Bosentan Monohydrate

Approved Indications:

• Pulmonary Arterial Hypertension (PAH):
• WHO Group 1 PAH (idiopathic or heritable, or associated with connective tissue disorders or congenital systemic-to-pulmonary shunts).
• Improves exercise capacity and delays clinical worsening in functional class II-IV patients.

Pediatric Indication:

• Approved for use in children aged ≥3 years with PAH to improve pulmonary hemodynamics and exercise capacity.

Off-label/Clinically Accepted Uses:

• Systemic sclerosis-related digital ulcers (to reduce new ulcer formation).
• Chronic thromboembolic pulmonary hypertension (CTEPH) (investigational use, not universally recommended).
• Raynaud’s phenomenon (off-label, limited evidence).

Adults (≥12 years):

• Initial dose: 62.5 mg orally twice daily for 4 weeks.
• Maintenance dose: Increase to 125 mg orally twice daily thereafter.

Children (≥3 years):

• Dose depends on body weight:
• <10 kg: 10 mg twice daily.
• 10–20 kg: 31.25 mg twice daily.
• >20–40 kg: 62.5 mg twice daily.
• >40 kg: Same as adult dosing.

Special Populations:

• Hepatic Impairment:
• Contraindicated in moderate to severe impairment (Child-Pugh B or C).
• Use with extreme caution in mild impairment.
• Renal Impairment:
• No dosage adjustment needed; monitor for fluid retention.
• Elderly:
• No dosage adjustment, but monitor liver function and hemoglobin closely.

Administration:

• Oral use only.
• May be taken with or without food.
• Tablets should be swallowed whole.

Bosentan is a dual endothelin receptor antagonist (ETA and ETB). It competitively inhibits the binding of endothelin-1 (ET-1), a potent vasoconstrictor and smooth muscle mitogen, to ETA and ETB receptors on vascular endothelium and smooth muscle cells. By blocking these receptors, Bosentan causes vasodilation of pulmonary arteries, reduces vascular resistance, and slows disease progression in PAH.

• Absorption: Oral bioavailability is approximately 50%. Peak plasma concentration occurs in 3–5 hours.
• Distribution: Highly bound to plasma proteins (>98%). Volume of distribution ~18 L.
• Metabolism: Extensively metabolized by CYP3A4 and CYP2C9 in the liver. Forms three metabolites; one is pharmacologically active.
• Elimination: Primarily excreted in bile after hepatic metabolism. Only ~3% excreted in urine.
• Half-life: Terminal half-life is about 5 hours.

• Pregnancy Category X (FDA):
• Teratogenic in animals; contraindicated in pregnancy. Effective contraception required during treatment.
• Lactation:
• Unknown whether excreted in human milk.
• Avoid use while breastfeeding due to potential adverse effects in the infant.
• Contraceptive Note:
• Reduces efficacy of hormonal contraceptives—recommend barrier methods or dual contraception.

• Primary Class: Endothelin Receptor Antagonist (ERA)
• Subclass: Dual ETA/ETB receptor antagonist

• Known hypersensitivity to Bosentan or its components.
• Pregnancy.
• Moderate to severe hepatic impairment (Child-Pugh B or C).
• Concomitant use with cyclosporine A.
• Elevated liver aminotransferases (>3× ULN) at baseline.

• Hepatotoxicity: Monitor ALT/AST monthly. Interrupt therapy if levels >3× ULN with symptoms.
• Anemia: Monitor hemoglobin regularly, especially during the first few months.
• Fluid Retention: Risk of worsening heart failure—monitor for signs of edema.
• Teratogenicity: Mandatory monthly pregnancy tests during treatment.
• Pulmonary Veno-Occlusive Disease (PVOD): Use with caution; may worsen symptoms.
• Decreased Sperm Counts: Reported in males; fertility impact uncertain.

Common:

• Hematologic: Anemia, decreased hemoglobin
• Hepatic: Elevated liver enzymes
• Cardiovascular: Peripheral edema, hypotension
• Respiratory: Nasopharyngitis
• Gastrointestinal: Nausea, vomiting

Serious:

• Hepatotoxicity
• Teratogenicity
• Severe anemia
• Hypersensitivity reactions (rare)

Rare:

• Infertility in males (due to impaired spermatogenesis)
• Liver failure (extremely rare)

• Cyclosporine A: Contraindicated; significantly increases bosentan levels.
• Rifampin: Strong CYP3A4 inducer; increases bosentan metabolism (use with caution).
• Hormonal contraceptives: Reduced efficacy; avoid as sole method.
• Warfarin: Possible INR reduction; monitor closely.
• Glyburide: Increased liver enzyme elevation risk; avoid combination.
• CYP3A4/CYP2C9 inhibitors (e.g., ketoconazole): May increase bosentan exposure.

• Updated EMA and FDA guidelines reinforce monthly liver function and pregnancy testing.
• EMA added stronger warnings on male infertility and emphasized risk mitigation programs for pregnancy prevention.
• Pediatric dosing has been clarified and included in newer PAH treatment algorithms.
• Ongoing studies assess long-term use in systemic sclerosis and Raynaud’s disease.

• Temperature: Store below 30°C.
• Humidity & Light: Protect from moisture and direct light.
• Handling: Keep in original packaging until use. Do not crush or split tablets.
• Special Instructions: No refrigeration required. Follow expiration date strictly.