Tracleer (Bosentan)
bosentan
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| PAH (WHO Group 1) — to improve exercise ability and decrease clinical worsening | Adults (WHO FC II-IV) | Monotherapy or combination | FDA Approved |
| PAH (idiopathic or congenital) — to improve pulmonary vascular resistance | Pediatric ≥3 years | Monotherapy | FDA Approved |
Bosentan was the first oral endothelin receptor antagonist approved for PAH (2001). The pivotal trials (Study 351 and BREATHE-1) enrolled predominantly patients with idiopathic or heritable PAH (60%), connective tissue disease-associated PAH (21%), and congenital heart disease-associated PAH with left-to-right shunts (18%). Pediatric approval was granted based on PVR bridging from the BREATHE-3 study. Bosentan remains widely used globally, though its hepatotoxicity monitoring requirements and extensive drug interaction profile have shifted many prescribers toward newer ERAs such as ambrisentan and macitentan.
Digital ulcers in systemic sclerosis: Approved in the EU (Tracleer/bosentan label) for reducing new digital ulcers. Not FDA-approved for this indication but used off-label in the US. Evidence quality: Moderate (RAPIDS-1 and RAPIDS-2 trials).
Eisenmenger syndrome (WHO Group 1 CHD-PAH): BREATHE-5 demonstrated improved 6MWD without worsening oxygen saturation. Evidence quality: Moderate.
Dosing
Adult and Adolescent Dosing — By Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| PAH — adults >12 yrs, body weight >40 kg | 62.5 mg BID for 4 weeks | 125 mg BID | 125 mg BID | Mandatory 4-week uptitration; 250 mg BID not recommended (increased hepatotoxicity without additional benefit) Take with or without food; do not split film-coated tablets |
| PAH — adults >12 yrs, body weight ≤40 kg | 62.5 mg BID | 62.5 mg BID | 62.5 mg BID | No uptitration for lower weight patients |
| PAH with concurrent ritonavir (already on ritonavir ≥10 days) | 62.5 mg once daily or every other day | Based on tolerability | 62.5 mg daily | Ritonavir causes up to 48-fold initial increase in bosentan levels via OATP inhibition If starting ritonavir while on bosentan: stop bosentan ≥36 h before ritonavir, then resume at reduced dose after ≥10 days |
| PAH with aminotransferase elevation >3–5x ULN | Reduce to 62.5 mg BID or interrupt; recheck ALT/AST q2wk | If levels normalize, may re-challenge at 62.5 mg BID with recheck within 3 days Permanently stop if >8x ULN | ||
Pediatric Dosing (≤12 years) — By Body Weight
| Body Weight | Dose | Formulation | Notes |
|---|---|---|---|
| ≥4–8 kg | 16 mg BID | Dispersible tablet | No titration period |
| >8–16 kg | 32 mg BID | Dispersible tablet | No titration period |
| >16–24 kg | 48 mg BID | Dispersible tablet | No titration period |
| >24–40 kg | 64 mg BID | Dispersible tablet or film-coated | No titration period |
Bosentan induces its own metabolism through upregulation of CYP3A4 and CYP2C9. Over the first 3–5 days of repeated dosing, plasma concentrations decrease by approximately 50% due to a 2-fold increase in clearance. This auto-induction is one reason the initial 62.5 mg BID phase is 4 weeks: it allows the clinician to assess tolerability at a dose that produces relatively higher initial exposure before uptitrating to 125 mg BID.
