Ambrisentan

Ambrisentan is an oral, ETA-selective endothelin receptor antagonist for pulmonary arterial hypertension (group 1), usually combined with tadalafil. It is contraindicated in idiopathic pulmonary fibrosis. Start only in a PAH centre after right heart catheterisation.

Classification. Endothelin receptor antagonist, selective for ETA.

Mechanism. Blocks the ETA receptor, reducing vasoconstriction and smooth muscle proliferation while preserving ETB-mediated vasodilatation and clearance of endothelin.

Pharmacokinetics. Rapid absorption. Highly protein bound. Half-life about 15 hours. Metabolised by glucuronidation, with minor CYP3A4 and CYP2C19 contribution. Biliary excretion.

Specialist, PAH, adults. 5 mg once daily. Increase to 10 mg once daily after at least 4 weeks if tolerated. Maximum 10 mg daily.

Initial combination. Ambrisentan 5 mg once daily with tadalafil 20 mg once daily. Raise tadalafil to 40 mg once daily after 4 weeks, and ambrisentan to 10 mg after a further period if tolerated.

With ciclosporin. Limit ambrisentan to 5 mg once daily.

Children. Weight-banded dosing under a paediatric specialist; label values are not stated here with confidence.

Emergency. Not used.

Titration. One step only, from 5 mg to 10 mg, after 4 weeks. No loading dose.

Boxed-warning-level risk. Embryo-foetal toxicity. Contraindicated in pregnancy. Exclude pregnancy before starting and each month. Reliable contraception is needed throughout treatment and for 1 month after.

Contraindications. Pregnancy, idiopathic pulmonary fibrosis, severe liver impairment, hypersensitivity.

Serious adverse effects. Fluid retention and heart failure, anaemia, liver enzyme rises (uncommon), pulmonary veno-occlusive disease with pulmonary oedema, hypersensitivity.

Common adverse effects. Peripheral oedema, headache, nasal congestion, flushing, palpitations, anaemia.

Interactions. Ciclosporin raises ambrisentan exposure: limit to 5 mg daily. Rifampicin may transiently lower exposure at the start of treatment. No important interaction with hormonal contraceptives, but reliable contraception is still needed.

Common prescribing errors. Using in pulmonary hypertension from lung disease or fibrosis. Not repeating pregnancy tests. Using 10 mg with ciclosporin.

Special groups.

• Pregnancy: contraindicated. Breastfeeding: avoid.

• Older adults: no adjustment.

• Kidney impairment: no adjustment for mild to moderate; limited data when GFR is under 30 mL/min. Liver impairment: avoid in severe impairment.

• East Africa: use only when schistosomiasis-related or HIV-related PAH has been confirmed as group 1 disease. Rifampicin regimens call for specialist review.

Formulations. Tablets 5 mg and 10 mg, swallowed whole.

Administration. Once daily with or without food.

Baseline. ALT, AST, bilirubin, haemoglobin, pregnancy test, right heart catheter results, functional class, 6 minute walk distance, NT-proBNP.

Monitoring. Pregnancy test monthly. Haemoglobin at 1 month and then periodically. Liver tests at baseline and when clinically indicated. Weight and oedema at each visit. Clinical review every 3 to 6 months.

Stop and reduce rules. Stop for ALT or AST over 5 times the upper limit of normal, or symptoms of liver injury. Reduce or stop for severe anaemia or heart failure. Stop if pulmonary oedema suggests veno-occlusive disease. Therapeutic drug monitoring is not used.

Referral and escalation. Manage in a PAH centre. Refer urgently for right heart failure or syncope.