Considering TRACLEER® (bosentan)

PAH improvement

TRACLEER has demonstrated improvements in pulmonary arterial hypertension (PAH) in clinical studies of Functional Class II-IV patients.1-4

Mean change in 6MWD Functional class Clinical worsening: event‑free patients* Hemodynamics (Placebo‑corrected values)
Week 16:
TRACLEER: +36 m; placebo: –8 m
Improved, Week 16:
placebo: 30%
Week 28§:
TRACLEER (n=35): 89%;
placebo (n=13): 63%
Not studied
Study 3511,7
Week 12:
TRACLEER: +70 m; placebo: –6 m
Improved, Week 12:
placebo: 9%
Week 12:
placebo: 73%
Week 12:
CI: +1.0 L/min/m2;
PVR: –415 dyn•sec/cm5
mRAP: –6.2 mmHg;
mPAP: –6.7 mmHg
Week 26:
TRACLEER: +11 m; placebo: –8 m
Improved or
maintained, Week 26:
TRACLEER: 97%#; placebo: 87%
Week 26:
placebo: 86%
Month 6:
CI: +0.24 L/min/m2#
PVR: –197 dyn•sec/cm5
mRAP: –0.6 mmHg;
mPAP: –5.7 mmHg#

6MWD: 6-minute walk distance; BID: twice daily; CI: cardiac index; mRAP: mean right atrial pressure; mPAP: mean pulmonary artery pressure; PVR: pulmonary vascular resistance.

*Definitions of clinical worsening: BREATHE-1 and Study 351: death, hospitalization related to PAH, discontinuation of therapy due to PAH, or need for epoprostenol. EARLY: death, hospitalization due to PAH complications, or symptomatic progression of PAH.1

†Walking distance was somewhat greater with 250 mg BID, but the potential for increased hepatotoxicity causes this dosage not to be  recommended.1

‡Functional class improvement was for 125 mg BID dose.

§Based on Kaplan-Meier estimate.

‖Not significant.

#These secondary endpoints were exploratory, and no formal hypothesis testing was conducted.

Trial designs1

BREATHE-1 and Study 351:

Two randomized, double-blind, multicenter, placebo-controlled trials were conducted in 32 and 213 patients. The larger study (BREATHE-1) compared 2 doses (125 mg twice daily and 250 mg twice daily) of TRACLEER with placebo. The smaller study (Study 351) compared 125 mg twice daily with placebo. Patients had severe (World Health Organization [WHO] Functional Class III-IV) pulmonary arterial hypertension: idiopathic or heritable pulmonary arterial hypertension (72%) or pulmonary arterial hypertension associated with scleroderma or other connective tissue diseases (21%), or with autoimmune diseases (7%). There were no patients with pulmonary arterial hypertension associated with other conditions such as human immunodeficiency virus (HIV) disease or recurrent pulmonary emboli. In both studies, TRACLEER or placebo was added to patients’ current therapy, which could have included a combination of digoxin, anticoagulants, diuretics, and vasodilators (eg, calcium channel blockers, angiotensin-converting enzyme inhibitors), but not epoprostenol. TRACLEER was given at a dose of 62.5 mg twice daily for 4 weeks and then at 125 mg twice daily or 250 mg twice daily for either 12 (BREATHE-1) or 8 (Study 351) additional weeks. The primary study endpoint was 6-minute walk distance. In addition, symptoms and functional status were assessed. Hemodynamic measurements were made at 12 weeks in Study 351. The mean age was about 49 years. About 80% of patients were female, and about 80% were Caucasian. Patients had been diagnosed with pulmonary hypertension for a mean of 2.4 years.


A randomized, double-blind, multicenter, placebo-controlled trial was conducted in 185 mildly symptomatic PAH patients with WHO Functional Class II (mean baseline 6-minute walk distance of 443 meters) received TRACLEER 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily (n=93), or placebo (n=92) for 6 months. Enrolled patients were treatment-naïve (n=156) or on a stable dose of sildenafil (n=29). The coprimary endpoints were change from baseline to Month 6 in PVR and 6-minute walk distance. Time to clinical worsening (assessed as the sum of death, hospitalization due to PAH complications, or symptomatic progression of PAH), Borg dyspnea index, change in WHO Functional Class and hemodynamics were assessed as secondary endpoints.

Required monitoring—liver aminotransferase levels

Liver aminotransferase levels must be measured prior to initiation of treatment and monitored on a monthly basis.

  • If elevated aminotransferase levels are seen, changes in monitoring and treatment must be initiated. See the full Prescribing Information for treatment and monitoring recommendations for ALT/AST levels >3 × ULN.
  • If liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥2 × ULN, treatment with TRACLEER should be stopped. There is no experience with reintroduction of TRACLEER in these circumstances.

TRACLEER should generally be avoided in patients with moderate or severe liver impairment. Initiation of TRACLEER should generally be avoided in patients with elevated aminotransferases >3 × ULN. No dose adjustment is required in patients with mildly impaired liver function.

Prescribing TRACLEER for females of reproductive potential

Initiate TRACLEER in females of reproductive potential only after a negative pregnancy test and only in females who are using two reliable methods of contraception.

  • Females who have had tubal sterilization or an intrauterine device (IUD) inserted do not require other forms of contraception.
  • Effective contraception must be practiced throughout treatment and for one month after stopping TRACLEER.
  • Pregnancy tests should be obtained monthly in females of reproductive potential taking TRACLEER and one month after stopping treatment with TRACLEER.

Drug-drug interactions1

  • TRACLEER is contraindicated for use with cyclosporine A and with glyburide.
  • TRACLEER is metabolized by CYP2C9 and CYP3A.
    • Co-administration with agents that are metabolized by these pathways may affect plasma concentrations of one or both agents.
    • Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when TRACLEER is co-administered.
    • When initiating lopinavir/ritonavir and other ritonavir-containing HIV regimens, dosage adjustment of TRACLEER is necessary.
    • When co-administered with simvastatin, or other statins that are CYP3A substrates, dosage adjustment of such statins may need to be considered.
    • When co-administered with rifampin, a CYP3A inducer, liver function should be monitored weekly.
    • When co-administered with ketoconazole, a potent CYP3A inhibitor, no dose adjustment of TRACLEER is necessary, but increased effects of TRACLEER may need to be considered.
  • There are no clinically relevant interactions between TRACLEER and warfarin, digoxin, nimodipine, losartan, or sildenafil.
    • Dose adjustments are not necessary when TRACLEER and sildenafil are co-administered.

Treatment discontinuation1

Gradual dose reduction (62.5 mg twice daily for three to seven days) should be considered to avoid the potential for clinical deterioration, as there is limited experience with abrupt discontinuation of TRACLEER. No evidence for acute rebound has been observed.

REFERENCES: 1. TRACLEER® (bosentan) full Prescribing Information. Actelion Pharmaceuticals US, Inc. 2. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension. J Am Coll Cardiol. 2009;53:1573-1619. 3. Galiè N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62(suppl D):D60-D72. 4. Galiè N, Humbert M, Vachiery J-L, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Eur Respir J. 2015;46:903-975. 5. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896-903. 6. Data on file, Actelion Pharmaceuticals. 7. 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;358:1119-1123. 8. Galiè N, Rubin LJ, Hoeper MM, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008;371:2093-2100.

Indication and Important Safety Information Including Boxed Warning

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