Schedule H

Oral, Intravenous

• Capsule: 500 mg

• Injection: 2.5 g/vial (lyophilized powder for reconstitution) — limited availability

Note: Availability in India is limited; may require hospital pharmacy access or special procurement through import channels.

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Cryptococcal Meningitis (Induction Phase — in combination with Amphotericin B)

Standard of care for HIV-associated cryptococcal meningitis per NACO/ICMR guidelines

Component Details

Starting dose 100 mg/kg/day orally or IV in 4 divided doses (25 mg/kg every 6 hours)

Titration Not applicable

Usual maintenance dose 100 mg/kg/day in 4 divided doses

Maximum dose 150 mg/kg/day

Clinical Notes:

• Duration: 2 weeks induction phase (in combination with Amphotericin B deoxycholate or liposomal amphotericin B)

• Must always be used in combination — monotherapy leads to rapid resistance development

• Therapeutic drug monitoring (TDM) recommended if available: target peak serum concentration 30–80 mcg/mL (toxicity risk at >100 mcg/mL)

• Calculate dose using ideal body weight in obese patients

• Excellent CSF penetration (70–80% of serum levels)

1. Chromoblastomycosis (Adjunctive Therapy)

Component Details

Starting dose 100 mg/kg/day orally in 4 divided doses

Titration May increase to 150 mg/kg/day based on response

Usual maintenance dose 100–150 mg/kg/day in 4 divided doses

Maximum dose 150 mg/kg/day

Clinical Notes:

• Duration: Up to 6 months or longer depending on clinical and mycological response

• Used in combination with itraconazole or amphotericin B

• Specialist supervision mandatory

• Monitor for bone marrow toxicity with prolonged use

Secondary Indications – Adults (Off-label)

Indication Dose Duration Notes

Candida Endocarditis (combination therapy) — OFF-LABEL 100–150 mg/kg/day orally in 4 divided doses ≥6 weeks; depending on valve involvement and surgical intervention Specialist only; used with amphotericin B or echinocandin

Evidence basis: Limited data; Indian infectious disease specialist practice for refractory cases; international guidelines supportive

PAEDIATRIC DOSING (Specialist Only)

Primary Indication: Cryptococcal Meningitis (HIV-associated)

Minimum age: 6 months (limited safety data below this age)

Weight-based dosing:

≥6 months to <18 years 25 mg/kg Every 6 hours (100 mg/kg/day total) 150 mg/kg/day

Component Details

Starting dose 100 mg/kg/day in 4 divided doses

Titration Not applicable

Usual maintenance dose 100 mg/kg/day

Maximum dose 150 mg/kg/day

Clinical Notes:

• Duration: 2 weeks induction phase in combination with Amphotericin B (as per NACO/ICMR paediatric HIV guidelines)

• Must always be used in combination therapy

• Oral route preferred if tolerated; IV for patients unable to take oral medications

Safety Monitoring:

• Complete blood count with differential: twice weekly during therapy

• Renal function (serum creatinine, eGFR): at baseline and weekly

• Liver function tests: at baseline and weekly

• Serum flucytosine levels if available (target peak <100 mcg/mL)

Secondary Indications – Paediatrics (Off-label)

Not applicable. No established off-label paediatric indications in India.

Age restriction: Not recommended below 6 months of age except under specialist supervision in exceptional life-threatening circumstances with no alternative options.

Haemodialysis:

• Flucytosine is dialysable

• Administer 25 mg/kg after each dialysis session

• TDM strongly recommended if available

Peritoneal Dialysis:

• 25 mg/kg every 24–48 hours

• Monitor serum levels

Note: Use ideal body weight for dose calculations in obese patients. TDM is strongly recommended in all patients with renal impairment — target peak level 30–80 mcg/mL; toxicity increases significantly at levels >100 mcg/mL.

• Mild impairment: No dose adjustment required; monitor liver function tests more frequently

• Moderate impairment: Use with caution; monitor LFTs at least twice weekly; consider dose reduction if hepatotoxicity develops

• Severe impairment: Avoid if possible; use only if benefit clearly outweighs risk with close hepatic monitoring and TDM; specialist supervision essential

• Known hypersensitivity to flucytosine or 5-fluorouracil (metabolic conversion product)

• Severe pre-existing bone marrow suppression (not attributable to fungal infection)

• Monotherapy for any fungal infection (rapid resistance development)

• Renal impairment — toxic accumulation risk; dose adjustment and TDM essential

• Pre-existing bone marrow suppression — may be exacerbated

• Concurrent use with other myelosuppressive drugs (zidovudine, ganciclovir, trimethoprim)

• Elderly patients — often have reduced renal reserve

• Prolonged therapy (>4 weeks) — increased risk of resistance and toxicity

• HIV patients on multiple medications — monitor for drug interactions

• Gastrointestinal intolerance — may limit oral dosing

• Concurrent amphotericin B therapy — monitor renal function closely as amphotericin-induced nephrotoxicity will increase flucytosine levels

Aspect Details

Overall safety Potential teratogen based on animal studies; limited human data

Risk category Avoid in pregnancy unless life-threatening infection with no safer alternative

Preferred alternatives Amphotericin B (lipid formulations) for invasive fungal infections

When it may be used Life-threatening cryptococcal meningitis where benefit clearly outweighs risk; specialist decision

Monitoring Maternal CBC (twice weekly), renal function, LFTs; fetal growth monitoring

Aspect Details

Compatibility Not recommended; excretion in breast milk likely

Preferred alternatives Amphotericin B if antifungal therapy required during lactation

