Schedule H

Oral, Intravenous

• Tablets: 50 mg, 200 mg

• Powder for oral suspension: 200 mg per vial (for reconstitution)

• IV injection: 200 mg/vial (lyophilised powder for infusion)

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Invasive Aspergillosis — Adults

Parameter Intravenous Oral (≥40 kg) Oral (<40 kg)

Starting dose 6 mg/kg q12h × 2 doses (Day 1) 400 mg q12h × 2 doses (Day 1) 200 mg q12h × 2 doses (Day 1)

Titration Not applicable Not applicable Not applicable

Usual maintenance dose 4 mg/kg q12h from Day 2 200 mg q12h from Day 2 100 mg q12h from Day 2

Maximum dose 4 mg/kg q12h (IV) 300 mg q12h (if inadequate response) 150 mg q12h (if inadequate response)

Duration: Minimum 6–12 weeks; guided by clinical response and immune reconstitution

Clinical Notes:

• First-line therapy for invasive aspergillosis

• Step-down from IV to oral permissible after clinical stabilisation

• Oral bioavailability excellent (>90%) — enables early switch

1. Candidemia and Disseminated Candidiasis in Non-Neutropenic Adults

Parameter Intravenous Oral (≥40 kg)

Starting dose 6 mg/kg q12h × 2 doses (Day 1) 400 mg q12h × 2 doses (Day 1)

Titration Not applicable Not applicable

Usual maintenance dose 4 mg/kg q12h from Day 2 200 mg q12h from Day 2

Maximum dose 4 mg/kg q12h 300 mg q12h

Duration: Minimum 14 days after blood culture clearance and symptom resolution

Clinical Notes:

• Step-down to oral therapy in clinically stable patients

• Reserve for fluconazole-resistant species or where azole susceptibility favours voriconazole

1. Scedosporiosis and Fusariosis (Salvage/Primary Therapy)

Parameter Recommendation

Starting dose IV: 6 mg/kg q12h × 2 doses (Day 1)

Titration Not applicable

Usual maintenance dose IV: 4 mg/kg q12h OR Oral: 200 mg q12h (≥40 kg)

Maximum dose 300 mg q12h orally; 4 mg/kg q12h IV

Duration: Prolonged (weeks to months); determined by clinical and radiological response

Clinical Notes:

• Voriconazole is agent of choice for Scedosporium apiospermum

• Fusariosis therapy often requires combination approaches — specialist input mandatory

Secondary Indications — Adults (Off-label)

Indication Dose Duration Notes

Empirical antifungal in febrile neutropenia Loading: 6 mg/kg IV q12h × 2 doses; Maintenance: 4 mg/kg q12h Until neutropenia resolves OFF-LABEL • Specialist only • Indian tertiary centre practice; IDSA supportive

Cerebral aspergillosis / Fungal CNS infections Standard aspergillosis dosing Prolonged (months) OFF-LABEL • Specialist only • High CNS penetration favours use over amphotericin B

Allergic bronchopulmonary aspergillosis (ABPA) refractory to itraconazole Oral: 200 mg q12h 16–24 weeks OFF-LABEL • Specialist only • Indian pulmonology practice

PAEDIATRIC DOSING (Specialist Only)

Primary Indications (Approved / Standard in India)

1. Invasive Aspergillosis / Invasive Candidiasis

2 to <12 years IV: 9 mg/kg q12h × 2 doses IV: 8 mg/kg q12h OR Oral: 9 mg/kg q12h 350 mg per dose

12–14 years (<50 kg) IV: 9 mg/kg q12h × 2 doses IV: 8 mg/kg q12h OR Oral: 9 mg/kg q12h 350 mg per dose

≥15 years OR ≥50 kg Use adult dosing Use adult dosing Adult maximum

Duration: Minimum 6–12 weeks for aspergillosis; 14 days after culture clearance for candidiasis

Safety Monitoring:

• Baseline and weekly liver function tests

• Periodic visual assessment (report blurred vision, photophobia)

• Electrolytes and renal function monitoring

Secondary Indications — Paediatric (Off-label)

Indication Dose Duration Notes

Fungal CNS infections (aspergillosis) As per age-based dosing above Prolonged (months) OFF-LABEL • Specialist only • Paediatric ID expert centres

