral capsules, 2013).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Flucytosine is used to treat serious systemic fungal infections, caused by susceptible strains of candida and cryptococcus. Flucytosine has been used in combination with amphotericin B in the treatment of systemic candidiasis and cryptococcosis because of emergence of resistance with flucytosine.
    B) PHARMACOLOGY: Flucytosine's antifungal activity is a result of interference with fungal DNA synthesis. Flucytosine is deaminated, in vivo, to 5-fluorouracil (5-FU) and then converted to 5-fluorodeoxyuridylic acid monophosphate, a noncompetitive inhibitor of thymidylate synthetase which interferes with DNA synthesis.
    C) TOXICOLOGY: The mechanism for toxicity is not fully understood; however, it has been hypothesized that the conversion of flucytosine to a specific metabolite like fluorouracil could account for the toxicity observed (ie, bone-marrow depression and hepatotoxicity).
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) DOSE-LIMITING TOXICITIES: Bone marrow depression and hepatotoxicity. COMMON: Nausea, vomiting, diarrhea, and skin rashes. INFREQUENT: Seizures, headache, sedation, vertigo, confusion, hallucinations, cardiac arrest, myocardial toxicity, ventricular dysfunction, allergic reactions, toxic epidermal necrolysis, ulcerative colitis, and bowel perforation.
    F) WITH POISONING/EXPOSURE
    1) Clinical events are anticipated to be similar to adverse events reported with flucytosine therapy. Gastrointestinal (eg, nausea, vomiting, diarrhea), hematologic (eg, leukopenia, thrombocytopenia), or hepatic toxicity (eg, hepatitis) may occur with serum concentrations exceeding 100 mcg/mL.
    0.2.20) REPRODUCTIVE
    A) In rats, flucytosine was found to be teratogenic.
    0.2.21) CARCINOGENICITY
    A) The carcinogenic potential of flucytosine has yet to be determined.

Laboratory Monitoring

    A) Monitor vital signs and mental status following significant overdose.
    B) Obtain an ECG, and institute continuous cardiac monitoring.
    C) Monitor CBC with differential, renal function, and liver enzymes in symptomatic patients.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Myelosuppression has been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg, filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with significant CNS depression, persistent seizures, or severe allergic reactions.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Hemodialysis has been effectively used in anuric patients to reduce serum flucytosine concentrations.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected overdose, the treating physician should be cognizant of the possibility of multi-drug involvement.
    I) PHARMACOKINETICS
    1) Tmax: Within 2 hours following a 2 g oral dose. Bioavailability: 78% to 89% following oral administration. Protein binding: Approximately 3% to 4%. Vd: Flucytosine is widely distributed into body tissues and fluids, including the CSF. The volume of distribution approaches that of total body water. Excretion: Greater than 90% of a dose is excreted unchanged by glomerular filtration. Elimination half-life: 2.4 to 4.8 hours for patients with normal renal function; an average of 85 hours (range from 29.9 to 250 hours) has been reported in the presence of renal insufficiency.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression or hepatotoxicity.

Range Of Toxicity

    A) TOXICITY: Gastrointestinal (eg, nausea, vomiting, diarrhea), hematologic (eg, leukopenia, thrombocytopenia), or hepatic toxicity (eg, hepatitis) may occur with serum concentrations exceeding 100 mcg/mL.
    B) THERAPEUTIC DOSE: ADULT: 50 to 150 mg/kg/day administered in divided doses at 6-hour intervals. PEDIATRIC: The safety and effectiveness of flucytosine in children has not been determined.

