Dosage & Administration
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Tracleer Prescribing Information
- Healthcare professionals who prescribe TRACLEER must review the prescriber educational materials, enroll in the Bosentan REMS and comply with its requirements.
- Healthcare professionals must (1) review serum aminotransferases (ALT/AST) and bilirubin, and agree to order and monitor these tests monthly.
- To receive TRACLEER, all patients must understand the risks and benefits, and complete a patient enrollment form with their prescriber.
- Pharmacies that dispense TRACLEER must enroll in the program and agree to comply with the Bosentan REMS requirements.
Because of the risk of hepatotoxicity, TRACLEER is available only through a restricted program called the Bosentan Risk Evaluation and Mitigation Strategy (REMS). Under the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program [see Warnings and Precautions (5.2)] .WARNING: RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. TRACLEER is available only through a restricted distribution program called the Bosentan Risk Evaluation and Mitigation Strategy (REMS) because of the risk of hepatotoxicity : Elevations of liver aminotransferases (ALT, AST) and liver failure have been reported with TRACLEER .
Based on animal data, TRACLEER may cause fetal harm if used during pregnancy .
Hepatotoxicity In clinical studies, TRACLEER caused at least 3-fold upper limit of normal (ULN) elevation of liver aminotransferases (ALT and AST) in about 11% of patients, accompanied by elevated bilirubin in a small number of cases. Because these changes are a marker for potential serious hepatotoxicity, serum aminotransferase levels must be measured prior to initiation of treatment and then monthly [see Dosage and Administration (2.4), Warnings and Precautions (5.1)] . In the postmarketing period, in the setting of close monitoring, rare cases of unexplained hepatic cirrhosis were reported after prolonged (>12 months) therapy with TRACLEER in patients with multiple comorbidities and drug therapies. There have also been reports of liver failure. The contribution of TRACLEER in these cases could not be excluded.In at least one case, the initial presentation (after >20 months of treatment) included pronounced elevations in aminotransferases and bilirubin levels accompanied by non-specific symptoms, all of which resolved slowly over time after discontinuation of TRACLEER. This case reinforces the importance of strict adherence to the monthly monitoring schedule for the duration of treatment and the treatment algorithm, which includes stopping TRACLEER with a rise of aminotransferases accompanied by signs or symptoms of liver dysfunction [see Dosage and Administration (2.4)] .Elevations in aminotransferases require close attention [see Dosage and Administration (2.4)] . TRACLEER should generally be avoided in patients with elevated aminotransferases (>3×ULN) at baseline because monitoring for hepatotoxicity may be more difficult. 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 the reintroduction of TRACLEER in these circumstances.Embryo-Fetal Toxicity TRACLEER is contraindicated for use during pregnancy because it may cause fetal harm if used by pregnant females based on animal data. Therefore, for females of reproductive potential, exclude pregnancy before the start of treatment with TRACLEER. Advise use of effective contraception before initiation, during treatment and for one month after stopping TRACLEER. When pregnancy is detected, discontinue TRACLEER as soon as possible [see Dosage and Administration (2.1), Contraindications (4.1), Warnings and Precautions (5.3), Drug Interactions (7.2), Use in Specific Populations (8.1, 8.3)] . | 11/2025 |
Dosage and Administration (Healthcare professionals who prescribe TRACLEER must enroll in the Bosentan REMS and must comply with the required monitoring to minimize the risks associated with TRACLEER [see Warnings and Precautions (5.2)]. Measure liver aminotransferase levels prior to initiation of treatment and then monthly [see Boxed Warning, Warnings and Precautions (5.1, 5.2)]. Exclude pregnancy before initiating treatment with TRACLEER in females of reproductive potential [see Boxed Warning, Contraindications (4.1), Warnings and Precautions (5.3), Use in Specific Populations (8.1, 8.3)] . | 11/2025 |
Contraindications (Use of TRACLEER is contraindicated in females who are pregnant [see Boxed Warning, Dosage and Administration (2.1), Warnings and Precautions (5.3), Use in Specific Populations (8.1)] . | 11/2025 |
