Flucytosine

Registered South African indications: 

• Severe systemic fungal infections caused by susceptible pathogens, in candidiasis and cryptococcosis

Registered South African contraindications

• Hypersensitivity to the active substance or to any of the excipients
• Known dihydropyrimidine dehydrogenase (DPD) deficiency
• In combination with irreversible inhibitors of dihydropyrimidine dehydrogenase (DPD), such as brivudine, sorivudine and their analogues or 5-fluorouracil and capecitabine, reversible DPD inhibitors
• Breastfeeding women

South African recommendations

Caution in the following patients

• Pregnancy
• Renal impairment
• Hepatic impairment
• Elderly

Strain identification and medical supervision

• Before initiating flucytosine therapy, the strain’s susceptibility to flucytosine should be confirmed due to possible primary resistance
• Continuous medical supervision is essential during the course of treatment

Coadministration with amphotericin B

• Exercise caution when flucytosine is prescribed to patients already receiving Amphotericin B treatment

Testing for dihydropyrimidine dehydrogenase (DPD) deficiency

• Patients planned to be treated with 5-fluorouracil, capecitabine, or tegafur must undergo testing for dihydropyrimidine dehydrogenase (DPD) deficiency prior to treatment initiation

Management of partial DPD deficiency

• For patients with partial DPD deficiency, consider starting with a reduced dose of flucytosine to minimise the risk of severe and potentially life-threatening toxicity
• Depending on the patient's response and absence of serious toxicity, subsequent doses may be adjusted. Note that the efficacy of reduced doses has not been fully established

Women of childbearing potential

• Women of childbearing potential must use effective contraception during treatment with flucytosine and for up to 1 month after the end of treatment. This is due to flucytosine being partially metabolised to 5-fluorouracil, which can be genotoxic and is considered potentially teratogenic in humans

Male patients

• Male patients (or their female partners of childbearing potential) are advised to use effective contraception during treatment and for up to 3 months after discontinuing treatment with flucytosine

Ability to drive and use machines

• Flucytosine has no or negligible influence on the ability to drive and use machines

Forms avail. in SA and covered in this monograph: tab

South African registered indications and dosages

Severe systemic fungal infections caused by susceptible pathogens, in candidiasis and cryptococcosis (Additional agent required)

• Oral (tab): 100-200mg/kg, per day in 3-4 divided doses, depending on the nature of the infection, its site and sensitivity of the causative microorganism

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Combination with another antifungal medicine
Flucytosine must be used in combination, in order to avoid as much as possible the selection of resistant mutations, especially in the treatment of candidiasis and cryptococcosis. Combination with amphotericin B is often synergistic, in some cases, it allows a dose reduction and reduces the risk of the emergence of secondary resistance to flucytosine. Strict monitoring of renal function is necessary with this combination. There does not seem to be antagonism with imidazole derivatives

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A reduced starting dose should be considered to limit the risk of severe toxicity for patients with partial dihydropyrimidine dehydrogenase (DPD) deficiency (as they are at an increased risk of severe and potentially life-threatening toxicity). Subsequent doses may be increased in the absence of serious toxicity, as the efficacy of a reduced dose has not been established

Not established for use in paediatric patients, including newborn and preterm infants

Pregnancy

South African recommendations

• Caution; not recommended
• Studies in animals have shown reproductive toxicity for flucytosine and one of its metabolites (5‐fluorouracil) (teratogenicity and embryotoxicity)
• In humans, flucytosine crosses the placenta
• There are very limited data from the use of flucytosine in pregnant women
• Embryonic or foetal toxicity cannot be excluded, especially in the event of exposure during the first trimester
• Therefore, flucytosine must not be used during pregnancy and in women of childbearing potential without effective contraception, unless absolutely necessary in case of life‐threatening infections and in the absence of an effective therapeutic alternative
• If flucytosine is administered during pregnancy, the patient must be advised of the teratogenic risk with flucytosine and careful prenatal and postnatal monitoring must be performed
• Furthermore, if administered up until delivery and in view of the safety profile of flucytosine, neonatal surveillance (haematological and hepatic) must be performed

Contraception in males and females

• Flucytosine is partially metabolised to 5‐fluorouracil, which is genotoxic and considered to be potentially teratogenic in humans
• Women of childbearing potential have to use effective contraception during treatment and up to 1 month after discontinuation of treatment
• Male patients (or their female partners of childbearing potential) have to use effective contraception during treatment and up to 3 months after discontinuation of treatment

Breastfeeding

South African recommendations

• Contraindicated
• There are no data on the excretion of flucytosine in human milk
• Breastfeeding is contraindicated during treatment with flucytosine

Fertility

South African recommendations

• No information available

South African recommendations

• Caution; dose adjustment recommended

Doses must be administered at longer intervals, according to the following dosing regimen

Creatinine Clearance	Single Dose	Interval
≥40ml/min	25-50mg/kg	6 hours
20≤ CrCl <40 ml/min	25-50mg/kg	12 hours
10≤ CrCl <20 ml/min	25-50mg/kg	24 hours
CrCl <10 ml/min	Single dose of 25mg/kg, then plasma monitoring 12 hours after the initial dose, before repeating the dose

