Schedule H

Oral

• Tablets: 200 mg, 400 mg, 600 mg, 800 mg, 1000 mg

• Dispersible tablets: 100 mg (paediatric, under NTEP)

• Fixed-dose combinations (FDCs): Multiple adult and paediatric formulations with rifampicin (R), isoniazid (H), and pyrazinamide (Z) under NTEP

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

Pulmonary and Extrapulmonary Tuberculosis — Intensive Phase

Ethambutol is an essential component of the standard first-line 4-drug regimen (HRZE) during the initial 2-month intensive phase of TB treatment. It provides bacteriostatic activity and helps prevent emergence of resistance to companion drugs.

Adult Dosing (per NTEP/Index TB Guidelines):

Weight-band Based Daily Dosing:

Body Weight Daily Dose Ethambutol Component

25–39 kg 600 mg once daily 600 mg tablet

40–54 kg 800 mg once daily 800 mg tablet OR 2 × 400 mg

55–69 kg 1000 mg once daily 1000 mg tablet OR 2 × 400 mg + 200 mg

≥70 kg 1200 mg once daily 1200 mg (3 × 400 mg)

Alternative mg/kg Dosing:

Parameter Recommendation

Starting dose 15–20 mg/kg/day once daily (typically 15 mg/kg; round to nearest weight band)

Titration Not applicable

Usual maintenance dose 15–20 mg/kg/day once daily

Maximum dose 1600 mg/day (daily therapy); 25 mg/kg (absolute maximum)

Duration:

• Intensive phase: 2 months (with HRZ)

• Continuation phase: Ethambutol typically NOT included in continuation phase unless:

• Initial H-resistance suspected or confirmed

• Drug-resistant TB regimens

• Retreatment cases per NTEP protocol

Clinical Notes:

• Always use as part of combination therapy (never as monotherapy)

• Preferably use fixed-dose combinations (FDCs) for better compliance

• Administer once daily, preferably in the morning with or without food

• Daily regimen preferred over intermittent regimen per current NTEP guidelines

• Baseline visual acuity and colour vision assessment mandatory before initiating therapy

Secondary Indications — Adults (Off-label)

Indication Dose Duration Notes

Mycobacterium avium Complex (MAC) Infection 15 mg/kg/day once daily (usually 800–1200 mg/day) Minimum 12 months after culture conversion OFF-LABEL — Specialist only (Infectious Diseases/Pulmonology). Always used in combination with clarithromycin/azithromycin ± rifabutin. Based on international guidelines and Indian tertiary centre practice.

Other Non-tuberculous Mycobacterial (NTM) Infections 15 mg/kg/day once daily 12–24 months depending on species and response OFF-LABEL — Specialist only. Used as part of multi-drug regimens.

PAEDIATRIC DOSING (Specialist Only)

Primary Indications (Approved / Standard in India)

Pulmonary and Extrapulmonary Tuberculosis — Intensive Phase

Used as part of HRZ(E) combination during intensive phase (2 months) per IAP and NTEP paediatric TB guidelines.

Weight-band Based Dosing (per NTEP Paediatric Guidelines):

Body Weight Daily Dose Ethambutol Component

4–7 kg 100 mg once daily 1 dispersible tablet (100 mg)

8–11 kg 200 mg once daily 2 dispersible tablets

12–15 kg 300 mg once daily 3 dispersible tablets

16–24 kg 400 mg once daily 4 dispersible tablets OR 1 × 400 mg tablet

25–29 kg 500 mg once daily 5 dispersible tablets

30–39 kg 600 mg once daily 600 mg tablet

≥40 kg Use adult weight-band dosing Adult tablet formulation

Alternative mg/kg Dosing:

Parameter Recommendation

Starting dose 15–25 mg/kg/day once daily (optimal: 20 mg/kg/day)

Titration Not applicable

Usual maintenance dose 15–25 mg/kg/day once daily

Maximum dose 1200 mg/day

Duration: 2 months (intensive phase)

Clinical Notes:

• Use paediatric dispersible FDC tablets (available under NTEP) whenever possible

• Dispersible tablets should be dissolved in small amount of water before administration

• Higher mg/kg dosing in children compared to adults reflects different pharmacokinetics

• Weight should be measured at each visit and dose adjusted accordingly

Minimum Age Statement: May be used in infants and young children under specialist supervision. Historically avoided in children <5 years due to difficulty monitoring visual acuity; however, current WHO and NTEP guidelines recommend inclusion of ethambutol in paediatric regimens with appropriate monitoring.