Drug levels in milk Unknown; potentially significant given low molecular weight

Recommendation Avoid breastfeeding during flucytosine therapy

Infant monitoring (if exposure occurs) Diarrhoea, feeding difficulties, signs of bone marrow suppression

• Recommended starting dose: 75–100 mg/kg/day orally in 4 divided doses (reduced from standard adult dose)

• Titration: Slower; assess renal function before each dose adjustment

• Extra risks:

• Age-related decline in renal function — increased risk of drug accumulation and toxicity

• Higher susceptibility to bone marrow suppression

• CNS toxicity (confusion, hallucinations) may occur at elevated serum levels

• Monitor renal function frequently and adjust dose accordingly

• TDM strongly recommended if available

Interacting Drug Effect/Mechanism Recommendation

Amphotericin B Reduces renal clearance of flucytosine → increased flucytosine levels and toxicity risk Essential combination for cryptococcal meningitis; monitor renal function closely and adjust flucytosine dose as renal function changes

Cytarabine Enhanced bone marrow toxicity; competitive inhibition of cellular uptake Avoid combination

Zidovudine Additive bone marrow suppression Monitor CBC closely; may require dose modification of either drug

Ganciclovir/Valganciclovir Additive myelosuppression Avoid if possible; if essential, monitor CBC twice weekly

Interacting Drug Effect/Mechanism Recommendation

Phenytoin May reduce flucytosine absorption Monitor antifungal efficacy; consider TDM

Probenecid Reduces renal excretion of flucytosine → increased serum levels Monitor for flucytosine toxicity

Aminoglycosides Additive nephrotoxicity → increased flucytosine accumulation Monitor renal function and flucytosine levels

Vancomycin Additive nephrotoxicity Monitor renal function closely

Trimethoprim/Co-trimoxazole Additive bone marrow suppression Monitor CBC frequently

• Nausea and vomiting

• Diarrhoea

• Abdominal discomfort

• Elevated transaminases (ALT, AST)

• Rash

• Headache

• Reversible leukopenia

• Reversible thrombocytopenia

• Severe bone marrow suppression (agranulocytosis, pancytopenia, aplastic anaemia) — may be fatal; requires immediate discontinuation

• Hepatotoxicity — including hepatic necrosis; discontinue if severe elevation of transaminases

• CNS toxicity (confusion, hallucinations, psychosis) — usually at serum levels >100 mcg/mL; reduce dose or discontinue

• Enterocolitis — rare; with high doses

• Anaphylaxis — rare

• Cardiac toxicity (ventricular dysfunction) — rare; reported at toxic serum levels

→ Serious adverse effects require immediate discontinuation and supportive care

Phase Parameters

Baseline CBC with differential, serum creatinine/eGFR, LFTs (ALT, AST, bilirubin, ALP), serum flucytosine level (if available)

During treatment (first 2 weeks) CBC with differential: twice weekly; serum creatinine: twice weekly; LFTs: weekly; serum flucytosine levels (if available): twice weekly initially

After 2 weeks CBC weekly; renal and hepatic function weekly

TDM targets Peak serum concentration: 30–80 mcg/mL (optimal); avoid levels >100 mcg/mL (toxicity threshold)

Clinical monitoring Signs of bone marrow suppression (infection, bleeding, fatigue); CNS symptoms; GI intolerance

• Ancobon® (Valeant/Bausch — imported; limited availability)

• Ancotil® (imported; limited availability)

Note: Flucytosine has very limited commercial availability in India. Often requires:

• Hospital pharmacy special procurement

• Import through authorised channels

• Access through government or NGO programmes for HIV-associated opportunistic infections

• NLEM status: Not included in NLEM 2022

• NPPA controlled: No

• Government supply: May be available through NACO-supported centres for HIV-associated cryptococcal meningitis; availability varies by state

• Never use as monotherapy — flucytosine resistance develops rapidly within days when used alone; always combine with amphotericin B (for cryptococcal meningitis) or other antifungals

• Combination with Amphotericin B is synergistic — the combination improves outcomes in cryptococcal meningitis despite additive nephrotoxicity; monitor renal function closely

• TDM is critical but often unavailable — if TDM not available, use clinical monitoring (CBC, renal function) and reduce dose empirically if toxicity suspected

• Bone marrow suppression is dose-limiting — CBC twice weekly is mandatory; hold therapy if neutrophils <1000/mm³ or platelets <50,000/mm³

• Renal function determines toxicity — as amphotericin B causes nephrotoxicity, flucytosine levels rise; anticipate need for dose reduction during treatment course

• Oral route preferred when feasible — excellent oral bioavailability (>90%); reserve IV for patients unable to take oral medications

Flucytosine; antifungal; pyrimidine analogue; cryptococcal meningitis; HIV opportunistic infection; CNS-penetrant; renal-dose-adjust; bone-marrow-toxicity; TDM-recommended; pregnancy-avoid

RxIndia v1.1 — 18 Jan 2025

• CDSCO approved prescribing information

• Indian Pharmacopoeia / National Formulary of India

• NACO National Guidelines for HIV Care and Treatment

• ICMR Guidelines for Management of Opportunistic Infections in HIV/AIDS

• API Textbook of Medicine (11th Edition) — Fungal Infections chapter

• AIIMS Antifungal Treatment Protocols

• Harrison's Principles of Internal Medicine (21st Edition)

• Goodman & Gilman's The Pharmacological Basis of Therapeutics (13th Edition)