Bosentan

Bosentan is a dual endothelin receptor antagonist (ERA) with affinity for both ETA and ETB receptors. Endothelin-1 (ET-1) is one of the most potent vasoconstrictors known and can also promote fibrosis, cell proliferation, cardiac hypertrophy and remodelling, and is pro-inflammatory. These effects are mediated by endothelin binding to ETA and ETB receptors located in the endothelium and vascular smooth muscle cells.

Bosentan decreases both pulmonary and systemic vascular resistance resulting in increased cardiac output without increasing heart rate. It improves exercise capacity and symptoms in patients with WHO functional class III PAH; improvements have also been shown in WHO class II patients.

• Pulmonary arterial hypertension (PAH) - WHO functional class II and III

Adults (>12 years, >40 kg):
First 4 weeks: 62.5 mg twice daily
Maintenance dose: 125 mg twice daily

Children (≥2 years): 2 mg/kg twice daily (optimal maintenance dose not established in controlled studies)

Elderly (≥65 years): No dose adjustment needed

Hepatic impairment: Mild (Child-Pugh A): No dose adjustment; Moderate-severe (Child-Pugh B/C): Contraindicated

Renal impairment: No dose adjustment needed; dialysis patients also require no adjustment

Discontinuation: Do not stop abruptly (withdraw gradually over 3-7 days by reducing to half the dose to minimize risk of clinical deterioration)

Common side effects:
Headache, ankle swelling (edema), diarrhea, anemia (hemoglobin decrease), respiratory tract infection.

Hepatic: Dose-dependent elevations in liver aminotransferases, hepatitis, jaundice, rare cases of liver cirrhosis and liver failure.

Other: Thrombocytopenia, neutropenia, leukopenia, hypersensitivity reactions, syncope, palpitations, flushing, hypotension, gastroesophageal reflux disease, erythema.

• Liver aminotransferases (AST/ALT) must be measured prior to initiation and monthly during treatment; measure 2 weeks after any dose increase.
• Monitor hemoglobin for anemia.
• Do not stop abruptly (withdraw gradually over 3-7 days by reducing to half the dose to minimize risk of clinical deterioration).
• Consider discontinuation if pulmonary edema occurs.
• Highly unsafe during pregnancy (Category X); women of reproductive potential must use reliable contraception during and for 1 month after stopping treatment.
• May cause dizziness; know your response before driving or operating machinery.
• Inform your doctor if you notice yellowing of skin/eyes, dark urine, stomach pain, weight gain, swelling of arms/legs, or difficulty breathing.

• Hypersensitivity to bosentan or any excipient
• Moderate to severe hepatic impairment (Child-Pugh class B or C)
• Baseline AST/ALT >3 times upper limit of normal
• Concomitant use of cyclosporine A
• Pregnancy

• CYP3A4 inhibitors (ketoconazole, ritonavir, diltiazem): Increase bosentan levels.
• CYP2C9 inhibitors (amiodarone, fluconazole): Increase bosentan levels.
• Tacrolimus: Increases bosentan levels.
• Rifampicin: Initially increases, then decreases bosentan concentration.
• Warfarin, statins (simvastatin, lovastatin), hormonal contraceptives, sildenafil, tadalafil: Plasma levels may be decreased.
• Glibenclamide: Increased risk of hepatotoxicity (potentially fatal).
• Cyclosporine: Markedly increases bosentan concentration (contraindicated).