Schedule H

Oral

• Tablets: 62.5 mg, 125 mg

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Pulmonary Arterial Hypertension (PAH) — WHO Group 1

Includes idiopathic PAH, heritable PAH, and PAH associated with connective tissue disease or congenital heart disease (Eisenmenger syndrome).

Parameter Recommendation

Starting dose 62.5 mg orally twice daily

Titration Increase to 125 mg twice daily after 4 weeks if tolerated and LFTs remain acceptable

Usual maintenance dose 125 mg twice daily

Maximum dose 125 mg twice daily

Clinical Notes:

• Initiate only after PAH diagnosis confirmed via right heart catheterisation

• Clinical benefit includes improved exercise capacity (6-minute walk distance) and delayed clinical worsening

• Mandatory monthly LFT monitoring due to hepatotoxicity risk

• Do not use empirically for hypoxic or left heart disease-related pulmonary hypertension

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

Indication Dose Duration Notes

Systemic Sclerosis-Related Digital Ulcers Starting: 62.5 mg twice daily for 4 weeks, then 125 mg twice daily 6–24 months based on response OFF-LABEL; Specialist only (Rheumatology/Pulmonology); Evidence: RAPIDS-1 & RAPIDS-2 RCTs; Not CDSCO-approved for this indication

PAEDIATRIC DOSING (Specialist Only)

Primary Indications (Approved / Standard in India)

Pulmonary Arterial Hypertension in Children ≥1 Year

Use only under paediatric cardiology or pulmonology specialist supervision.

Weight-Based Dosing:

Body Weight Starting Dose Titration Maintenance Dose Maximum Dose

10–20 kg 31.25 mg twice daily After 4 weeks if tolerated 31.25–62.5 mg twice daily 62.5 mg twice daily

20–40 kg 62.5 mg twice daily After 4 weeks if tolerated 62.5 mg twice daily 125 mg twice daily

40 kg 62.5 mg twice daily After 4 weeks if tolerated 125 mg twice daily 125 mg twice daily

Clinical Notes:

• Minimum age: 1 year

• No paediatric liquid formulation available in India; tablets must be scored appropriately

• Monthly liver function tests mandatory

• Baseline haemoglobin required; monitor periodically for anaemia

Not recommended in children <1 year except under specialist supervision in tertiary centres.

Secondary Indications – Paediatrics (Off-label, if any)

Not applicable.

• No established off-label paediatric indications supported by Indian practice

Mild to moderate impairment No dose adjustment required

Severe impairment Use with caution; monitor for fluid retention

Haemodialysis Not removed by dialysis; no supplemental dosing required

Baseline ALT/AST >3× ULN Contraindicated — do not initiate

• Pregnancy (teratogenic — Category X equivalent)

• Moderate to severe hepatic impairment (Child-Pugh B or C)

• Baseline aminotransferases (ALT/AST) >3× upper limit of normal

• Concurrent use with cyclosporine A

• Concurrent use with glyburide (glibenclamide)

• Known hypersensitivity to bosentan or any excipient

• Liver enzyme elevations — requires monthly transaminase monitoring

• Pre-existing anaemia — monitor haemoglobin at baseline and periodically

• Fluid retention and peripheral oedema — dose-dependent; more common in elderly

• Women of childbearing potential — must use two reliable forms of contraception

• Potential decrease in sperm count with long-term use (reversible upon discontinuation)

• Patients with pulmonary veno-occlusive disease — may worsen pulmonary oedema

• Interstitial lung disease in connective tissue disorders — specialist supervision required

Parameter Details

Risk Category Contraindicated — highly teratogenic (Category X equivalent)

Known Risks Craniofacial malformations, cardiovascular defects, and other congenital anomalies

Pre-treatment Requirement Exclude pregnancy before initiation; monthly pregnancy testing mandatory

Contraception Two reliable methods required throughout treatment and for 1 month after discontinuation

Preferred Alternatives Sildenafil (with obstetric and pulmonology input) if PAH treatment essential during pregnancy

If Pregnancy Occurs Discontinue immediately; urgent specialist referral

Parameter Details

Compatibility Not recommended during breastfeeding

Drug Levels in Milk Excreted in animal milk; human data not available

Preferred Alternatives Sildenafil (limited safety data but more accepted in PAH during lactation)

Recommendation Avoid breastfeeding during treatment and for 1 month after discontinuation

Infant Monitoring If inadvertent exposure, monitor for poor feeding, lethargy, hepatic dysfunction

Parameter Recommendation

Starting dose 62.5 mg twice daily

Titration Slower titration recommended; reassess at 4–6 weeks

Special Risks Increased risk of peripheral oedema, hypotension, and falls; reduced hepatic reserve

