Comprehensive Guide to Bosentan: Uses, Dosage, Side Effects, and More

What is Bosentan?

Overview of Bosentan

Generic Name: Bosentan

Brand Name: Tracleer, generics

Drug Group: Endothelin receptor antagonist

Commonly Used For

• Treat pulmonary arterial hypertension (PAH).
• Manage digital ulcers in systemic sclerosis.
• Improve exercise tolerance in heart failure.

Key Characteristics

Form: Oral tablets (62.5 mg, 125 mg) (detailed in Dosage section).

Mechanism: Dual antagonist of endothelin A and B receptors.

Approval: FDA-approved (2001) and EMA-approved for PAH.

Indications and Uses of Bosentan

Bosentan is indicated for specific cardiovascular and connective tissue conditions, leveraging its vasodilatory properties:

Pulmonary Arterial Hypertension (PAH): Treats WHO Group I PAH (e.g., idiopathic, associated with scleroderma) to improve exercise capacity and delay clinical worsening, suitable for functional Class II–IV patients.

Exercise Capacity Improvement: Enhances 6-minute walk distance in PAH, reducing dyspnea and fatigue, often combined with other therapies.

Digital Ulcers in Systemic Sclerosis: Reduces the number and severity of digital ulcers in systemic sclerosis patients, improving hand function and quality of life.

Congenital Heart Disease: Used off-label to manage PAH in Eisenmenger syndrome, stabilizing hemodynamics under cardiology supervision.

Off-Label Uses: Includes treatment of portopulmonary hypertension to reduce portal vein pressure, management of chronic thromboembolic pulmonary hypertension (CTEPH) as an adjunct, and palliation of Raynaud’s phenomenon in severe cases, supported by clinical studies and expert consensus.

Right Heart Failure: Adjunctive therapy in right ventricular failure secondary to PAH, improving cardiac output, based on hemodynamic data.

Pre-Capillary Pulmonary Hypertension: Off-label use in rare pre-capillary forms to reduce pulmonary pressure, under specialist care.

Dosage of Bosentan

Dosage for Adults

Pulmonary Arterial Hypertension (PAH):

• Initial: 62.5 mg twice daily for 4 weeks, increased to 125 mg twice daily (max 250 mg/day) based on tolerance.
• Severe PAH (WHO Class IV): Start at 31.25 mg twice daily, titrate to 62.5 mg if tolerated.

Digital Ulcers in Systemic Sclerosis: 62.5 mg twice daily for 4 weeks, then 125 mg twice daily, continued for 6–12 months or until ulcer healing.

Off-Label (Raynaud’s Phenomenon): 62.5 mg once daily, increased to 125 mg/day if vasospasm persists, under rheumatologist supervision.

Combination Therapy: 62.5 mg twice daily with sildenafil (20 mg thrice daily) for PAH, adjusting based on pulmonary pressure response.

Pediatric Use (PAH): 2 mg/kg twice daily (max 125 mg/dose), titrated over 4 weeks, under pediatric cardiology care.

Dosage for Children

PAH (2–12 years): 2 mg/kg twice daily, max 4 mg/kg or 125 mg/dose, adjusted for weight and liver function.

Adolescents (12–18 years): Same as adults, starting at 31.25–62.5 mg twice daily.

Special Consideration: Monitor growth and liver enzymes closely in long-term use.

Dosage for Pregnant Women

Dosage Adjustments

Renal Impairment: No adjustment needed (minimal renal excretion), but monitor for fluid retention.

Hepatic Impairment: Reduce to 62.5 mg once daily in mild-moderate impairment; avoid in severe liver disease.

Elderly: Start with 31.25 mg twice daily; increase cautiously to 125 mg, monitoring liver and blood pressure.

Concomitant Medications: Adjust if combined with CYP2C9/3A4 inducers (e.g., rifampin), potentially doubling the dose under supervision.

Additional Considerations

• Take this active ingredient with or without food, maintaining a consistent schedule for steady levels.
• Avoid abrupt discontinuation; taper over 1–2 weeks to prevent rebound hypertension.

