OTYCULF 250

Indications

• Systemic yeast infections
• Severe systemic candidiasis
• Cryptococcal meningitis (adjunct to amphotericin B)

Dosage

Children: For neonates, the recommended dose is 50 mg/kg every 12 hours. For children 2-12 years, typical dosing is 50 mg/kg every 6 hours, not exceeding 7 days, while for children 12-17 years, an initial loading

Adults: For adults, the usual initial dose is 100 mg/kg daily in 4 divided doses for severe infections, with adjustments based on plasma-flucytosine concentration and renal function.

Mechanism of action

Flucytosine enters fungal cells via cytosine permease and is converted to 5-fluorouracil by cytosine deaminase. The 5-fluorouracil is then incorporated into fungal RNA, disrupting protein synthesis and ultimately leading to the death of the fungal organism. Additionally, it inhibits thymidylate synthase, affecting DNA synthesis. Its action is fungistatic or fungicidal depending on the concentration.

Pharmacodynamics

Flucytosine is classified as an antimetabolite with antifungal properties. It exhibits in vitro and in vivo activity against Candida species and Cryptococcus. By disrupting the synthesis of nucleic acids, it results in unbalanced growth and death of the fungal cells. The drug has been noted to have synergistic effects when used in combination with polyene antibiotics such as amphotericin B.

Pharmacokinetics

Flucytosine is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 1-2 hours after oral administration. It is widely distributed in body fluids and tissues, including the central nervous system. The drug is primarily eliminated via renal excretion, necessitating dose adjustments in patients with renal impairment. It has a half-life of approximately 3-6 hours in individuals with normal renal function.

Contra-indications

• Known complete dihydropyrimidine dehydrogenase (DPD) deficiency
• Acute porphyrias
• Systemic lupus erythematosus (risk of exacerbation)

Adverse effects

• Diarrhoea
• Epigastric discomfort
• Headache
• Nausea
• Vomiting
• Decreased appetite
• Confusion
• Dizziness
• Drowsiness
• Insomnia
• Irritability
• Peripheral neuropathy
• Photosensitivity reactions
• Skin reactions

Interactions

• Cytarabine (decreases concentration of flucytosine)
• Amphotericin B (increases risk of toxicity with flucytosine)

Precautions

• Caution in patients with renal impairment
• Monitor renal function during treatment
• Monitor liver function before starting treatment and periodically thereafter

Pregnancy

Flucytosine is not recommended during pregnancy due to potential risks to the fetus.

Breast-feeding

Flucytosine is excreted in breast milk; caution is advised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and light. Keep out of reach of children.

Formulations

• Oral suspension (50 mg/ml)
• Tablets (various strengths)
• Solution for infusion (2.5 g/250 ml)

Mechanism of action

Although the exact mode of action is unknown, it has been proposed that flucytosine acts directly on fungal organisms by competitive inhibition of purine and pyrimidine uptake and indirectly by intracellular metabolism to 5-fluorouracil. Flucytosine enters the fungal cell via cytosine permease; thus, flucytosine is metabolized to 5-fluorouracil within fungal organisms. The 5-fluorouracil is extensively incorporated into fungal RNA and inhibits synthesis of both DNA and RNA. The result is unbalanced growth and death of the fungal organism. It also appears to be an inhibitor of fungal thymidylate synthase. Flucytosine may be fungistatic or fungicidal in action depending on the concentration of the drug. Two possible mechanisms of action have been identified for flucytosine. Flucytosine appears to enter fungal cells via the action of fungal-specific cytosine permease. Inside the cell, flucytosine is converted into fluorouracil (5-FU) by cytosine deaminase and then after several intermediate steps is converted into 5-fluorouridine triphosphate (FUTP). FUTP is incorporated into fungal RNA and interferes with protein synthesis. Flucytosine also appears to be converted to 5-fluorodeoxyuridine monophosphate, which noncompetitively inhibits thymidylate synthetase and interferes with DNA synthesis. Flucytosine does not appear to have antineoplastic activity.

Pharmacodynamics

Flucytosine is an antimetabolite that acts as an antifungal agent with <i>in vitro</i> and <i>in vivo</i> activity against Candida and Cryptococcus. Flucytosine enters the fungal cell via cytosine permease; thus, flucytosine is metabolized to 5-fluorouracil within fungal organisms. The 5-fluorouracil is extensively incorporated into fungal RNA and inhibits synthesis of both DNA and RNA. The result is unbalanced growth and death of the fungal organism. Antifungal synergism between Ancobon and polyene antibiotics, particularly amphotericin B, has been reported.