Clinical Effects

Summary Of Exposure

    A) USES: Flucytosine is used to treat serious systemic fungal infections, caused by susceptible strains of candida and cryptococcus. Flucytosine has been used in combination with amphotericin B in the treatment of systemic candidiasis and cryptococcosis because of emergence of resistance with flucytosine.
    B) PHARMACOLOGY: Flucytosine's antifungal activity is a result of interference with fungal DNA synthesis. Flucytosine is deaminated, in vivo, to 5-fluorouracil (5-FU) and then converted to 5-fluorodeoxyuridylic acid monophosphate, a noncompetitive inhibitor of thymidylate synthetase which interferes with DNA synthesis.
    C) TOXICOLOGY: The mechanism for toxicity is not fully understood; however, it has been hypothesized that the conversion of flucytosine to a specific metabolite like fluorouracil could account for the toxicity observed (ie, bone-marrow depression and hepatotoxicity).
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) DOSE-LIMITING TOXICITIES: Bone marrow depression and hepatotoxicity. COMMON: Nausea, vomiting, diarrhea, and skin rashes. INFREQUENT: Seizures, headache, sedation, vertigo, confusion, hallucinations, cardiac arrest, myocardial toxicity, ventricular dysfunction, allergic reactions, toxic epidermal necrolysis, ulcerative colitis, and bowel perforation.
    F) WITH POISONING/EXPOSURE
    1) Clinical events are anticipated to be similar to adverse events reported with flucytosine therapy. Gastrointestinal (eg, nausea, vomiting, diarrhea), hematologic (eg, leukopenia, thrombocytopenia), or hepatic toxicity (eg, hepatitis) may occur with serum concentrations exceeding 100 mcg/mL.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIAC ARREST
    1) WITH THERAPEUTIC USE
    a) Cardiac arrest, myocardial toxicity, and ventricular dysfunction have been reported infrequently following use (Prod Info ANCOBON(R) oral capsules, 2013a; JEF Reynolds , 2000).
    B) HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 34-year-old woman with no history of cardiac disease developed chest pain following flucytosine for genital candidiasis (500 mg orally 12 times/day for 2 days (total dose 12,000 mg)). ST elevations were noted on ECG and treated with diltiazem and molsidomine. Angiography showed normal coronary arteries. One month later, flucytosine was repeated (new onset of infection) with severe chest pain reported after the standard two days of treatment. An echocardiography indicated severe hypokinesia and a left ventricular ejection fraction of less than 15%. Cardiac index declined to 1.8 L/min/m(2) despite positive inotropic agents (dopamine, dobutamine, epinephrine). The patient required intra-aortic balloon pump counterpulsation. Cardiac function improved following the addition of milrinone and veno-venous hemodiafiltration. The patient had a complete recovery with no permanent sequelae reported two years after the initial exposure (Isetta et al, 2000).
    C) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) Chest pain has been reported with flucytosine use (Prod Info ANCOBON(R) oral capsules, 2013a).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY ARREST
    1) WITH THERAPEUTIC USE
    a) Respiratory arrest and dyspnea have been reported during therapeutic use (Prod Info ANCOBON(R) oral capsules, 2013a).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Ataxia, hearing loss, headache, paresthesia, parkinsonism, peripheral neuropathy, vertigo, sedation, fatigue, confusion, and seizures have been reported during therapeutic use (Prod Info ANCOBON(R) oral capsules, 2013a).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal effects are the most commonly reported adverse events reported with flucytosine use (Vermes et al, 2000; Vermes et al, 2000a). Symptoms usually include nausea and diarrhea, but can also include vomiting and diffuse abdominal pain (Francis & Walsh, 1992; Vermes et al, 2000; Vermes et al, 2000a; JEF Reynolds , 2000). Duodenal ulcer formation and gastrointestinal bleeding have also been reported (Prod Info ANCOBON(R) oral capsules, 2013a).
    b) INCIDENCE: Approximately 6% of patients experience gastrointestinal symptoms after receiving flucytosine (Vermes et al, 2000; Vermes et al, 2000a). Prolonged serum concentrations in excess of 100 micrograms/mL are more likely to produce symptoms (Prod Info ANCOBON(R) oral capsules, 2013a).
    c) Rare cases of ulcerative colitis and bowel perforation have occurred (Vermes et al, 2000; Vermes et al, 2000a).
    2) WITH POISONING/EXPOSURE