Pharmacology
Mechanism of Action
Bosentan is a sulfonamide-class, competitive dual endothelin receptor antagonist that blocks both ETA and ETB receptors, with a slightly higher affinity for ETA. In PAH, endothelin-1 (ET-1) concentrations are elevated in both plasma and lung tissue, driving vasoconstriction and vascular smooth muscle proliferation through ETA and ETB2 receptors. By blocking both receptor subtypes, bosentan reduces pulmonary vascular resistance, improves cardiac index, and decreases pulmonary artery pressure. Unlike selective ETA antagonists such as ambrisentan, bosentan also blocks ETB1-mediated vasodilation and ET-1 clearance in the endothelium, though the net clinical effect of dual versus selective blockade remains uncertain from comparative outcome data.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Bioavailability ~50%; Tmax 3–5 h; food does not clinically affect absorption; dose-linear PK up to 500 mg/day | Can be taken with or without food; twice-daily dosing required due to short half-life |
| Distribution | Vd ~18 L; >98% protein bound (albumin); does not enter erythrocytes; substrate of OATP1B1, OATP1B3, OATP2B1 | OATP-mediated hepatic uptake is the rate-limiting step for clearance, explaining extreme sensitivity to OATP inhibitors (cyclosporine, ritonavir) |
| Metabolism | CYP2C9 and CYP3A4 (possibly CYP2C19); 3 metabolites identified; Ro 48-5033 is active (~10–20% of parent effect); strong auto-inducer of CYP3A4 and CYP2C9 | Auto-induction causes ~50% decline in steady-state levels vs first dose; induces metabolism of co-administered CYP3A4/2C9 substrates (sildenafil, hormonal contraceptives, simvastatin, warfarin) |
| Elimination | Primarily biliary excretion; <3% in urine; t1/2 ~5 h (unchanged at steady state); total clearance ~8 L/h (single IV dose) rising to ~17 L/h at steady state due to auto-induction | Short half-life requires BID dosing; PAH patients have 2-fold higher exposure than healthy volunteers; renal impairment does not require dose adjustment |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Respiratory tract infection | 22% (vs 17% placebo) | Includes nasopharyngitis, URI, and lower RTI; mechanism unclear |
| Headache | 15% (vs 14% placebo) | Vasodilatory; marginal excess over placebo; usually self-limiting |
| Edema | 11% (vs 9% placebo) | Class effect; monitor for right heart failure decompensation; may need diuretics |
| Abnormal aminotransferases | 11% (>3x ULN; N=658 pooled; vs 2% placebo) | From Boxed Warning pooled analysis; Table 3 reports 4% vs 2% in PAH placebo-controlled trials (N=258). Dose-dependent: 12% at 125 mg BID, 14% at 250 mg BID. Usually asymptomatic and reversible; requires mandatory monthly LFT monitoring |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Syncope | 5% (vs 4% placebo) | May reflect vasodilation or PAH-related; evaluate hemodynamics if recurrent |
| Flushing | 4% (vs 3% placebo) | Vasodilatory mechanism; tends to diminish |
| Hypotension | 4% (vs 2% placebo) | Mean systemic BP decrease ~3–4 mmHg; rarely clinically significant at recommended doses |
| Sinusitis | 4% (vs 2% placebo) | Related to vasodilation-mediated nasal congestion |
| Palpitations | 4% (vs 2% placebo) | Likely secondary to vasodilation |
| Anemia | 3% (vs 0% placebo) | Mean Hb decrease 0.9 g/dL; marked decrease (>15% to <11 g/dL) in 6% of patients at 125 mg BID; onset first weeks, stabilizes 4–12 weeks |
| Arthralgia | 4% (vs 2% placebo) | Treat symptomatically |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Hepatotoxicity (ALT/AST >3x ULN) | 11% | Both early and late; may occur at any point | Follow Table 2 dose-reduction algorithm; stop permanently if >8x ULN or if accompanied by symptoms or bilirubin ≥2x ULN |
| Hepatic cirrhosis / liver failure | Rare (postmarketing) | >12 months of treatment | Reinforces mandatory monthly LFT monitoring for entire duration of therapy; discontinue if signs of liver injury |
| Embryo-fetal toxicity | Expected if exposed | First trimester | Absolute contraindication; monthly pregnancy testing; two forms of contraception required (hormonal contraception unreliable as sole method due to CYP induction) |
| Anemia requiring transfusion | Rare (postmarketing) | First weeks to months | Investigate cause; consider discontinuation if marked and unexplained |
| Hypersensitivity (angioedema, DRESS, rash) | Rare (postmarketing) | 8 hours to 21 days after initiation | Discontinue permanently; standard allergy management |
| Decreased sperm count (≥50% decline) | 25% in open-label study | 3–6 months | Counsel males before initiation; reversible after discontinuation in reported cases |
Hepatotoxicity is the defining safety concern for bosentan. Monthly ALT/AST monitoring is mandatory throughout treatment. If ALT/AST rises to >3–5x ULN, reduce to 62.5 mg BID or interrupt, then rechallenge at 62.5 mg BID once levels normalize, with recheck within 3 days. If >5–8x ULN, stop and consider reintroduction at 62.5 mg BID only after normalization. If >8x ULN, discontinue permanently. If any elevation is accompanied by clinical symptoms (jaundice, nausea, fever, abdominal pain, fatigue) or bilirubin ≥2x ULN, stop permanently with no rechallenge.
