Bosentan

Usage

Bosentan is prescribed for the treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and slow the progression of the disease. It is also used for the treatment of digital ulcers in systemic sclerosis. Bosentan is classified as an endothelin receptor antagonist. It competitively antagonizes both endothelin-A and endothelin-B receptors, blocking the vasoconstricting and proliferative effects of endothelin-1, a potent vasoconstrictor implicated in the pathogenesis of PAH.

Alternate Names

While “bosentan” is the generic name, it’s marketed under brand names such as Tracleer.

How It Works

Pharmacodynamics: Bosentan primarily acts by blocking the effects of endothelin-1 on vascular smooth muscle, leading to vasodilation and decreased pulmonary vascular resistance. This reduces the strain on the right side of the heart and improves cardiac output.

Pharmacokinetics:

• Absorption: Bosentan is orally administered and exhibits approximately 50% absolute bioavailability, unaffected by food intake. Peak plasma concentrations are reached in 3-5 hours.
• Metabolism: Primarily metabolized in the liver by CYP2C9 and CYP3A4 enzymes into three metabolites. One metabolite (Ro 48-5033) possesses some activity, but significantly less than the parent drug.
• Elimination: Excreted primarily in bile and feces, with a small portion eliminated in urine. The elimination half-life is approximately 5 hours.

Mode of Action: Bosentan competitively binds to endothelin-A and endothelin-B receptors, preventing endothelin-1 from binding and exerting its vasoconstricting effects. This reduces pulmonary vascular resistance and improves blood flow through the lungs.

Elimination Pathways: Hepatic metabolism (CYP2C9 and CYP3A4) followed by biliary excretion is the primary route of elimination.

Dosage

Standard Dosage

Adults:

Initial dose: 62.5 mg twice daily for 4 weeks.

Maintenance dose: 125 mg twice daily for patients weighing > 40 kg. Patients weighing ≤ 40 kg maintain 62.5 mg twice daily.

Children:

Dosage is weight-based:

• 4-8 kg: 16 mg twice daily

• 8-16 kg: 32 mg twice daily

• 16-24 kg: 48 mg twice daily

• 24-40 kg: 64 mg twice daily

• 40 kg: 62.5 mg twice daily for 4 weeks, then 125 mg twice daily.

Special Cases:

• Elderly Patients: No specific dosage adjustment is recommended, but caution is advised due to potential age-related decline in hepatic function.
• Patients with Renal Impairment: No dosage adjustment is necessary.
• Patients with Hepatic Dysfunction: Contraindicated in moderate to severe hepatic impairment (Child-Pugh class B or C). Use with caution in mild hepatic impairment.
• Patients with Comorbid Conditions: Close monitoring is necessary for patients with heart failure, anemia, or those taking medications metabolized by CYP2C9 or CYP3A4.

Clinical Use Cases

Bosentan’s clinical use is primarily focused on PAH and digital ulcers related to systemic sclerosis. It is not indicated for use in settings like intubation, surgical procedures, mechanical ventilation, or emergency situations.

Dosage Adjustments

Dosage adjustments may be necessary based on liver function tests (LFTs). If ALT/AST levels elevate:

• 3 to ≤5 times ULN: Confirm with repeat LFTs. Reduce dose to 62.5 mg twice daily or interrupt treatment until LFTs normalize.

• 5 to ≤8 times ULN: Interrupt treatment until LFTs normalize. Consider reintroduction at 62.5 mg twice daily once LFTs return to baseline.

• 8 times ULN: Discontinue permanently.

Side Effects

Common Side Effects:

Headache, flushing, nasal congestion, peripheral edema, anemia, abnormal LFTs.

Rare but Serious Side Effects:

Hepatotoxicity (jaundice, elevated liver enzymes), allergic reactions (rash, angioedema, anaphylaxis), fluid retention.

Long-Term Effects:

Potential for chronic liver damage with prolonged use. Regular LFT monitoring is essential.