• Patient on dialysis: Caution; dose adjustment recommended
  Flucytosine is dialysable, the dose of flucytosine must be repeated after each blood‐cleansing session
• In anuric or nephrectomised patients on haemodialysis: Caution; dose adjustment recommended
  The initial dose must not be repeated before the next dialysis session under any circumstances

South African recommendations

• Caution; no information available
  The use of flucytosine has not been studied in patients with hepatic impairment
  Although hepatic impairment is not expected to have a significant effect on the pharmacokinetics of flucytosine, strict monitoring is necessary when treating with flucytosine in patients with hepatic impairment

South African recommendations

• Caution; no dose adjustment recommended
  Since clinical data on the use of flucytosine in elderly patients are limited, this medicinal product may only be used in these patients if the expected benefit outweighs the potential risks
  Particular attention must be paid to renal function in this population

Blood and Lymphatic System Disorders

Less frequent

• Leukopenia, thrombocytopenia (mainly moderate and transient and more frequent in patients with renal impairment or when serum flucytosine levels exceed 100μg/ml)
• More severe disorders (potentially irreversible and possibly fatal in exception cases, have sometimes been observed; mainly, however, in patients undergoing treatment with bone marrow toxicity)
  - Aplasia
  - Agranulocytosis

Cardiac Disorders

Less frequent

• Cardiac disorders in exceptional cases, usually ischaemic in nature
• Myocardial toxicity
• Ventricular function disorders
• Cardiac arrest
• Tachycardia
• Dysrhythmia

Gastrointestinal Disorders

Less frequent

• Nausea
• Diarrhoea
• Vomiting

Hepato-biliary Disorders

Less frequent

• Acute hepatitis
• Elevated transaminase levels (AST, ALT), alkaline phosphatases (regressing upon discontinuation of treatment)
• Acute cases of hepatitis

Skin and Subcutaneous Tissue Disorders

Less frequent

• Pruritus
• Maculopapular erythema
• Photosensitivity reaction
• Lyell’s syndrome

Immune System Disorders

Not known

• Urticaria
• Hypersensitivity

Metabolism and Nutrition Disorders

Not known

• Hypokalaemia

Psychiatric Disorders

Not known

• Confusion
• Hallucinations

Nervous System Disorders

Not known

• Headache
• Sedation
• Convulsions
• Paraesthesias
• Peripheral neuropathy

Ear and Labyrinth Disorders

Not known

• Vertigo

Respiratory and Thoracic Disorders

Not known

• Dyspnoea
• Chest pain
• Respiratory arrest
• Acute respiratory insufficiency

Renal and Urinary Disorders

Not known

• Renal impairment
• Elevated serum creatinine and blood urea

General Disorders and Administration Site Conditions

Not known

• Fever

• Irreversible inhibitors of dihydropyrimidine dehydrogenase (DPD) and their analogues
• Antiviral antiherpetic nucleoside medicines and their analogues
• Uracil
• Brivudine
• Sorivudine
• 5-fluorouracil
• Capecitabine
• Reversible DPD inhibitors
• Zidovudine
• In combination with a medicinal product with bone marrow or renal toxicity
• Amphotericin B

Other interactions

• Diagnostic tests (see Additional Prescribing Points)
  - Enzymatic (2‐step) creatinine assay

Pretreatment

• Electrolytes (particularly potassium)
• Complete blood count (CBC) with differential
• Blood urea nitrogen (BUN)
• Renal function

During treatment

• CBC with differential
• Renal function
• Liver function tests (eg, alkaline phosphatase, AST/ALT) frequently
• Serum flucytosine concentrations (2 hours after administration of a dose) after 3 to 5 doses and as clinically indicated (eg, following dosage adjustment, change in renal function, bone marrow toxicity)
  - If serum flucytosine concentrations cannot be monitored, CBC should be monitored at least twice weekly

Interference with diagnostic tests

• Influence on diagnostic tests: Flucytosine may interfere in the enzymatic (2‐step) creatinine assay, by causing an artificial elevation of the values observed

Cells of flucytosine‐sensitive pathogens are able to absorb flucytosine (5‐FC), which is subsequently metabolised to 5‐fluorouracil (5‐FU) via a specific cytosine deaminase. The amount of 5‐FU incorporated into the ribonucleic acids of the pathogen is proportional to this same pathogen’s susceptibility. 5-fluorouracil incorporates itself into the RNA strand by competing with uracil, disrupting the RNA synthesis, and impairing protein synthesis within the fungus. 5- fluorouracil also further inhibits DNA synthesis by its conversion into fluorodeoxyuridylic acid and inhibiting thymidylate synthase, which causes DNA damage within fungal cells. The enzyme cytosine deaminase is not present in mammalian cells, which is the understanding of its inactivity in bacteria and human cells.

Spectrum of activity:  Candida albicans serotype A, Cryptococcus neoformans, chromoblastomycosis microorganisms and to a lesser extent: Aspergillus