Scedosporiosis As per age-based dosing above Guided by response OFF-LABEL • Limited Indian data

Age Restrictions:

• Not recommended in children <2 years except in life-threatening situations under specialist infectious diseases supervision

• Neonatal use: NOT AVAILABLE in India (insufficient safety data)

Formulation CrCl ≥50 mL/min CrCl <50 mL/min

Oral No adjustment required No adjustment required

Intravenous No adjustment required Avoid IV formulation — cyclodextrin vehicle accumulates; switch to oral

Dialysis: Not significantly removed by haemodialysis; no supplemental dosing required

• Known hypersensitivity to voriconazole or other azole antifungals

• Co-administration with:

• Rifampicin, rifabutin (potent CYP inducers — renders voriconazole ineffective)

• Carbamazepine, long-acting barbiturates (phenobarbital)

• Sirolimus (marked increase in sirolimus levels — contraindicated)

• Terfenadine, astemizole, cisapride, pimozide, quinidine (risk of fatal QT prolongation/torsades)

• Ergot alkaloids (ergotamine, dihydroergotamine) — risk of ergotism

• St John's Wort (marked reduction in voriconazole levels)

• Pre-existing hepatic disease — increased hepatotoxicity risk; requires close monitoring

• Visual disturbances — common; advise caution with driving and operating machinery

• QT prolongation risk factors — electrolyte abnormalities, concurrent QT-prolonging drugs, cardiac disease

• Extensive CYP450 metabolism — multiple drug interactions via CYP2C19, CYP2C9, CYP3A4

• Photosensitivity and phototoxicity — advise sun protection during prolonged therapy

• Galactose intolerance (tablets contain lactose)

• CYP2C19 poor metabolisers — higher drug exposure; consider therapeutic drug monitoring

Parameter Information

Risk Category Contraindicated (teratogenic in animal studies; human data limited)

Overall Safety Avoid during pregnancy unless life-threatening infection with no alternatives

Preferred Alternatives Liposomal amphotericin B

When May Be Used Only if no suitable alternative; specialist decision with documented informed consent

Monitoring Fetal anomaly scans; maternal hepatic function

Parameter Information

Compatibility Not recommended

Expected Milk Levels Unknown; likely excreted based on pharmacokinetic profile

Preferred Alternatives Liposomal amphotericin B for systemic infections

Decision Avoid breastfeeding during therapy and for at least 1 week after last dose

Infant Monitoring If exposure unavoidable: monitor for hepatic effects, feeding difficulties, GI disturbance

Parameter Recommendation

Starting dose Initiate at lower end of standard dosing; no specific age-based reduction mandated

Titration Slower dose escalation if needed; monitor response

Special considerations Increased risk of hepatotoxicity and visual disturbances

Extra monitoring Baseline and frequent LFTs; renal function (affects IV formulation use); ECG if cardiac risk factors

Risk factors Polypharmacy increasing drug interactions; reduced hepatic reserve

Interacting Drug Effect & Mechanism Management

Rifampicin Reduces voriconazole levels by >90% (potent CYP inducer) CONTRAINDICATED

Rifabutin Bidirectional interaction; reduces voriconazole, increases rifabutin toxicity CONTRAINDICATED

Carbamazepine Strong CYP induction; substantially reduces voriconazole levels CONTRAINDICATED

Phenobarbital (long-acting) CYP induction; reduces voriconazole efficacy CONTRAINDICATED

Sirolimus Voriconazole increases sirolimus levels dramatically (CYP3A4 inhibition) CONTRAINDICATED

Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine QT prolongation; risk of torsades de pointes CONTRAINDICATED

Efavirenz Complex bidirectional interaction; both drug levels affected Avoid combination; if unavoidable, increase voriconazole to 400 mg q12h and reduce efavirenz to 300 mg daily — specialist only

Phenytoin Phenytoin induces voriconazole metabolism; voriconazole increases phenytoin levels Increase voriconazole maintenance dose by 100%; monitor phenytoin levels

Tacrolimus Voriconazole inhibits CYP3A4; tacrolimus levels increase 2–3 fold Reduce tacrolimus dose by 50–66%; monitor trough levels

Cyclosporine Voriconazole increases cyclosporine levels ~1.7 fold Reduce cyclosporine dose by 50%; monitor levels