Monitoring Close monitoring of LFTs, haemoglobin, blood pressure, and weight

Interacting Drug Mechanism / Effect Recommendation

Cyclosporine A OATP inhibition → marked increase in bosentan plasma levels Contraindicated

Glyburide (Glibenclamide) Increased risk of hepatotoxicity; reduced efficacy of both drugs Contraindicated

Hormonal contraceptives Bosentan induces CYP3A4 → reduced contraceptive efficacy Not reliable as sole method; use additional barrier contraception

Strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir) Increased bosentan exposure Avoid or use with extreme caution

Tacrolimus Increased tacrolimus and bosentan levels Avoid combination

Interacting Drug Mechanism / Effect Recommendation

Warfarin Bosentan induces CYP metabolism → reduced warfarin levels Monitor INR closely; dose adjustment may be needed

Sildenafil Mutual interaction — bosentan decreases sildenafil levels; sildenafil increases bosentan levels Use under PAH specialist supervision; dose adjustments may be necessary

Rifampicin Strong CYP3A4 induction → reduced bosentan efficacy Avoid if possible; monitor for therapeutic failure

Simvastatin / Atorvastatin Bosentan induces statin metabolism → reduced statin levels Monitor lipid control; consider alternative statins or dose adjustment

Lopinavir/Ritonavir Complex interaction affecting both drug levels Close monitoring; specialist guidance required

• Headache

• Flushing

• Peripheral oedema (dose-dependent)

• Nasopharyngitis / Upper respiratory tract symptoms

• Elevated liver transaminases (ALT/AST)

• Anaemia (haemoglobin reduction)

• Hypotension

• Palpitations

• Dyspepsia

Adverse Effect Clinical Action

Hepatotoxicity (ALT/AST >3× ULN) Recheck LFTs; consider dose reduction or discontinuation; may be dose-dependent and reversible

Severe anaemia (Hb drop >2 g/dL) Investigate cause; consider dose reduction or transfusion support

Hypersensitivity reactions (rash, angioedema) Discontinue immediately; supportive management

Teratogenicity Immediate discontinuation if pregnancy detected

Pulmonary oedema (in pulmonary veno-occlusive disease) Discontinue; specialist review urgently

Monthly LFTs; pregnancy test in women of childbearing potential

Every 3 months Haemoglobin, clinical assessment (6-minute walk distance, functional class, weight, oedema)

Long-term Periodic echocardiography; right heart catheterisation as clinically indicated

LFT Management Algorithm:

• ALT/AST 3–5× ULN: Confirm with repeat test; reduce dose or interrupt; monitor every 2 weeks

• ALT/AST 5–8× ULN: Stop treatment; monitor until normalised; may rechallenge at lower dose under close supervision

• ALT/AST >8× ULN: Discontinue permanently

• Tracleer (Actelion/Janssen) — Originator brand

• Bosentas (Cipla)

• Pulmonext (Sun Pharma)

• Bosen (Zydus)

• Lupibose (Lupin)

• Bonstan (Various generics)

62.5 mg tablet ₹75–₹120

• Not included in NLEM; pricing not NPPA-controlled

• Significant cost variation between originator and generic brands

• Government supply availability limited

• Always confirm PAH diagnosis with right heart catheterisation before initiating bosentan — empiric use for other forms of pulmonary hypertension is inappropriate

• Baseline LFTs and pregnancy test are mandatory before starting therapy; never skip monthly LFT monitoring

• Peripheral oedema is dose-limiting in some patients, especially the elderly — consider slower titration or diuretic support

• Hormonal contraception alone is unreliable with bosentan — always advise dual contraception methods

• When combining with sildenafil (common in PAH), be aware of pharmacokinetic interactions — specialist supervision required

• In connective tissue disease-associated PAH (especially systemic sclerosis with ILD), use cautiously as bosentan may worsen interstitial lung disease

Bosentan; pulmonary arterial hypertension; PAH; endothelin receptor antagonist; hepatotoxicity; pregnancy-contraindicated; teratogenic; specialist-only; CYP3A4 inducer; Schedule H

RxIndia v1.0 — 01 Apr 2025

• CDSCO approved product information

• Indian Pharmacopoeia (IP)

• API Textbook of Medicine — Pulmonary Hypertension chapter

• AIIMS Pulmonary Medicine and Cardiology Treatment Protocols

• Goodman & Gilman's: The Pharmacological Basis of Therapeutics

• Harrison's Principles of Internal Medicine

• RAPIDS-1 & RAPIDS-2 Trials (for off-label digital ulcer indication)

• BREATHE-1 Trial (supportive evidence for PAH)

• Indian hospital protocols (AIIMS, PGIMER)