Adverse Drug Reactions (ADR):

Hepatotoxicity, anaphylaxis, angioedema, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

Contraindications

• Pregnancy
• Moderate to severe hepatic impairment (Child-Pugh class B or C)
• Baseline ALT/AST > 3x ULN
• Concomitant use of cyclosporine A or glyburide
• Hypersensitivity to bosentan

Drug Interactions

Bosentan is metabolized by CYP2C9 and CYP3A4 and can induce these enzymes, affecting the metabolism of other drugs. Clinically significant interactions include:

• CYP3A4 inhibitors (ketoconazole, itraconazole): Increased bosentan levels.
• CYP2C9 inhibitors (fluconazole): Increased bosentan levels.
• CYP inducers (rifampin): Decreased bosentan levels.
• Hormonal contraceptives: Reduced efficacy.
• Warfarin: Decreased warfarin levels. Monitor INR closely.
• Glyburide: Decreased glyburide levels and increased risk of liver enzyme elevations. Contraindicated.
• Cyclosporine A: Markedly increased bosentan levels. Contraindicated.

Pregnancy and Breastfeeding

Pregnancy Safety Category: X. Contraindicated in pregnancy due to the risk of teratogenicity and fetal harm. Strict contraception is necessary during treatment and for one month after discontinuation. Monthly pregnancy tests are recommended.

Breastfeeding: Bosentan is present in breast milk at low levels. While limited data suggests minimal risk, breastfeeding is generally not recommended due to the potential for adverse effects in the infant.

Drug Profile Summary

• Mechanism of Action: Endothelin receptor antagonist.
• Side Effects: Headache, flushing, nasal congestion, peripheral edema, anemia, hepatotoxicity.
• Contraindications: Pregnancy, hepatic impairment, concomitant use of cyclosporine or glyburide.
• Drug Interactions: CYP3A4 and CYP2C9 inhibitors and inducers, hormonal contraceptives, warfarin.
• Pregnancy & Breastfeeding: Contraindicated in pregnancy. Breastfeeding not recommended.
• Dosage: Adults: 62.5 mg twice daily initially, then 125 mg twice daily. Pediatric: Weight-based.
• Monitoring Parameters: LFTs, hemoglobin/hematocrit, pregnancy tests.

Popular Combinations

Bosentan is sometimes used in combination with other PAH therapies, such as phosphodiesterase-5 inhibitors (sildenafil, tadalafil), but combination therapy requires careful monitoring due to the potential for increased side effects.

Precautions

• General Precautions: LFTs and hemoglobin/hematocrit should be monitored regularly. Pregnancy must be excluded before starting treatment.
• Specific Populations: Use with caution in patients with mild hepatic impairment.
• Lifestyle Considerations: Avoid alcohol as it may worsen liver toxicity.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Bosentan?

A: Adults: Initial dose is 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily for patients weighing > 40 kg. Pediatric dosing is weight-based.

Q2: What are the most serious side effects of Bosentan?

A: Hepatotoxicity, allergic reactions, and fluid retention.

Q3: Is Bosentan safe to use during pregnancy?

A: No, it is contraindicated during pregnancy due to the risk of teratogenicity.

Q4: What are the key drug interactions with Bosentan?

A: CYP3A4 and CYP2C9 inhibitors and inducers, hormonal contraceptives, warfarin, cyclosporine, and glyburide.

Q5: What monitoring parameters are essential for patients on Bosentan?

A: Liver function tests (LFTs), hemoglobin/hematocrit, and pregnancy tests for women of childbearing potential.

Q6: How does Bosentan work in PAH?

A: It blocks the action of endothelin-1, leading to vasodilation of pulmonary arteries and reduced pulmonary vascular resistance.

Q7: What should be done if a patient on Bosentan develops elevated liver enzymes?

A: Dosage adjustments or treatment interruption may be required depending on the severity of the elevation. Consult the dosage adjustment section for details.

Q8: Can Bosentan be used in patients with renal impairment?

A: Yes, no dose adjustment is needed in patients with renal impairment, including those on dialysis.

Q9: What are the contraindications for the use of Bosentan?

A: Pregnancy, moderate-to-severe liver impairment, hypersensitivity to bosentan, concurrent use of cyclosporine A or glyburide.

Q10: Are there any special precautions for elderly patients taking Bosentan?

A: While no specific dosage adjustment is required, caution should be exercised due to potential age-related decline in hepatic function. Close monitoring of LFTs is important.