Safety Monitoring:

• Baseline visual acuity assessment (age-appropriate method)

• Monthly visual assessment during treatment (colour vision if possible)

• For children unable to report visual symptoms: enhanced clinical vigilance, parental education about behavioural changes suggesting visual problems

• Clinical assessment for optic neuritis symptoms at each visit

Secondary Indications — Paediatrics (Off-label)

Indication Age Dose Notes

Non-tuberculous Mycobacterial (NTM) Infections All ages 15–25 mg/kg/day once daily (max 1200 mg) OFF-LABEL — Specialist only (Paediatric ID/Pulmonology). Used as part of multi-drug regimens for MAC and other NTM. Duration: 12–18 months after culture conversion.

50 No dose adjustment required; use standard weight-band dosing

30–50 Reduce dose to 15 mg/kg once every 24–36 hours; alternatively, standard dose every 36–48 hours

10–29 15–20 mg/kg three times weekly (e.g., Monday, Wednesday, Friday)

<10 (not on dialysis) 15–20 mg/kg three times weekly

Haemodialysis 15–25 mg/kg three times weekly; administer after dialysis session on dialysis days

Peritoneal dialysis 15–20 mg/kg three times weekly

Notes:

• Ethambutol is significantly removed by haemodialysis (approximately 40–60%)

• Optic toxicity risk increases with drug accumulation — visual monitoring even more critical in renal impairment

• Coordinate with nephrologist for optimal dosing in dialysis patients

• Therapeutic drug monitoring (if available) may guide dosing in severe renal impairment

Notes:

• Ethambutol is NOT hepatotoxic and is a safe option when other first-line TB drugs need to be avoided due to hepatotoxicity

• When drug-induced hepatotoxicity from other ATT occurs, ethambutol can usually be continued safely

• Monitor LFTs when used in combination with other antitubercular drugs

• Known hypersensitivity to ethambutol or any excipient

• Pre-existing optic neuritis (regardless of cause)

• Severe visual impairment where adequate visual monitoring is not possible

• Patients who cannot reliably report visual symptoms AND cannot undergo objective visual testing (relative contraindication — may use with enhanced monitoring if no alternative)

• Renal impairment — dose reduction required; increased risk of accumulation and optic toxicity

• Children <5 years — use with caution due to difficulty in monitoring visual acuity; however, current guidelines support use with appropriate monitoring

• Elderly patients — increased susceptibility to optic toxicity; often have pre-existing visual impairment and reduced renal function

• Pre-existing visual impairment — careful baseline documentation and monitoring essential

• Diabetes mellitus — may have pre-existing retinopathy; careful differentiation required

• History of gout or hyperuricaemia — ethambutol may elevate uric acid levels

• Concurrent use of other drugs causing optic toxicity (linezolid, isoniazid at high doses)

• Alcoholism — may have nutritional deficiencies predisposing to optic neuritis

• Inability to distinguish red-green colours at baseline — difficulty in monitoring for early toxicity

Parameter Recommendation

Safety Category Generally considered safe in pregnancy; extensive clinical experience without documented teratogenicity; crosses placenta but no evidence of fetal harm

Preferred Alternatives No alternative required; ethambutol is included in standard pregnancy TB regimen in India per NTEP and ICMR guidelines

When to Use Throughout intensive phase (2 months) as part of first-line HRZE regimen; benefits of adequate TB treatment outweigh theoretical risks

Monitoring Baseline and monthly visual assessment; standard antenatal monitoring

Notes:

