Bosentan

Bosentan is an oral dual endothelin receptor antagonist used for pulmonary arterial hypertension (PAH, group 1) and for prevention of new digital ulcers in systemic sclerosis. It must only be started in a PAH centre after right heart catheterisation has confirmed the diagnosis. It is not for pulmonary hypertension from left heart disease or chronic lung disease.

Classification. Endothelin receptor antagonist, dual ETA and ETB.

Mechanism. Blocks endothelin-1 at both receptor subtypes, reducing pulmonary vasoconstriction and vascular remodelling.

Pharmacokinetics. Bioavailability about 50%. Highly protein bound. Metabolised by CYP2C9 and CYP3A4 and induces both enzymes. Half-life about 5 hours. Biliary excretion.

Specialist, PAH, adults. 62.5 mg twice daily for 4 weeks, then 125 mg twice daily. Maximum 125 mg twice daily; higher doses add liver injury without more benefit. For body weight under 40 kg, the maintenance dose is 62.5 mg twice daily.

Specialist, digital ulcers in systemic sclerosis, adults. 62.5 mg twice daily for 4 weeks, then 125 mg twice daily. Review need at 6 months or earlier.

Children from 1 year with PAH. 2 mg/kg twice daily using dispersible tablets, under a paediatric specialist, with weight-banded dosing in the label.

Combination. Often combined with a phosphodiesterase-5 inhibitor. Sildenafil levels fall and bosentan levels rise slightly with the pair.

Emergency. Not used.

Titration. One step only, from 62.5 mg to 125 mg after 4 weeks if liver enzymes are acceptable. No loading dose.

Boxed-warning-level risks. Hepatotoxicity (dose-dependent rises in ALT and AST, rare liver failure) and embryo-foetal toxicity. Pregnancy must be excluded before starting, then monthly. Women of childbearing potential need two reliable contraceptive methods, because bosentan reduces hormonal contraceptive levels. Male fertility and sperm counts may fall.

Contraindications. Pregnancy, moderate or severe liver impairment, baseline ALT or AST over 3 times the upper limit of normal, ciclosporin, glibenclamide, hypersensitivity.

Serious adverse effects. Liver injury, anaemia (haemoglobin fall), fluid retention and heart failure, thrombocytopenia, hypersensitivity.

Common adverse effects. Headache, flushing, oedema, nasal congestion, nasopharyngitis, anaemia.

Interactions.

• Contraindicated: ciclosporin and glibenclamide.

• Levels of bosentan rise with ketoconazole, itraconazole, fluconazole and ritonavir or lopinavir. If starting on ritonavir for over 10 days, begin at 62.5 mg once daily or every other day.

• Levels of bosentan fall with rifampicin.

• Bosentan lowers levels of sildenafil, simvastatin, warfarin and hormonal contraceptives.

Common prescribing errors. Not repeating pregnancy tests monthly. Relying on hormonal contraception alone. Skipping liver tests. Starting 125 mg twice daily without the 4 week lead-in. Missing the ritonavir adjustment.

Special groups.

• Pregnancy: contraindicated. Breastfeeding: avoid.

• Children: weight-banded dosing; specialist only.

• Older adults: no adjustment.

• Kidney impairment: no adjustment. Dialysis: no adjustment. Liver impairment: contraindicated in moderate to severe disease.

• East Africa: PAH from schistosomiasis and HIV occurs. Rifampicin in tuberculosis regimens and ritonavir-boosted antiretroviral regimens both change bosentan exposure and need planning with a specialist.

Formulations. Tablets 62.5 mg and 125 mg, dispersible tablets 32 mg.

Administration. Morning and evening, with or without food.

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

Monitoring. ALT, AST and bilirubin monthly. Haemoglobin monthly for 4 months and then every 3 months. Pregnancy test monthly in women of childbearing potential. Review clinical response every 3 to 6 months.

Stop and reduce rules.

• ALT or AST over 3 and up to 5 times the upper limit of normal: confirm, then reduce the dose or interrupt, and monitor at least every 2 weeks.

• Over 5 and up to 8 times: stop, monitor at least every 2 weeks and restart only when back at baseline.

• Over 8 times: stop and do not restart.

• Bilirubin over 2 times the upper limit of normal, or symptoms of liver injury: stop.

• Therapeutic drug monitoring is not used.

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