Warfarin Increased INR due to CYP2C9 inhibition Monitor INR frequently; anticipate warfarin dose reduction

Interacting Drug Effect Management

Omeprazole, Esomeprazole Increase voriconazole levels via CYP2C19 inhibition Consider halving PPI dose if high voriconazole levels suspected

Simvastatin, Lovastatin Increased statin levels; myopathy/rhabdomyolysis risk Avoid combination; prefer atorvastatin or rosuvastatin at low doses

Benzodiazepines (midazolam, triazolam) Prolonged sedation (CYP3A4 inhibition) Reduce benzodiazepine dose; monitor for excessive sedation

Sulfonylureas (glipizide, glimepiride) Hypoglycaemia risk due to CYP2C9 inhibition Monitor blood glucose closely

Methadone Increased methadone levels; QT prolongation risk Monitor ECG; consider methadone dose reduction

Erythromycin, Clarithromycin Additive QT prolongation; potential hepatotoxicity Monitor ECG; avoid if possible

HIV protease inhibitors Complex interactions; varies by specific PI Consult HIV specialist; consider TDM

Fentanyl Increased fentanyl exposure Reduce fentanyl dose; monitor for respiratory depression

• Visual disturbances (blurred vision, altered colour perception, photophobia) — occurs in ~30%

• Elevated hepatic transaminases

• Rash

• Nausea, vomiting

• Diarrhoea

• Headache

• Fever

• Peripheral oedema

Adverse Effect Clinical Action

Hepatotoxicity (severe transaminase elevation, cholestasis, hepatic failure) Discontinue immediately; hepatology consultation

QT prolongation / Torsades de pointes Discontinue; cardiac monitoring; correct electrolytes

Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis Immediate discontinuation; dermatology/ICU referral

Anaphylaxis / Severe hypersensitivity Discontinue; supportive care

Phototoxicity (severe skin reactions, increased skin malignancy risk with prolonged use) Discontinue or minimise sun exposure; dermatology review

Periostitis / Fluorosis-like bone pain (with prolonged therapy) Consider drug discontinuation; rheumatology consultation

Visual hallucinations Dose reduction or discontinuation

After initiation LFTs weekly for first 4–6 weeks

During therapy LFTs every 2–4 weeks; therapeutic drug monitoring if poor response or suspected toxicity (target trough: 1–5.5 mg/L)

Long-term (>3 months) Periodic skin examination for phototoxicity; visual assessment; consider bone imaging if periostitis suspected

• Vorier (Pfizer)

• Voritek (Cipla)

• Vfend (Pfizer)

• Veflo (Macleods)

• Vorizol (Natco)

• Vobitaz (Biocon)

• Vozole (Sun Pharma)

• Voriconazole (generic — multiple manufacturers)

FDCs: Not commonly available with this molecule

Note: Not included in NLEM 2022; prices vary by brand and procurement source (government tender vs private retail)

• First-line agent for invasive aspergillosis — superior to amphotericin B in efficacy and tolerability

• Oral bioavailability is excellent (~96%); facilitates early IV-to-oral switch in stable patients

• Avoid IV formulation in CrCl <50 mL/min — cyclodextrin carrier accumulates; oral route remains safe

• Visual disturbances are common but usually reversible; warn patients and advise against night driving initially

• Therapeutic drug monitoring recommended in treatment failure, suspected toxicity, hepatic impairment, or drug interactions (target trough: 1–5.5 mg/L)

• Prolonged therapy (>6 months) requires vigilant sun protection due to phototoxicity and risk of cutaneous malignancy

Voriconazole; antifungal; triazole; invasive aspergillosis; candidemia; scedosporiosis; fusariosis; hepatotoxicity; QT prolongation; CYP inhibitor; CNS penetration; TDM recommended

RxIndia v1.0 — 05 Jan 2025

• CDSCO Approved Drug Formulations Database

• Indian Pharmacopoeia 2022

• National Formulary of India 2021

• AIIMS Antifungal Use Policy

• API Textbook of Medicine, 11th Edition

• Harrison's Principles of Internal Medicine, 21st Edition

• Goodman & Gilman's The Pharmacological Basis of Therapeutics

• Manufacturer Product Inserts (India-specific)

• IDSA Guidelines 2016 (referenced for off-label indications; consistent with Indian practice)

• Indian tertiary hospital antifungal protocols