What is the recommended dose of Bosentan (endothelin receptor antagonist) for preventing new digital ulcers?

Bosentan Dosing for Digital Ulcer Prevention in Systemic Sclerosis

The recommended dose of bosentan for preventing new digital ulcers is 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily for maintenance therapy. 1

Dosing Regimen

Initial Titration Phase

• Start with 62.5 mg orally twice daily for the first 4 weeks 1
• This lower initial dose allows for tolerance assessment, particularly regarding hepatotoxicity 1

Maintenance Phase

• Increase to 125 mg orally twice daily after 4 weeks 1
• Continue this maintenance dose for the duration of therapy 1
• Some evidence suggests lower doses (62.5-125 mg daily total) may be effective for digital ulcers specifically, though this is less well-established 2

Evidence Supporting This Dosing

The RAPIDS-1 and RAPIDS-2 trials (both high-quality RCTs with Jadad score 5) established this dosing regimen, demonstrating:

• 48% reduction in new digital ulcers compared to placebo using this exact dosing schedule 1
• 30-39% reduction in new ulcers over 12-24 weeks in RAPIDS-2 1
• Greatest benefit in diffuse SSc with active digital ulcers (67% reduction) 1

Clinical Context and Patient Selection

Bosentan should be reserved for patients with diffuse SSc and multiple digital ulcers who have failed first-line therapies 1

Treatment Algorithm

1. First-line: Calcium channel blockers (nifedipine 30 mg/day) 1
2. Second-line: Intravenous prostanoids (iloprost or epoprostenol) for severe cases 1
3. Third-line: Bosentan at the dosing described above, particularly for patients with multiple recurrent ulcers 1

Patient Characteristics Most Likely to Benefit

• Diffuse SSc subtype (61% reduction in new ulcers vs 38% in limited SSc) 1
• Active digital ulcers at baseline (67% reduction in diffuse SSc with active ulcers) 1
• Multiple digital ulcers (greater effect observed in patients entering trials with more ulcers) 3

Critical Safety Considerations

Mandatory Monitoring

• Liver function tests must be checked monthly due to risk of hepatotoxicity 1
• Elevations >3-fold upper limit of normal occurred in clinical trials 1, 4
• Three of six patients in one case series discontinued due to severe liver dysfunction 2

Contraindications and Warnings

• Absolute contraindication in pregnancy due to teratogenicity 1
• Hormonal contraceptives are unreliable when co-administered with bosentan due to cytochrome P450 interference 1
• Alternative contraception methods must be used in women of childbearing potential 1

Important Limitations

Bosentan does NOT heal existing digital ulcers 1

• No difference in healing time of cardinal ulcers compared to placebo in both RAPIDS trials 1, 3
• The drug's benefit is purely preventive for new ulcer formation 1
• For healing active ulcers, intravenous iloprost or epoprostenol remain the evidence-based options 1

Additional Benefits

• Improved hand function measured by Scleroderma-HAQ scores 1
• Reduced pain in some case series 2
• Effect size 0.4 for functional improvement (95% CI 0.0 to 0.8) 1

Duration of Therapy

The clinical trials evaluated treatment for 12-24 weeks 1, 3, but long-term therapy may be necessary given the chronic recurrent nature of digital ulcers in SSc. One case report documented successful prevention for 4.5 years 2. Recurrence of ulcers after discontinuation has been observed, with improvement upon re-initiation 2.