Flucytosine


Concise Prescribing Info
Indications/Uses
Systemic fungal infections.
Dosage/Direction for Use
Adult : PO 50-150 mg/kg/day in 4 divided doses; given w/ amphotericin B or fluconazole in severe cases. IV 200 mg/kg/day in 4 divided dose; given w/ amphotericin B or fluconazole in severe cases.
Dosage Details
Intravenous
Systemic fungal infections
Adult: 200 mg/kg daily in 4 divided doses via infusion over 20-40 min. Adjust dose to produce trough plasma levels of 25-50 mcg/mL. In severe systemic candidiasis, cryptococcal meningitis and other severe infections, it is usually given in combination w/ amphotericin B or fluconazole. Treatment duration is individualised based on sensitivity of the organism and patient response (usually ≤7 days, except for cryptococcal meningitis when it is continued for at least 4 mth).

Oral
Systemic fungal infections
Adult: 50-150 mg/kg daily in 4 divided doses. Commonly used w/ amphotericin B or fluconazole in severe infections.
Renal Impairment
Oral:
Initiate at lower doses. Monitor plasma levels and adjust subsequent doses accordingly to prevent drug accumulation.

Intravenous:
CrCl (mL/min) Dosage
<10 50 mg/kg; further doses should be based on plasma levels (not exceeding 80 mcg/mL).
10-<20 50 mg/kg 24 hrly.
20-40 50 mg/kg 12 hrly.
Administration
May be taken with or without food. Nausea & vomiting may be minimised if the dose is spaced over a 15-min period.
Contraindications
Hypersensitivity to flucytosine. Co-administration w/ antiviral nucleoside drugs and their analogues. Lactation.
Special Precautions
Patient w/ blood dyscrasias or bone marrow depression, dihydropyrimidine dehydrogenase (DPD) deficiency. Patients receiving radiation therapy. Renal and hepatic impairment.
Adverse Reactions
Nervous: Ataxia, confusion, hallucinations, psychosis, headache, paraesthesia, peripheral neuropathy, parkinsonism, seizures, vertigo, sedation.
CV: Cardiac arrest, myocardial toxicity, ventricular dysfunction, chest pain.
GI: Abdominal pain, dry mouth, bloating, diarrhoea, duodenal ulcer, GI haemorrhage, nausea, vomiting, ulcerative colitis, anorexia.
Resp: Dyspnoea, resp arrest.
Hepatic: Hepatic dysfunction, jaundice, elevated serum alkaline phosphatase, AST, ALT, and bilirubin.
Genitourinary: Increased BUN and serum creatinine, azotaemia, crystalluria, renal failure.
Endocrine: Hypoglycaemia.
Haematologic: Leucopenia, anaemia, pancytopenia, thrombocytopenia, eosinophilia, agranulocytosis.
Otic: Hearing loss.
Dermatologic: Pruritus, rash, urticaria, photosensitivity, toxic epidermal necrolysis.
Others: Fatigue, pyrexia, hypokalaemia, weakness.
Potentially Fatal: Bone marrow toxicity, acute hepatic injury.
MonitoringParameters
Monitor renal, hepatic, and haematologic functions prior to and during treatment (at least wkly in patients w/ renal impairment or blood dyscrasia).
Overdosage
Symptoms: GI effects (e.g. diarrhoea, nausea, vomiting), haematologic effects (e.g. leucopenia, thrombocytopenia), and hepatic effects (e.g. hepatitis). Management: Employ prompt gastric lavage or an emetic. Maintain adequate fluid intake. IV fluids may be given as necessary.
Drug Interactions
May result in synergistic effect when combined w/ amphotericin B or fluconazole. May increase phenytoin plasma levels. Cytarabine antagonises the antifungal activity of flucytosine by competitive inhibition.
Potentially Fatal: Co-administration w/ antiviral nucleoside drugs (e.g. brivudine, sorivudine, and their analogues) may result in severe drug toxicity due to inhibition of DPD, a key enzyme involved in the metabolism of 5-FU.
Food Interaction
Decreased rate of absorption w/ food.
Lab Interference
May interfere w/ dual-slide enzymatic measurement of creatinine using Ektachem® or Vitros DT 60 analyser; use Jaffe reaction or other alkaline picrate method in determining serum creatinine.
Action
Description: Flucytosine is a fluorinated pyrimidine antifungal that is taken up by cytosine permease into the fungal cells. It is rapidly converted to fluorouracil (5-FU) and subsequently into 5-fluorouridine triphosphate (FUTP), which is then incorporated into fungal RNA, resulting to faulty protein biosynthesis. 5-FU is also converted to fluorodeoxyuridine monophosphate which interferes w/ thymidylate synthase, thereby causing disruption of DNA synthesis.
Pharmacokinetics:
Absorption: Absorbed rapidly and almost completely from the GI tract. Bioavailability: 78-89%. Time to peak plasma concentration: W/in 1-2 hr (oral).
Distribution: Widely distributed in body tissues and fluids, including CSF. Crosses the placenta. Volume of distribution: 0.5-1 L/kg.  Plasma protein binding: Approx 2-4%.
Metabolism: Undergoes minimal hepatic metabolism into 5-FU via deamination in yeasts and probably by gut bacteria.
Excretion: Via urine (approx 90%, as unchanged drug). Elimination half-life: 2.5-6 hr.
Chemical Structure

Chemical Structure Image
Flucytosine

Source: National Center for Biotechnology Information. PubChem Database. Flucytosine, CID=3366, https://pubchem.ncbi.nlm.nih.gov/compound/Flucytosine (accessed on Jan. 21, 2020)

Storage
Cap: Store between 15-30°C. IV Soln: Store between 18-25°C.
MIMS Class
ATC Classification
J02AX01 - flucytosine ; Belongs to the class of other systemic antimycotics.
References
Ancobon Capsule (Valeant Pharmaceuticals North America LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 07/03/2017.

Anon. Flucytosine. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 07/03/2017.

Buckingham R (ed). Flucytosine. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 07/03/2017.

Joint Formulary Committee. Flucytosine. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 07/03/2017.

McEvoy GK, Snow EK, Miller J et al (eds). Flucytosine. AHFS Drug Information (AHFS DI) [online]. American Society of Health-System Pharmacists (ASHP). https://www.medicinescomplete.com. Accessed 07/03/2017.

Disclaimer: This information is independently developed by MIMS based on Flucytosine from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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