Schedule H

Oral

• Tablets: 5 mg, 10 mg

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Pulmonary Arterial Hypertension (PAH) — WHO Group 1 (Functional Class II–III)

Parameter Recommendation

Starting dose 5 mg orally once daily

Titration May increase to 10 mg once daily after ≥4 weeks if tolerated and clinically indicated

Usual maintenance dose 5–10 mg once daily

Maximum dose 10 mg once daily

Clinical notes:

• Indicated for idiopathic PAH, heritable PAH, and PAH associated with connective tissue disease

• Can be used as monotherapy or in combination with PDE-5 inhibitors (e.g., sildenafil, tadalafil)

• Demonstrated improvement in 6-minute walk distance and WHO functional class

• Administer once daily without regard to food; do not crush or split tablets

• Response assessment typically at 3–6 months using clinical parameters and functional testing

Secondary Indications — Adults Only (Off-label)

Not applicable. No documented off-label indications in Indian practice.

PAEDIATRIC DOSING (Specialist Only)

Primary Indications (Approved / Standard in India)

Not applicable. Ambrisentan is not approved for paediatric use in India.

Secondary Indications — Paediatric Doses (Off-label)

Indication Dose Duration Evidence Basis Notes

Pulmonary Arterial Hypertension 0.1–0.2 mg/kg once daily (maximum 5 mg/day initially; may increase to 10 mg/day in older children) Long-term Limited international RCTs and case series; specialist centres only OFF-LABEL; Specialist only

Clinical notes:

• Use only in tertiary centres with expertise in paediatric PAH management

• Not recommended below 8 years of age except under specialist supervision with documented justification

• Monitor liver function tests, haemoglobin, and clinical response closely

• Ensure pregnancy prevention counselling in post-pubertal females

• Monthly pregnancy testing mandatory in females of childbearing potential

• No dose adjustment required in mild, moderate, or severe renal impairment

• Use with caution in patients with pre-existing fluid retention or heart failure

• No significant removal by haemodialysis

Additional notes:

• Do not initiate if baseline ALT or AST >3× upper limit of normal (ULN)

• Discontinue if aminotransferases rise to >5× ULN or if clinical symptoms of hepatic injury develop

• Pregnancy — absolute contraindication (documented teratogenicity)

• Known hypersensitivity to ambrisentan or any excipient

• Severe hepatic impairment

• Baseline aminotransferases (ALT/AST) >3× ULN

• Idiopathic pulmonary fibrosis (IPF) — with or without secondary pulmonary hypertension (ARTEMIS trial demonstrated harm)

• Concomitant use with cyclosporine A (significantly increases ambrisentan exposure)

• Pre-existing hepatic dysfunction — monitor liver enzymes closely

• Anaemia — check baseline haemoglobin; may cause dose-related decrease in haemoglobin

• Fluid retention and peripheral oedema — particularly in patients with underlying cardiac or renal comorbidities

• Heart failure — may worsen fluid status

• Women of childbearing potential — ensure effective contraception and monthly pregnancy testing

• Concomitant use with strong CYP3A4 inhibitors or inducers — may alter drug levels

Aspect Recommendation

Overall safety Contraindicated — known teratogen (Category X equivalent)

Risk Animal studies demonstrate skeletal, cardiovascular, and craniofacial abnormalities

Preferred alternatives Sildenafil or tadalafil may be considered under specialist supervision; supportive care

Contraception requirements Two reliable methods of contraception required (one hormonal + one barrier, or IUD)

Pregnancy testing Monthly pregnancy testing mandatory before dispensing

If pregnancy occurs Discontinue immediately; urgent specialist referral

Aspect Recommendation

Compatibility Not recommended — advise against breastfeeding

Expected drug levels in milk Unknown; no human data available

Preferred alternatives Sildenafil has more established safety profile in lactation

Monitoring in infant Not applicable — avoid use during breastfeeding

• Starting dose: 5 mg once daily

• Titration: Slower titration recommended; increase to 10 mg only after careful assessment of tolerability

• Risks: Higher incidence of peripheral oedema, anaemia, and hypotension observed in elderly patients

• Monitoring: Close monitoring for volume overload, hepatic function, and haemoglobin essential