• WHO, NTEP, and ICMR guidelines recommend ethambutol in pregnancy

• Untreated TB in pregnancy carries significant maternal and fetal risks

• Theoretical concern about fetal optic nerve development not substantiated by clinical evidence

Parameter Recommendation

Breastfeeding Compatibility Compatible with breastfeeding; continue breastfeeding during TB treatment

Drug Levels in Milk Low (approximately 1–3% of maternal dose)

Preferred Alternatives Not required; ethambutol is safe during lactation

Infant Monitoring Routine monitoring only; theoretical concern about infant optic nerve exposure not clinically significant at low milk concentrations

Notes:

• Amount excreted in breast milk is insufficient to provide therapeutic or prophylactic effect in infant

• Infant should receive isoniazid preventive therapy (IPT) if mother is smear-positive, followed by BCG vaccination

Parameter Recommendation

Starting dose Use lower end of dosing range (15 mg/kg/day rather than 20 mg/kg/day)

Titration Not applicable

Maximum dose Consider limiting to 1000 mg/day unless body weight clearly warrants higher dose

Additional Risks Increased risk of optic toxicity (age-related decline in optic nerve reserve); pre-existing age-related macular degeneration or cataracts may complicate monitoring; reduced renal function affecting drug clearance; polypharmacy increasing interaction risk

Monitoring Baseline visual acuity with dilated fundoscopy if possible; monthly visual assessment; renal function at baseline and periodically; document any pre-existing visual abnormalities carefully

Interacting Drug Mechanism/Effect Management

Aluminium hydroxide-containing antacids Reduced ethambutol absorption (chelation in GI tract); up to 20–25% reduction in bioavailability Avoid co-administration; administer ethambutol at least 2 hours before or 4 hours after aluminium-containing antacids

Magnesium hydroxide-containing antacids Similar chelation effect; reduced absorption Space administration as above

Other optic nerve-toxic drugs (linezolid, high-dose isoniazid, chloramphenicol) Additive optic neuritis risk Monitor visual function more frequently; consider alternative agents if possible; early symptoms warrant immediate review

Interacting Drug Effect Management

Cycloserine Additive neurotoxicity (peripheral and optic); both drugs used in MDR-TB regimens Monitor closely for neurological symptoms; pyridoxine supplementation may help; regular neurological and visual assessment

Isoniazid (standard doses) Additive risk of peripheral neuropathy; concurrent use is standard in TB treatment Pyridoxine (vitamin B6) supplementation recommended; monitor for neuropathy symptoms

Rifampicin No significant pharmacokinetic interaction; standard combination in TB treatment Routine monitoring as per TB protocols

Pyrazinamide Ethambutol and pyrazinamide both may elevate uric acid; additive hyperuricaemia Monitor for symptoms of gout; treat if symptomatic; asymptomatic hyperuricaemia usually does not require intervention

Ethionamide Additive GI intolerance and potential neurological effects Used together in MDR-TB regimens; monitor tolerability

• Visual disturbances (dose-related; occurs in 1–6% at doses ≥15 mg/kg):

• Decreased visual acuity

• Red-green colour blindness (dyschromatopsia)

• Central or peripheral scotoma

• Blurred vision

• Gastrointestinal upset (nausea, vomiting, abdominal discomfort)

• Arthralgia

• Hyperuricaemia (usually asymptomatic)

• Headache

• Dizziness

• Peripheral neuropathy (rare)

• Pruritus, rash

Adverse Effect Clinical Significance

Optic neuritis (retrobulbar neuritis) Most important toxicity; dose- and duration-dependent; typically bilateral; presents with decreased visual acuity, colour vision changes (especially red-green), central scotoma; usually reversible if detected early and drug discontinued; may be IRREVERSIBLE if treatment continued despite symptoms; requires immediate discontinuation

Irreversible blindness Rare; occurs if optic neuritis not recognized and drug continued; more likely at doses >25 mg/kg or with renal impairment

Acute gouty arthritis Due to hyperuricaemia; may require treatment with NSAIDs or colchicine; ethambutol can usually be continued if gout managed

Hypersensitivity reactions Rash, fever, eosinophilia; rare; discontinue if severe