Drug Interactions
Bosentan has one of the most complex drug interaction profiles of any PAH therapy. It is both a substrate and an inducer of CYP3A4 and CYP2C9, and a substrate of hepatic OATP transporters. This dual role as a CYP inducer means it reduces the exposure of many co-administered medications, while being highly sensitive to drugs that inhibit its hepatic uptake via OATP (cyclosporine, ritonavir).
Monitoring
- Liver Aminotransferases (ALT/AST)Baseline, then monthly throughout treatment
RoutineMANDATORY under REMS. 11% of patients develop >3x ULN elevations. Follow dose-adjustment algorithm if elevated. Discontinue if symptomatic or bilirubin ≥2x ULN. Monthly monitoring continues for entire treatment duration — no exemptions regardless of treatment length. - Pregnancy TestBaseline, then monthly
RoutineRequired under REMS for all females of reproductive potential. Must also test 1 month after stopping therapy. Two forms of contraception mandatory (hormonal methods unreliable as sole method due to CYP3A4 induction). - Hemoglobin / HematocritBaseline, 1 month, 3 months, then q3 months
RoutineMean Hb decrease ~0.9 g/dL. Marked decrease (>15% from baseline to <11 g/dL) in 6% at 125 mg BID. Onset first weeks; stabilizes by 4–12 weeks. Investigate other causes if marked drop. - Functional Capacity (6MWD, WHO FC)Baseline, 3–6 months, then periodically
RoutineImprovement in walk distance expected by 4–8 weeks, fully developed by ~2 months. If declining, consider combination therapy escalation. - INR (if on warfarin)When initiating or changing bosentan
Trigger-basedCYP2C9 induction may reduce warfarin efficacy; recheck INR within 1–2 weeks of starting or stopping bosentan and adjust warfarin dose accordingly.
Contraindications & Cautions
Absolute Contraindications
- Pregnancy: Bosentan is teratogenic in rats at doses near human therapeutic levels. Major birth defects are expected. Two forms of contraception are required; hormonal methods unreliable as sole method due to CYP3A4 induction of estrogen/progestin metabolism.
- Co-administration with cyclosporine A: Markedly increases bosentan trough levels (~30-fold on first day) via OATP inhibition. Contraindicated.
- Co-administration with glyburide: Increased risk of hepatic aminotransferase elevations. Contraindicated.
- Hypersensitivity to bosentan or excipients: Observed reactions include DRESS, anaphylaxis, angioedema, and rash.
Relative Contraindications (Specialist Input Recommended)
- Baseline ALT/AST >3x ULN: Initiation should generally be avoided because monitoring for additional hepatotoxicity is more difficult when baseline values are already elevated.
- Moderate or severe hepatic impairment (Child-Pugh B or C): Exposure increased ~4.7-fold in moderate impairment; not studied in severe impairment.
Use with Caution
- WHO Functional Class II patients: The FDA PI specifically notes that the benefits of bosentan should be weighed against the risk of hepatotoxicity in milder disease, which could preclude future use of the drug if disease progresses.
- Males desiring fertility: 25% of patients showed ≥50% sperm count decline in a dedicated study; reversible after discontinuation.
- Patients on multiple CYP3A4/2C9 substrates: Bosentan will reduce their efficacy (statins, contraceptives, warfarin, sildenafil).