    a) Gastrointestinal (eg, nausea, vomiting, diarrhea), hematologic (eg, leukopenia, thrombocytopenia), or hepatic toxicity (eg, hepatitis) may occur with serum concentrations exceeding 100 mcg/mL (Prod Info ANCOBON(R) oral capsules, 2013a).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH THERAPEUTIC USE
    a) Hepatotoxicity has been reported during therapeutic use of flucytosine. Concentrations below 100 mcg/mL are less likely to produce toxicity. Laboratory values usually reverse with drug cessation (Prod Info ANCOBON(R) oral capsules, 2013a; Vermes et al, 2000; Vermes et al, 2000a).
    b) INCIDENCE: Most studies report hepatotoxicity rates between 0% to 25% during drug therapy. However, on study reported hepatotoxicity rates in up to 41% of patients (Vermes et al, 2000; Vermes et al, 2000a).
    c) CASE REPORT: Hepatic injury, which included elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase and total bilirubin, was reported in one patient (1 of 17) following therapeutic use of flucytosine. The patient had a history of hepatic dysfunction prior to the start of combination therapy with flucytosine and amphotericin B. Flucytosine was withheld for 4 days and therapy was then resumed (liver enzymes remained elevated). All liver function values returned to normal after combination therapy was completed (Francis & Walsh, 1992).
    2) WITH POISONING/EXPOSURE
    a) Gastrointestinal (eg, nausea, vomiting, diarrhea), hematologic (eg, leukopenia, thrombocytopenia), or hepatic toxicity (eg, hepatitis) may occur with serum concentrations exceeding 100 mcg/mL (Prod Info ANCOBON(R) oral capsules, 2013a).
    B) HEPATIC NECROSIS
    1) WITH THERAPEUTIC USE
    a) Two cases of severe liver necrosis have been reported (Vermes et al, 2000; Vermes et al, 2000a).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL RENAL FUNCTION
    1) WITH THERAPEUTIC USE
    a) Azotemia, elevated creatinine, crystalluria, and renal failure have been reported during therapeutic use (Prod Info ANCOBON(R) oral capsules, 2013a).
    B) AT RISK - FINDING
    1) WITH POISONING/EXPOSURE
    a) RISK FACTOR: Flucytosine is primarily excreted renally. Patients with a history of renal impairment or renal insufficiency are at greater risk of developing toxicity following overdose (Prod Info ANCOBON(R) oral capsules, 2013a; JEF Reynolds , 2000).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) Anemia, agranulocytosis, aplastic anemia, eosinophilia, leukopenia, pancytopenia, and thrombocytopenia have developed in some patients and resulted in serious or life-threatening illness (Prod Info ANCOBON(R) oral capsules, 2013a; Vermes et al, 2000; Vermes et al, 2000a). Severe toxicity is more likely to occur at serum concentrations above 100 to 125 micrograms/mL. Vermes et al noted that amphotericin B (often given in combination with flucytosine) does not have an apparent role in the development of bone marrow depression (Vermes et al, 2000; Vermes et al, 2000a).
    b) ONSET: During therapeutic use, bone marrow depression was likely to occur within the first 2 to 4 weeks of treatment at a concentration of greater than 100 mcg/mL (Vermes et al, 2000; Vermes et al, 2000a).
    c) INCIDENCE: In a study of 53 ICU patients receiving flucytosine, thrombocytopenia occurred in 32% (n=17) of the patients at a mean of 9.3 days (Vermes et al, 2000). The authors noted that this rate was comparable to other reports in the literature.
    d) RISK FACTORS: Patients with a history of hematological disorders, symptomatic HIV infection, radiation or myelosuppressive therapy are more likely to develop bone-marrow depression following flucytosine treatment (Prod Info ANCOBON(R) oral capsules, 2013a; Vermes et al, 2000; Vermes et al, 2000a).
    2) WITH POISONING/EXPOSURE
    a) Gastrointestinal (eg, nausea, vomiting, diarrhea), hematologic (eg, leukopenia, thrombocytopenia), or hepatic toxicity (eg, hepatitis) may occur with serum concentrations exceeding 100 mcg/mL (Prod Info ANCOBON(R) oral capsules, 2013a).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Rash, pruritus, urticaria and photosensitivity have been reported with flucytosine use (Prod Info ANCOBON(R) oral capsules, 2013a).
    B) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) Toxic epidermal necrolysis has been infrequently reported with therapeutic use (JEF Reynolds , 2000).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Acute allergic reactions have been reported during therapeutic use (Prod Info ANCOBON(R) oral capsules, 2013a).