Peripheral neuropathy Rare; usually with prolonged use or in combination with other neurotoxic drugs

Thrombocytopenia Very rare

Baseline (before initiating therapy):

• Visual acuity testing (Snellen chart)

• Colour vision testing (Ishihara plates for red-green colour discrimination)

• Dilated fundoscopy (if available, especially in elderly)

• Document any pre-existing visual abnormalities

• Renal function (serum creatinine, eGFR)

• Uric acid (optional; useful if history of gout)

After Initiation/During Treatment:

• Visual acuity and colour vision: Monthly during treatment

• Instruct patient to report any visual symptoms immediately (blurred vision, difficulty reading, colour perception changes)

• Renal function: At 1 month, then as clinically indicated

• Clinical assessment for optic neuritis at each visit

Special Populations:

• Children <5 years: Age-appropriate visual assessment; parental education about signs of visual problems (bumping into objects, behaviour changes)

• Elderly: More frequent visual monitoring (every 2–4 weeks if high-risk)

• Renal impairment: Monitor for accumulation; visual monitoring even more critical

When to Discontinue:

• Any confirmed decrease in visual acuity

• New-onset colour vision abnormality

• Visual field defects

• Patient complaints of visual symptoms

• Optic disc changes on fundoscopy

Single-drug Formulations:

• Mycobutol® (Lupin)

• Combutol® (Lupin)

• Embutol® (Macleods)

• Myambutol® (Lederle/Pfizer)

• Ebutol® (Cadila)

• Ethambuto® (various)

Fixed-Dose Combinations (FDCs) — extensively used under NTEP:

• AKT-4® (Lupin) — HRZE combination

• AKT-3® (Lupin) — HRE combination

• Forecox® (Lupin) — HRZE combination

• Fourtuf® (Macleods) — HRZE combination

• R-Cinex E® (Lupin) — HRE combination

• Paediatric dispersible FDCs (under NTEP supply)

Note: FDCs preferred over individual drugs for better compliance and reduced resistance development.

Paediatric dispersible FDC Supplied free under NTEP

• Included in NLEM 2022

• NPPA price-controlled

• Provided FREE under National Tuberculosis Elimination Programme (NTEP) through government health facilities

• Available in private market with significant price variation between brands

• Visual monitoring is non-negotiable: Baseline visual assessment (acuity + colour vision) is MANDATORY before starting ethambutol; monthly monitoring during treatment is essential; early detection prevents irreversible blindness

• Dose-dependent toxicity: Optic toxicity risk increases significantly above 15 mg/kg/day and with treatment duration >2 months; use lowest effective dose and limit duration when possible

• Renal impairment increases risk: Extend dosing interval (NOT daily dose) in renal impairment to prevent accumulation; visual monitoring even more critical in these patients

• Safe in hepatotoxicity: Ethambutol is not hepatotoxic and can be safely continued when isoniazid/rifampicin/pyrazinamide are stopped due to drug-induced liver injury

• Children can receive ethambutol: Despite historical concerns, current WHO and NTEP guidelines include ethambutol in paediatric TB regimens; enhanced visual monitoring and parental education are key

• Reversibility depends on early detection: If visual symptoms occur and ethambutol is stopped promptly, most patients recover; continued use despite symptoms leads to irreversible damage

ethambutol; tuberculosis; first-line ATT; antitubercular; optic neuritis; visual toxicity; NTEP; NLEM; pregnancy-safe; renal-adjustment; paediatric-TB

RxIndia v1.0 — 10 Jan 2025

• CDSCO approved prescribing information

• Indian Pharmacopoeia (IP)

• National Formulary of India (NFI)

• National List of Essential Medicines (NLEM 2022)

• Index TB Guidelines (NTEP India)

• ICMR Guidelines for Tuberculosis

• AIIMS TB Management Protocol

• Indian Academy of Pediatrics (IAP) Guidelines on Childhood TB

• API Textbook of Medicine

• Goodman & Gilman's The Pharmacological Basis of Therapeutics

• WHO Consolidated Guidelines on Tuberculosis