Macitentan

Macitentan is an oral dual endothelin receptor antagonist given once daily for pulmonary arterial hypertension (group 1) and chronic thromboembolic pulmonary hypertension in some regions. Start only in a PAH centre after right heart catheterisation.

Classification. Endothelin receptor antagonist, dual ETA and ETB.

Mechanism. Blocks endothelin-1 at both receptors, with sustained receptor binding and good tissue penetration.

Pharmacokinetics. Half-life about 16 hours. Metabolised by CYP3A4 to an active metabolite with a half-life of about 48 hours. Excreted in urine and faeces.

Specialist, PAH, adults. 10 mg once daily. No titration. Maximum 10 mg daily.

Fixed combination. Macitentan 10 mg with tadalafil 40 mg in one tablet once daily, where licensed.

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

Emergency. Not used.

Titration and loading. None.

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

Contraindications. Pregnancy, hypersensitivity.

Serious adverse effects. Anaemia, liver enzyme rise, fluid retention and heart failure, decreased sperm count, hypotension, hypersensitivity.

Common adverse effects. Nasopharyngitis, headache, anaemia, bronchitis, urinary tract infection, oedema.

Interactions. Strong CYP3A4 inducers including rifampicin lower exposure by about 80%; avoid. Strong CYP3A4 inhibitors (ketoconazole, ritonavir) roughly double exposure; avoid or use only with specialist advice.

Common prescribing errors. Missing monthly pregnancy tests. Giving with rifampicin. Using for pulmonary hypertension from left heart or lung disease.

Special groups.

• Pregnancy: contraindicated. Breastfeeding: avoid.

• Older adults: no adjustment.

• Kidney impairment: no adjustment. Liver impairment: no adjustment in mild to moderate; not advised in severe.

• East Africa: rifampicin-containing tuberculosis regimens and ritonavir-boosted antiretroviral regimens are the key interactions, and they may make macitentan unsuitable. Availability is limited.

Formulations. Tablets 10 mg; fixed-dose combination with tadalafil; dispersible tablets in some regions.

Administration. Once daily with or without food.

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

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

Stop and reduce rules. Stop for ALT or AST over 5 times the upper limit of normal, symptoms of liver injury, or severe anaemia. Reduce or stop for fluid retention with heart failure. Therapeutic drug monitoring is not used.

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