Reproductive

    3.20.1) SUMMARY
    A) In rats, flucytosine was found to be teratogenic.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) In animal studies, teratogenic effects were reported in rats at doses of 40 mg/kg/day (0.27 times the maximum human dose), while teratogenicity was NOT reported in rabbits (doses up to 100 mg/kg/day (0.68 times the maximum human dose)), or in mice receiving 400 mg/kg/day (Prod Info Ancobon(R), flucytosine capsules, 1999).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    FLUCYTOSINEC
    Reference: Prod Info Ancobon(R), 1999
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is uncertain whether flucytosine is excreted in human milk (Prod Info Ancobon(R), flucytosine capsules, 1999).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) The carcinogenic potential of flucytosine has yet to be determined.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, studies to determine the carcinogenic potential of flucytosine have not been conducted (Prod Info Ancobon(R), flucytosine capsules, 1999).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status following significant overdose.
    B) Obtain an ECG, and institute continuous cardiac monitoring.
    C) Monitor CBC with differential, renal function, and liver enzymes in symptomatic patients.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) Summers et al (1997) examined several laboratory methods and found that the following could adequately measure serum or plasma flucytosine: bioassay, gas-liquid chromatography (GLC), high-performance liquid chromatography (HPLC) and fluorometry techniques. Based on the authors review, no method was found to be superior to another; methods used should be based on the availability or resources present at the time of testing (Summers et al, 1997).
    2) Francis & Walsh (1992) described the use of a modified creatinine iminohydrolase assay to evaluate drug levels and assess toxicity in patients receiving combination therapy with flucytosine and amphotericin B (Francis & Walsh, 1992).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Monitor vital signs and mental status following significant overdose.
    B) Obtain an ECG, and institute continuous cardiac monitoring.
    C) Monitor CBC with differential, renal function, and liver enzymes in symptomatic patients.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Myelosuppression has been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg, filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status following significant overdose.
    2) Obtain an ECG, and institute continuous cardiac monitoring.
    3) Monitor CBC with differential, renal function, and liver enzymes in symptomatic patients.
    4) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) MYELOSUPPRESSION
    1) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    2) Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or hemorrhage.
    D) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    E) HYPERSENSITIVITY REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Flucytosine is minimally protein bond (4% or less) and the volume of distribution is similar to total body water (Francis & Walsh, 1992). Hemodialysis has been effectively used in anuric patients to reduce serum flucytosine concentrations (Prod Info Ancobon(R), flucytosine capsules, 1999). Theoretically, its use may be an effective therapy in patients following a significant overdose.

Range Of Toxicity

Summary

    A) TOXICITY: Gastrointestinal (eg, nausea, vomiting, diarrhea), hematologic (eg, leukopenia, thrombocytopenia), or hepatic toxicity (eg, hepatitis) may occur with serum concentrations exceeding 100 mcg/mL.
    B) THERAPEUTIC DOSE: ADULT: 50 to 150 mg/kg/day administered in divided doses at 6-hour intervals. PEDIATRIC: The safety and effectiveness of flucytosine in children has not been determined.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended dose is 50 to 150 mg/kg/day administered in divided doses at 6 hour intervals (Prod Info ANCOBON(R) oral capsules, 2013).
    7.2.2) PEDIATRIC
    A) GENERAL
    1) The safety and effectiveness of flucytosine in children has not been determined (Prod Info ANCOBON(R) oral capsules, 2013).

Maximum Tolerated Exposure

    A) Gastrointestinal (eg, nausea, vomiting, diarrhea), hematologic (eg, leukopenia, thrombocytopenia), or hepatic toxicity (eg, hepatitis) may occur with serum concentrations exceeding 100 mcg/mL (Prod Info ANCOBON(R) oral capsules, 2013a).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 1190 mg/kg ((RTECS, 2000))
    B) LD50- (ORAL)MOUSE:
    1) >15 g/kg ((RTECS, 2000))
    C) LD50- (SUBCUTANEOUS)MOUSE:
    1) 1 g/kg ((RTECS, 2000))
    D) LD50- (INTRAPERITONEAL)RAT:
    1) 3811 mg/kg ((RTECS, 2000))
    E) LD50- (ORAL)RAT:
    1) >15 g/kg ((RTECS, 2000))
    F) LD50- (SUBCUTANEOUS)RAT:
    1) 3336 mg/kg ((RTECS, 2000))

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Flucytosine is a fluorinated pyrimidine antifungal which is related to fluorouracil and floxuridine (Prod Info ANCOBON(R) oral capsules, 2013a). It has in vitro and in vivo activity against Candida and Cryptococcus. Flucytosine's antifungal activity is a result of interference with fungal DNA synthesis. Flucytosine is deaminated, in vivo, to 5-fluorouracil (5-FU) and then converted to 5-fluorodeoxyuridylic acid monophosphate, a noncompetitive inhibitor of thymidylate synthetase which interferes with DNA synthesis (Diasio et al, 1978a).

Toxicologic Mechanism

    A) The mechanism for toxicity is not fully understood; however, it has been hypothesized that the conversion of flucytosine to a specific metabolite like fluorouracil could account for the toxicity observed (i.e., bone-marrow depression and hepatotoxicity) (Vermes et al, 2000a).
    B) Based on its minimal binding to serum proteins (less than 4%) and low molecular weight (MW 129.1), flucytosine would be expected to have excellent penetration into body tissues (JEF Reynolds , 2000; Vermes et al, 2000).

Physicochemical

Physical Characteristics

    A) It is a white to off-white crystalline powder that may or may not have a slight odor (JEF Reynolds , 2000).

Molecular Weight

    A) 129.1

References

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