How to Use Bosentan

Administration:

• Swallow tablets whole with a glass of water, with or without food; avoid crushing or chewing to ensure proper absorption.
• Take twice daily (morning and evening) at 12-hour intervals for optimal effect.
• For combination therapy, space doses of other medications (e.g., sildenafil) by 1–2 hours.

Timing: Use consistently at the same times daily, aligning with other PAH therapies if applicable.

Monitoring: Watch for yellowing skin, swelling, or fatigue; check for signs of liver dysfunction (e.g., dark urine).

Additional Tips:

• Store at 20–25°C (68–77°F), protecting from moisture and heat.
• Use a pill organizer for adherence, especially with long-term therapy.
• Avoid excessive sun exposure due to photosensitivity risk; wear sunscreen and protective clothing.
• Report severe shortness of breath or abdominal pain immediately.

Contraindications for Bosentan

Hypersensitivity: Patients with a known allergy to Bosentan or other endothelin receptor antagonists (e.g., ambrisentan).

Severe Hepatic Impairment: Contraindicated in Child-Pugh Class C liver disease due to toxicity risk.

Pregnancy: Category X due to teratogenic effects; mandatory contraception required.

Concurrent Use with Cyclosporine A or Glyburide: Avoid due to significant drug interaction and liver enzyme elevation.

Moderate to Severe Anemia: Contraindicated if hemoglobin <8 g/dL due to exacerbation risk.

Warnings & Precautions for Bosentan

General Warnings

Hepatotoxicity: Elevated liver enzymes (ALT/AST >3x ULN in 10–15%); monitor monthly for 12 months, then quarterly.

Teratogenicity: Category X; women must use two forms of contraception and undergo monthly pregnancy tests.

Anemia: Hemoglobin drop (>2 g/dL in 5–10%); check monthly and consider iron supplementation.

Hypotension: Risk of syncope or dizziness (5–10%); monitor blood pressure regularly.

Use in Specific Populations

Pregnancy: Category X; contraindicated unless life-saving.

Breastfeeding: Excreted in milk; avoid or discontinue breastfeeding.

Elderly: Higher risk of liver and fluid retention issues; use lowest effective dose.

Children: Use only under specialist supervision for PAH; monitor growth.

Renal/Hepatic Impairment: Adjust dose in hepatic cases; avoid in severe liver disease.

Additional Precautions

• Inform your doctor about liver disease, pregnancy plans, or prior anemia before starting this medication.
• Avoid abrupt cessation; taper to prevent rebound PAH symptoms.

Overdose and Management of Bosentan

Overdose Symptoms

• Severe hypotension, dizziness, or syncope.
• Hepatotoxicity (jaundice, coagulopathy) with high doses.
• Fluid retention, peripheral edema, or respiratory distress.
• Rare: Seizures or altered mental status due to liver failure.

Immediate Actions

Contact the Medical Team: Seek immediate medical help.

Supportive Care: Administer IV fluids for hypotension, monitor oxygen saturation, and provide ventilatory support if needed.

Specific Treatment: Use N-acetylcysteine for liver support if hepatotoxicity is suspected, correct electrolytes, and discontinue the drug.

Monitor: Check liver enzymes (ALT, AST), hemoglobin, and hemodynamic status for 24–48 hours.

Additional Notes

• Overdose risk increases with liver disease or polypharmacy; store in child-resistant containers.
• Report persistent symptoms (e.g., yellow skin, severe weakness) promptly.

Side Effects of Bosentan

Common Side Effects

• Headache (15–25%, manageable with hydration)
• Flushing (10–20%, related to vasodilation)
• Peripheral Edema (5–15%, reduced with diuretics)
• Nasal Congestion (5–10%, transient)
• Fatigue (5–10%, improved with rest)

These effects may subside with tolerance but require monitoring.

Serious Side Effects

• Hepatic: Yellow skin, dark urine, or severe abdominal pain.
• Cardiovascular: Chest pain, shortness of breath, or severe hypotension.
• Hematologic: Pale skin, weakness, or severe anemia.
• Allergic: Rash, swelling, or anaphylaxis (rare).
• Neurological: Confusion or seizures (liver-related).

