Article: Flucytosine

Flucytosine, a fluorinated pyrimidine analogue, is a synthetic antimycotic drug.

It is structurally related to the cytostatic fluorouracil and to floxuridine. It is available in oral and in some countries also in injectable form. A common brand name is Ancobon®. The drug is dispensed in capsules of 250 mg and 500 mg strength. The injectable form is diluted in 250ml NaCl-solution to contain 2.5 grams totally (10mg per ml). The solution is physically incompatible with other drugs including Amphotericin B.

Pharmacology

Mechanisms of action

Two major mechanisms of action have been elucidated, one is that the drug is intrafungally converted into the cytostatic flourouracil that undergoes further steps of activation and finally interacts as 5-fluorouridinetriphosphate with RNA-biosynthesis and disturbs therefore the building of certain essential proteins. The other mechanism is the conversion into 5-flourodeoxyuridinemonophosphate which inhibits fungal DNA-synthesis.

Spectrum of susceptible fungi and Resistance

Flucytosine is as well in vitro and in vivo active against some strains of Candida and Cryptococcus. Limited studies demonstrate that Flucytosine may be of value against infections with Sporothrix, Aspergillus, Cladosporium, Exophila, and Phialophora. Resistance is quite commonly seen as well in treatment naive patients and under current treatment with Flucytosine. In different strains of Candida resistance has been noted to occur in 1 to 50% of all specimen obtained from patients.

Pharmacokinetic data

Flucytosine is well absorbed (75 to 90%) from the GI-Tract. Intake with meals slows the resorption, but does not decrease the amount resorbed. Following an oral dose of 2 grams peak serum levels are reached after approximately 6 hours. The time to peak level decreases with continued therapy. After 4 days peak levels are measured after 2 hours. The drug is eliminated renally. In normal patients Flucytosine has reportedly a half-life of 2.5 to 6 hours. In patients with impared renal function higher serum levels are seen and the drug tends to cumulate in these patients. The drug is mainly excreted unchanged in the urine (90% of an oral dose) and only traces are metabolized and excreted in the feces. Therapeutic serum levels range from 25 to 100mcg/ml. Serum levels in exceed of 100mcg are associated with a higher incidence of side-effects. Periodic measurements of serum levels are recommended for all patients and are a must in patients with renal damage.

Human overdose

Symptoms and their severities are unknown, because Flucytosine is used under close medical supervision, but expected to be an excess of the usually encountered side-effects on bone-marrow, GI-Tract, liver, and kidney-function. Vigouros hydration and hemodialysis may be helpful to remove the drug from the body. Hemodialysis is particular useful in patients with impaired renal function.

Human carcinogenity

It is not known, if Flucytosine is a human carcinogen. The issue has been raised because traces of 5-fluorouracil, which is a known carcinogen, are found in the colon resulting from the metabolization of Flucytosine.

Indications

Oral Flucytosine is indicated for the treatment of serious infections caused by susceptible strains of Candida or Cryptococcus neoformans. It can also be used for the treatment of chronomycosis (chromoblastomycosis), if susceptible strains cause the infection. Flucytosine must in life-threatening fungal infections not be used as sole agent due to relatively weak antifungal effects and fast development of resistance but only in combination with Amphotericin B and/or azoles (e.g. Fluconazole, Itraconazole). Minor infections as candidal cystitis may be treated with Flucytosine alone. In some countries treatment with shorttime i.v.-infusions is also a therapeutic option, particular if the disease is life-threatening.

Contraindications and cautions

• All patients receiving Flucytosine should be under strict medical supervision.
• Hematological, renal and liver function studies should be done frequently during therapy (initially daily, twice a week for the rest of treatment).
• Patients with preexisting bone marrow depression and liver impairment should be treated with caution.
• Concomitant treatment with Brivudin is an absolute contraindication.
• Patients treated with drugs compromising bone marrow function (e.g. cytostatics) should be treated carefully. Blood cell counts should be taken very frequently.
• Patients with renal disease should receive Flucytosine cautiously and in reduced doses. Guidelines for proper dosing exist. Serum level determinations are mandatorily in these patients.
• Hypersensitivity to Flucytosine is an absolute contraindication

Special Patient Groups

Pregnancy and lactation

In animal models (rats) Flucytosine has been found to be teratogenic. Sufficient human data does not exist. Pregnant women should be treated only, if the potential benefits exceed the potential harm to the fetus.

It is not known, if Flucytosine is distributed in human milk. Given a potential risk to the child, the patient should not breastfeed during treatment with Flucytosine.

Pediatric patients

The efficacy and safety in patients under 18 years of age has not been determined.

Side-effects

• Antiproliferative Actions on Bone Marrow and GI Tissue: Due to the drug's preference to affect fast proliferating tissues, bone marrow depression (anemia, leukopenia, pancytopenia, or even rarely agranulocytosis) may frequently occur. Aplastic anemia has also been seen. Bone marrow toxicity can be irreversible and may cause death, particular in immunecompromised patients. GI-Tract toxicity may be severe or rarely fatal and consists of anorexia, abdominal bloating, abdominal pain, diarrhea, dry mouth, duodenal ulcer, GI hemorrhage, nausea, vomiting, and ulcerative colitis.

• Liver Function: Elevations of liver enzymes and bilirubin, hepatic dysfunction, jaundice and in one patient liver necrosis have all been seen. Some fatal cases have been reported, however the majority of cases was reversible.

• Renal function: Increased BUN and serum creatinine have been noted. Crystalluria (formation of crystalls and excretion in the urine), and acute renal failure have also been seen.

• Adverse Central Nervous System effects are frequent and include confusion, hallucinations, psychosis, ataxia, hearing loss, headache, paresthesia, parkinsonism, peripheral neuropathy, vertigo and sedation.

• Skin Reactions: Rash, pruritus, and photosensitivity have all been noticed. Toxic epidermal necrolysis (Lyell's syndrome) may also be encountered and may be life-threatening.

• Anaphylaxis: Sometimes cases of anaphylaxis consisting of diffuse erythema, pruritus, conjunctival injection, fever, abdominal pain, edema, hypotension and bronchospastic reactions are observed.

Interactions

For details see Contraindications and Cautions. Flucytosine may increase the toxicity of Amphotericin B and vice versa, although the combination may be life-saving and should be used whenever indicated. The cytostatic cytarabine inhibits the antimycotic activity of Flucytosine.

Dosage

The recommended daily dose is 50 to 150mg per kg bodyweight orally, divided in 4 equal doses every 6 hours. If problems exist to swallow a complete single dose, the dose may be given in several partial amounts over 15 minutes. The dose for i.v.-infusions (shorttime) is 50mg per kg every 6 hours. The duration of treatment depends on the clinical situation.

Use in immunecompromised patients

Serious fungal infections often occur in immunecompromised (e.g. HIV-infected) patients. These patients benefit from a combination therapy including Flucytosine. But the incidence of side-effects of a combination therapy, particular with Amphotericin B, may be higher than in immunecompetent patients.

Veterinary uses

In some countries like Switzerland Flucytosine has been licensed to treat cats, dogs and birds (in most cases together with Amphotericin B) for the same indications as in humans.