Bosentan carries a dual boxed warning for hepatotoxicity and embryo-fetal toxicity. In clinical studies, ALT/AST elevations >3x ULN occurred in approximately 11% of patients. Rare cases of unexplained hepatic cirrhosis and liver failure have been reported in postmarketing surveillance after prolonged (>12 months) use. Bosentan is only available through the Bosentan REMS Program, which requires prescriber, patient, and pharmacy enrollment. Monthly LFT and pregnancy testing are mandated by the REMS. As of 2025, the FDA revised the REMS to remove components related specifically to embryo-fetal toxicity for ERAs after review of human pregnancy data, but the hepatotoxicity REMS requirements and pregnancy contraindication in the label remain fully in effect.
Patient Counselling
Purpose of Therapy
Bosentan blocks endothelin, a substance that narrows blood vessels in the lungs. It is taken twice daily to lower pressure in the lung arteries, improve the ability to exercise, and slow disease progression. It does not cure PAH but is a key part of long-term management.
How to Take
Take one tablet in the morning and one in the evening, with or without food. Do not stop taking bosentan suddenly without consulting your doctor, as symptoms may worsen. If a dose is missed, take it as soon as remembered but do not double the dose. Store at room temperature.
Sources
- TRACLEER (bosentan) tablets / tablets for oral suspension. Full Prescribing Information. Actelion Pharmaceuticals / Janssen. Revised July 2025. FDA Label (2025)Primary reference for all dosing, REMS requirements, adverse reactions, hepatotoxicity algorithm, and drug interactions.
- Bosentan tablets (generic). DailyMed. DailyMedGeneric label with identical adverse reaction data and monitoring requirements.
- Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001;358(9288):1119-1123. doi:10.1016/S0140-6736(01)06250-XStudy 351: first randomized trial of bosentan in PAH; established proof of concept for oral ERA therapy.
- Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346(12):896-903. doi:10.1056/NEJMoa012212BREATHE-1: pivotal phase III trial (N=213) establishing 6MWD improvement and time-to-clinical-worsening benefit at 125 mg BID.
- Galiè N, Beghetti M, Gatzoulis MA, et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation. 2006;114(1):48-54. doi:10.1161/CIRCULATIONAHA.106.630715BREATHE-5: demonstrated safety and efficacy in Eisenmenger syndrome without worsening oxygen saturation.
- Galiè N, Rubin LJ, Hoeper MM, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study). Lancet. 2008;371(9630):2093-2100. doi:10.1016/S0140-6736(08)60919-8EARLY trial: showed PVR reduction and delayed time to clinical worsening in WHO FC II patients.
- Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43(38):3618-3731. doi:10.1093/eurheartj/ehac237Current comprehensive guideline positioning ERAs within PAH treatment algorithms and risk stratification.
- Klinger JR, Elliott CG, Levine DJ, et al. Therapy for pulmonary arterial hypertension in adults: update of the CHEST guideline. Chest. 2019;155(3):565-586. doi:10.1016/j.chest.2018.11.030CHEST 2019 guideline with recommendations for ERA monotherapy and combination approaches.
- Clozel M, Breu V, Gray GA, et al. Pharmacological characterization of bosentan, a new potent orally active nonpeptide endothelin receptor antagonist. J Pharmacol Exp Ther. 1994;270(1):228-235. PMID:8035319Foundational preclinical study characterizing bosentan as a dual ET receptor antagonist with in vivo activity.
- Dingemanse J, van Giersbergen PLM. Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet. 2004;43(15):1089-1115. doi:10.2165/00003088-200443150-00003Comprehensive PK review: bioavailability, auto-induction, CYP interactions, special populations, and metabolite pharmacology.
- Bosentan. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Updated December 2025. NBK542293Comprehensive clinical review with updated 2025 REMS information and adverse effect synthesis.
- Weber C, Schmitt R, Birnboeck H, et al. Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects. Clin Pharmacol Ther. 1996;60(2):124-137. doi:10.1016/S0009-9236(96)90127-7First-in-human PK/PD study establishing oral bioavailability (~50%), clearance, Vd, and ET-1 pharmacodynamic response.
- McLaughlin VV, Sitbon O, Badesch DB, et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J. 2005;25(2):244-249. doi:10.1183/09031936.05.00054804Long-term survival analysis of bosentan-treated patients from pivotal trials, showing 96% and 89% survival at 1 and 2 years respectively.