Additional Notes

• Regular monitoring for liver function, hemoglobin, and fluid status is advised.
• Report any unusual symptoms (e.g., jaundice, severe dizziness) immediately.

Drug Interactions with Bosentan

This active ingredient may interact with:

• CYP3A4 Inhibitors (e.g., Ketoconazole): Increases Bosentan levels; monitor liver function.
• CYP2C9 Inhibitors (e.g., Fluconazole): Raises toxicity risk; adjust dose if combined.
• Cyclosporine A: Significantly increases Bosentan levels; contraindicated.
• Warfarin: Enhances bleeding risk; monitor INR weekly.
• Hormonal Contraceptives: Reduces efficacy; use non-hormonal alternatives.

Patient Education or Lifestyle

Medication Adherence: Take this endothelin receptor antagonist as prescribed to manage PAH, following the exact schedule.

Monitoring: Report yellow skin, swelling, or fatigue immediately.

Lifestyle: Avoid alcohol to protect liver health; engage in light exercise if tolerated.

Diet: Maintain a balanced diet with adequate iron; limit high-sodium foods.

Emergency Awareness: Know signs of liver failure or severe hypotension; seek care if present.

Follow-Up: Schedule regular check-ups every 1–3 months to monitor liver and blood counts.

Pharmacokinetics of Bosentan

Absorption: Rapidly absorbed (peak at 3–5 hours); 50% bioavailability, increased with food.

Distribution: Volume of distribution ~18 L; 98% protein-bound.

Metabolism: Hepatic via CYP2C9 and CYP3A4 to active metabolites.

Excretion: Primarily biliary (90%) as metabolites; half-life 5–8 hours.

Half-Life: 5–8 hours, with steady-state reached in 3–5 days.

Pharmacodynamics of Bosentan

Blocking endothelin-1 receptors to reduce vasoconstriction and vascular remodeling.

Improving pulmonary hemodynamics and exercise capacity in PAH.

Demonstrating dose-dependent liver enzyme elevation, requiring monitoring.

Exhibiting mild vasodilatory effects on systemic circulation, risking hypotension.

Storage of Bosentan

• Temperature: Store at 20–25°C (68–77°F); protect from moisture.
• Protection: Keep in original container, away from light.
• Safety: Store out of reach of children.
• Disposal: Dispose of unused tablets per local regulations or consult a pharmacist.

Frequently Asked Questions (FAQs)

Q: What does Bosentan treat?
A: This medication treats pulmonary hypertension and digital ulcers.

Q: Can this active ingredient affect the liver?
A: Yes, liver damage is a risk; regular tests are needed.

Q: Is Bosentan safe for pregnant women?
A: No, it’s contraindicated; use contraception.

Q: How is this drug taken?
A: Orally as tablets, twice daily.

Q: How long is Bosentan treatment?
A: Long-term, often years, depending on condition.

Q: Can I stop Bosentan suddenly?
A: No, taper off to avoid rebound effects.

Regulatory Information for Bosentan

This medication is approved by:

U.S. Food and Drug Administration (FDA): Approved in 2001 (Tracleer) for PAH.

European Medicines Agency (EMA): Approved for PAH and digital ulcers.

Other Agencies: Approved globally for pulmonary hypertension; consult local guidelines.

References

1. U.S. Food and Drug Administration (FDA). (2023). Tracleer (Bosentan) Prescribing Information.
   • Official FDA documentation detailing the drug’s approved uses, dosage, and safety.
2. European Medicines Agency (EMA). (2023). Bosentan Summary of Product Characteristics.
   • EMA’s comprehensive information on the medication’s indications and precautions in Europe.
3. National Institutes of Health (NIH). (2023). Bosentan: MedlinePlus Drug Information.
   • NIH resource providing detailed information on the drug’s uses, side effects, and precautions.
4. World Health Organization (WHO). (2023). WHO Model List of Essential Medicines: Bosentan.
   • WHO’s consideration of Bosentan for PAH.
5. European Respiratory Journal. (2022). Bosentan in Pulmonary Hypertension.
   • Peer-reviewed article on Bosentan efficacy (note: access may require a subscription).