Schedule H1

Oral

• Tablets: 200 mg

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

▶ Drug-Resistant Pulmonary Tuberculosis (XDR-TB / Treatment-Intolerant or Non-Responsive MDR-TB) — Adults

Indicated exclusively as part of BPaL regimen (Bedaquiline + Pretomanid + Linezolid) under NTEP/PMDT framework

Pretomanid Dosing within BPaL Regimen:

Parameter Dosing Details

Starting dose 200 mg once daily with food

Titration Not applicable — fixed dose throughout

Usual maintenance dose 200 mg once daily

Maximum dose 200 mg once daily

Total duration 26 weeks (6 months); may extend based on clinical/microbiological response

Complete BPaL Regimen Overview:

Drug Dosing Duration

Bedaquiline 400 mg once daily × 14 days, then 200 mg three times weekly 26 weeks

Pretomanid 200 mg once daily 26 weeks

Linezolid 1200 mg once daily initially; dose reduction to 600 mg or 300 mg based on tolerability 26 weeks

Key Clinical Notes:

• Must be prescribed only under NTEP-approved specialist supervision at designated DR-TB centres

• Not for drug-sensitive TB, latent TB infection, or extrapulmonary TB

• Drug susceptibility testing (DST) results must justify use

• Linezolid dose frequently requires early reduction due to myelosuppression and neuropathy

• Administer with food to optimize absorption

• Strict adherence counselling essential

Secondary Indications — Adults (Off-label, if any)

Not applicable.

Pretomanid use is restricted exclusively to specified DR-TB settings under programmatic guidance. No off-label uses are established or recommended in India.

PAEDIATRIC DOSING (Specialist Only)

Primary Indications (Approved / Standard in India)

Not applicable.

Pretomanid is NOT approved for use in children or adolescents under 18 years of age.

• Safety and efficacy have not been established in paediatric population

• No weight-based or age-based dosing available

Secondary Indications — Paediatric Doses (Off-label, if any)

Not applicable.

Use in patients <18 years only under exceptional circumstances within clinical trial settings or with explicit national TB programme authorization.

End-stage renal disease / Haemodialysis Not recommended — pharmacokinetic data unavailable

Peritoneal dialysis Not recommended — data unavailable

• Known hypersensitivity to pretomanid or any excipient

• Severe hepatic impairment (Child-Pugh C)

• Pregnancy (teratogenic effects demonstrated in animal studies)

• Concomitant use with strong CYP3A4 inducers (rifampicin, rifapentine, efavirenz)

• Use outside of approved combination regimen (BPaL)

• Pre-existing hepatic dysfunction — increased hepatotoxicity risk

• Baseline peripheral neuropathy — may worsen with regimen (particularly linezolid component)

• Myelosuppression risk — baseline CBC abnormalities require close monitoring

• Pre-existing optic neuropathy or visual impairment — linezolid-related risk

• Elderly patients — reduced functional reserves; closer monitoring required

• Alcohol consumption — advise complete avoidance due to additive hepatotoxicity

• QT prolongation risk when used with bedaquiline — ECG monitoring essential

• Women of childbearing potential — strict contraception mandatory

Parameter Detail

Safety Contraindicated — teratogenic effects observed in animal studies

Use in pregnancy Avoid unless life-threatening situation with no alternative; requires expert committee review

Preferred alternatives No equivalent alternative; consider deferring treatment or alternative longer MDR-TB regimens under specialist guidance

Monitoring If unavoidably used: detailed fetal anomaly scan; close specialist supervision throughout

Parameter Detail

Compatibility Not recommended — no human data on excretion into breast milk

Milk levels Unknown

Preferred alternatives Standard MDR-TB regimens without pretomanid (under specialist guidance)

Infant monitoring If unavoidably used: monitor infant weight gain, feeding adequacy, GI symptoms, signs of hepatotoxicity

• Starting dose: 200 mg once daily (same as adults) as part of BPaL regimen

• Titration: Not applicable

• Special considerations:

• Limited safety data in patients >65 years

• Increased risk of cumulative toxicity (hepatotoxicity, neuropathy)

• Reduced renal and hepatic functional reserve may affect drug clearance

• More frequent monitoring of LFTs, CBC, and neurological status required

• Consider baseline nutritional status and comorbidities

Interacting Drug Effect/Risk Recommendation

Rifampicin, Rifapentine Strong CYP3A4 induction significantly reduces pretomanid levels Contraindicated — avoid co-administration