• No specific dose adjustment required based on age alone

Interacting Drug Effect / Risk Recommendation

Cyclosporine A Increases ambrisentan exposure approximately 2-fold via OATP inhibition Contraindicated — avoid concomitant use

Rifampicin May significantly reduce ambrisentan plasma levels via CYP3A4 and UGT enzyme induction Avoid if possible; if essential, monitor clinical response closely

Strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir) May increase ambrisentan exposure Monitor for adverse effects; dose adjustment may be needed

Interacting Drug Effect / Risk Recommendation

Warfarin No significant pharmacokinetic interaction; theoretical overlap in hepatic metabolism Monitor INR during initiation and dose changes

Oral contraceptives No clinically significant interaction; teratogenicity mandates strict contraception Use dual contraception methods — not sole reliance on oral contraceptives

PDE-5 inhibitors (sildenafil, tadalafil) Additive vasodilatory effects; combination improves PAH outcomes Combination permitted and often beneficial; monitor blood pressure

Digoxin Minimal interaction expected No dose adjustment; routine monitoring

• Peripheral oedema (most common, dose-related)

• Nasal congestion and sinusitis

• Headache

• Flushing

• Palpitations

• Anaemia (decrease in haemoglobin typically within first few weeks)

• Nausea

• Dizziness

Adverse Effect Clinical Note

Hepatotoxicity Elevated aminotransferases; discontinue if ALT/AST >5× ULN or symptomatic hepatic injury develops

Severe anaemia May require transfusion; assess for occult blood loss or haemolysis before attributing to drug

Fluid retention / Heart failure exacerbation May require diuretic adjustment or drug discontinuation

Hypotension Particularly when combined with other vasodilators

Teratogenicity Absolute contraindication in pregnancy; causes fetal harm

Phase Parameters

Baseline Liver function tests (ALT, AST, bilirubin), haemoglobin/haematocrit, pregnancy test (all women of childbearing potential), clinical assessment including functional class

Monthly (initial 3 months) Pregnancy test (mandatory), liver function tests, haemoglobin

Ongoing (every 3 months) Liver function tests, haemoglobin, clinical assessment

Long-term (every 6 months) 6-minute walk test, echocardiography, NT-proBNP as clinically indicated

• Volibris (GlaxoSmithKline)

• Endobloc (Cipla)

• Ambrican (Zydus Cadila)

• Ambripar (Panacea Biotec)

Note: Not currently under NPPA price control; not listed in NLEM. Available primarily through specialty procurement in tertiary care centres and select cardiology/pulmonology departments.

• Ambrisentan has a more favourable hepatic safety profile compared to bosentan, with lower incidence of aminotransferase elevations — however, liver monitoring remains mandatory

• Peripheral oedema is the most common adverse effect and is dose-related; manage with diuretics if needed rather than discontinuing therapy

• Always enrol patients in a comprehensive monitoring programme including monthly pregnancy testing, liver function assessment, and haemoglobin monitoring

• Combination therapy with PDE-5 inhibitors (sildenafil/tadalafil) is often used in practice for enhanced efficacy — AMBITION trial demonstrated superiority of upfront combination

• If anaemia develops, investigate for gastrointestinal blood loss or haemolysis before attributing solely to ambrisentan

• Avoid in idiopathic pulmonary fibrosis with or without pulmonary hypertension — ARTEMIS trial showed increased hospitalisation and disease progression

Ambrisentan; pulmonary arterial hypertension; PAH; endothelin receptor antagonist; teratogenic; pregnancy-contraindicated; hepatotoxicity; anaemia; specialist-only

RxIndia v1.0 — 05 Jun 2025

• CDSCO product insert — Volibris (GlaxoSmithKline)

• Indian Pharmacopoeia / National Formulary of India

• API Textbook of Medicine — Pulmonary Hypertension chapter

• AIIMS Pharmacology essential drug list

• Harrison's Principles of Internal Medicine — PAH management

• Goodman & Gilman's The Pharmacological Basis of Therapeutics

• AMBITION trial (for combination therapy evidence)

• ARTEMIS trial (for IPF contraindication evidence)