Flucytosine

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.

Flucytosine May be taken with or without food.

Hypersensitivity to flucytosine. Co-administration w/ antiviral nucleoside drugs and their analogues. Lactation.

Patient w/ blood dyscrasias or bone marrow depression, dihydropyrimidine dehydrogenase (DPD) deficiency. Patients receiving radiation therapy. Renal and hepatic impairment.

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.

Monitor renal, hepatic, and haematologic functions prior to and during treatment (at least wkly in patients w/ renal impairment or blood dyscrasia).

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.

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.

Decreased rate of absorption w/ food.

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.

Description:
Mechanism of Action: 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.

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

Cap: Store between 15-30°C. IV Soln: Store between 18-25°C.

Antifungals

J02AX01 - flucytosine ; Belongs to the class of other systemic antimycotics.

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.