Efavirenz CYP enzyme induction reduces pretomanid exposure Avoid combination; consult HIV specialist for alternatives

Bedaquiline Additive QT prolongation risk Co-use permitted only within BPaL regimen with mandatory ECG monitoring

Linezolid Additive myelosuppression and neuropathy risk Co-use permitted only within BPaL; close monitoring for toxicity essential

Interacting Drug Effect/Risk Recommendation

Protease inhibitors (ritonavir, lopinavir) Potential increased pretomanid exposure via CYP3A4 inhibition Use with caution; consult HIV specialist

Non-nucleoside reverse transcriptase inhibitors (nevirapine) May reduce pretomanid levels Monitor for efficacy; consider alternatives

Phenytoin, Carbamazepine, Phenobarbital CYP induction may reduce pretomanid exposure Avoid if possible; if essential, monitor for treatment failure

Alcohol Additive hepatotoxicity risk Advise complete avoidance throughout treatment

Moxifloxacin QT prolongation risk if co-administered Not standard in BPaL; if unavoidable, close ECG monitoring

Other hepatotoxic drugs Cumulative liver injury risk Monitor LFTs more frequently

• Nausea

• Vomiting

• Anorexia and weight loss

• Headache

• Transient elevation of hepatic transaminases

• Peripheral neuropathy (predominantly from linezolid in regimen)

• Acne

• Diarrhoea

Adverse Effect Clinical Note

Hepatotoxicity May require discontinuation if ALT/AST >5× ULN or symptomatic; monitor closely

Severe myelosuppression (anaemia, thrombocytopenia) Primarily linezolid-related; may require dose reduction or discontinuation

Optic neuritis Urgent ophthalmology referral if visual changes; consider linezolid discontinuation

QT prolongation Monitor ECG; risk increased with bedaquiline co-administration

Lactic acidosis Rare but potentially fatal; related to mitochondrial toxicity

Peripheral neuropathy (severe) May be irreversible; early recognition essential

After initiation LFTs every 2 weeks for first 2 months, then monthly; CBC every 2 weeks for first 2 months; ECG monthly

During treatment Visual acuity and colour vision assessment monthly; symptom review for neuropathy at each visit; weight monitoring; adherence assessment

Long-term Periodic LFTs and CBC throughout 26-week course; sputum culture monitoring for conversion; nutritional status

• Pretomanid (generic) — available through NTEP under programmatic access

• PA-824 formulations via conditional import pathways

Not commercially available in private retail market; distribution controlled through government programme at designated DR-TB centres

Supply Channel Cost

Government supply (NTEP/PMDT) Free of cost at designated DR-TB centres

Private procurement Not commercially available in open market

• Not included in NLEM 2022

• Supplied exclusively via national TB programme under conditional access

• Prescription restricted to NTEP-approved specialists

1. Never use as monotherapy: Pretomanid must always be part of BPaL regimen — isolated use will promote resistance and is ineffective.

1. Confirm eligibility before initiation: BPaL is indicated only for XDR-TB or treatment-intolerant/non-responsive MDR-TB; verify DST results and NTEP eligibility criteria.

1. Linezolid toxicity dominates management: Most adverse events requiring intervention (myelosuppression, neuropathy) are linezolid-related; anticipate dose reductions.

1. Strict contraception essential: Teratogenic risk mandates reliable contraception during treatment and for at least 6 months after completion in women of childbearing potential.

1. Food enhances tolerability: Administer with food to improve GI tolerability and optimize absorption.

1. Nutritional support important: Ensure adequate nutrition and consider pyridoxine supplementation to potentially reduce neuropathy risk.

pretomanid; MDR-TB; XDR-TB; BPaL-regimen; nitroimidazole; NTEP; drug-resistant-TB; hepatotoxicity; neuropathy-risk; specialist-only; pregnancy-contraindicated

RxIndia v1.0 — 02 Jun 2025

• CDSCO conditional import and use approvals

• NTEP National Guidelines for Use of New TB Drugs (2020, 2023)

• ICMR Guidance on Drug-Resistant TB Management

• AIIMS Nodal DR-TB Centre Treatment Protocols

• WHO Consolidated Guidelines on TB Treatment (2022) — supportive reference

• Indian Journal of Tuberculosis — operational research publications

• Goodman & Gilman's Pharmacological Basis of Therapeutics