What is the recommended dosage of bosentan (Endothelin Receptor Antagonist) for Pulmonary Arterial Hypertension (PAH)?

Recommended Dosage of Bosentan in Pulmonary Arterial Hypertension (PAH)

For adult patients with PAH, bosentan should be initiated at 62.5 mg twice daily for 4 weeks, then increased to the target maintenance dose of 125 mg twice daily. 1

Dosing Algorithm

Adult Dosing

• Initial dose: 62.5 mg twice daily for 4 weeks
• Maintenance dose: 125 mg twice daily
• The 250 mg twice daily dose showed slightly better improvement in 6-minute walk distance compared to 125 mg twice daily (+54m vs +35m) 1, but has higher risk of liver enzyme elevations

Pediatric Dosing

• For children ≥2 years of age:
  • Weight <30 kg: 4 mg/kg twice daily using dispersible formulation 2
  • Weight 10-20 kg: 31.25 mg twice daily
  • Weight >20-40 kg: 62.5 mg twice daily
  • Weight >40 kg: 125 mg twice daily (adult dose) 2

Efficacy Evidence

Bosentan has demonstrated significant clinical benefits in PAH patients:

• Improves exercise capacity with a placebo-corrected increase in 6-minute walk distance of 44-76 meters 1
• Improves cardiopulmonary hemodynamics including:
  • Decreased pulmonary vascular resistance
  • Decreased mean pulmonary arterial pressure
  • Improved cardiac index by 1.0 L/min/m² 1
• Improves functional class in many patients 1
• Long-term treatment (>1 year) maintains improvement in walk distance and functional class 1

Monitoring Requirements

• Liver function tests:

  • Before starting treatment
  • Monthly during treatment (required by FDA and EMEA) 1, 3
  • Elevations in hepatic aminotransferases occur in approximately 10% of patients and are dose-dependent 1

• Hemoglobin/hematocrit:

  • Regular monitoring recommended
  • Bosentan may cause mild anemia 1, 3

• Pregnancy testing:

  • Regular testing in women of childbearing age due to teratogenic potential 1

Important Precautions

• Hepatic impairment:

  • Avoid in moderate to severe hepatic impairment (Child-Pugh class B or C) 4
  • No dosage adjustment needed for mild hepatic impairment (Child-Pugh class A) 4

• Contraception:

  • Hormonal contraceptives alone are not sufficient due to decreased efficacy with bosentan
  • Double-barrier methods recommended (condom plus diaphragm with spermicide) 1

• Drug interactions:

  • Contraindicated with cyclosporine 1, 4
  • Not recommended with glibenclamide (glyburide) 1, 4
  • May reduce efficacy of warfarin and other CYP2C9/3A4 substrates 4

Special Populations

• Renal impairment: No dosage adjustment needed for severe renal impairment (CrCl 15-30 mL/min) 4
• Elderly: No specific dosage adjustment based on age 4
• Gender/ethnicity: No dosage adjustment needed 4

Common Side Effects

• Headache
• Peripheral edema
• Flushing
• Nasal congestion
• Dizziness
• Liver function abnormalities
• Anemia 4

Bosentan's efficacy has been demonstrated across various PAH etiologies, including idiopathic PAH, PAH associated with connective tissue disease, and PAH associated with congenital heart defects 5, 6. The recommended dosing regimen balances efficacy with the risk of adverse effects, particularly hepatotoxicity.