Warnings and Precautions (ALT or AST >3 × ULN were observed in 11% of TRACLEER-treated patients (n=658) compared to 2% of placebo-treated patients (n=280). Three-fold increases were seen in 12% of 95 pulmonary arterial hypertension (PAH) patients on 125 mg twice daily and 14% of 70 PAH patients on 250 mg twice daily. Eight-fold increases were seen in 2% of PAH patients on 125 mg twice daily and 7% of PAH patients on 250 mg twice daily. Bilirubin increases to ≥3× ULN were associated with aminotransferase increases in 2 of 658 (0.3%) of patients treated with TRACLEER. In a pooled analysis of four pediatric studies conducted in PAH (n=100), elevations in liver aminotransferases ≥3×ULN were observed in 2% of patients. The combination of hepatocellular injury (increases in aminotransferases of >3× ULN) and increases in total bilirubin (≥2× ULN) is a marker for potential serious hepatotoxicity.Elevations of AST or ALT associated with TRACLEER are dose-dependent, occur both early and late in treatment, usually progress slowly, are typically asymptomatic, and usually have been reversible after treatment interruption or cessation. Aminotransferase elevations also may reverse spontaneously while continuing treatment with TRACLEER. Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly and therapy adjusted accordingly [see Dosage and Administration (2.1, 2.4)] . Discontinue TRACLEER 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.Avoid initiation of TRACLEER in patients with elevated aminotransferases (>3 × ULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult[see Boxed Warning, Dosage and Administration (2.6), Use in Specific Populations (8.6)] .In WHO Functional Class II patients, consider whether the benefits of TRACLEER are sufficient to offset the risk of hepatotoxicity, which may preclude future use as their disease progresses. TRACLEER is only available through a restricted program under REMS [see Warnings and Precautions (5.2)]. Because of the risks of hepatotoxicity , TRACLEER is available only through a restricted program called the Bosentan REMS. As a component of the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program [see Boxed Warning, Warnings and Precautions (5.1)] .Required components of the Bosentan REMS are:
Further information about TRACLEER and the Bosentan REMS is available at www.BosentanREMSProgram.com or 1-866-359-2612. Based on data from animal reproduction studies, TRACLEER may cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. The available human data for endothelin receptor antagonists do not establish the presence or absence of major birth defects related to the use of TRACLEER. Advise females of reproductive potential about the potential risk to a fetus. Exclude pregnancy prior to TRACLEER treatment. Advise females of reproductive potential to use effective contraception prior to initiation of treatment with TRACLEER, during treatment, and for at least one month after the last dose. When pregnancy is detected, discontinue TRACLEER as soon as possible [see Dosage and Administration (2.1), Contraindications (4.1), Drug Interactions (7.2), Use in Specific Populations (8.1, 8.3)] . | 11/2025 |
TRACLEER is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1):
- in adults to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%)[see.]
14.1 Pulmonary Arterial HypertensionWHO Functional Class III-IVTwo randomized, double-blind, multi-center, 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 (WHO functional Class III–IV) PAH: idiopathic or heritable PAH (72%) or PAH associated with scleroderma or other connective tissue diseases (21%), or to autoimmune diseases (7%). There were no patients with PAH associated with other conditions such as 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 (e.g., calcium channel blockers, ACE 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.
Submaximal Exercise AbilityResults of the 6-minute walk distance at 3 months (Study 351) or 4 months (BREATHE-1) are shown in Table 4.
Table 4: Effects of TRACLEER on 6-Minute Walk Distance BREATHE-1 Study 351 TRACLEER
125 mg twice daily
(n=74)TRACLEER
250 mg twice daily
(n=70)Placebo
(n=69)TRACLEER
125 mg twice daily
(n=21)Placebo
(n=11)Distance in meters: mean ± standard deviation. Changes are to week 16 for BREATHE-1 and to week 12 for Study 351. Baseline326 ± 73 333 ± 75 344 ± 76 360 ± 86 355 ± 82 End point353 ± 115 379 ± 101 336 ± 129 431 ± 66 350 ± 147 Change from baseline27 ± 75 46 ± 62 -8 ± 96 70 ± 56 -6 ± 121 Placebo – subtracted35p=0.01; by Wilcoxon; 54p=0.0001; by Wilcoxon; 76p=0.02; by Student's t-test. In both trials, treatment with TRACLEER resulted in a significant increase in exercise ability. The improvement in walk distance was apparent after 1 month of treatment (with 62.5 mg twice daily) and fully developed by about 2 months of treatment (Figure 5). It was maintained for up to 7 months of double-blind treatment. Walking distance was somewhat greater with 250 mg twice daily, but the potential for increased hepatotoxicity causes this dose not to be recommended
[see Dosage and Administration (2.2)]. There were no apparent differences in treatment effects on walk distance among subgroups analyzed by demographic factors, baseline disease severity, or disease etiology, but the studies had little power to detect such differences.Figure 5. Mean Change in 6-min Walk Distance (BREATHE-1)
Change from baseline in 6-minute walking distance from start of therapy to week 16 in the placebo and combined TRACLEER (125 mg twice daily and 250 mg twice daily) groups. Values are expressed as mean ± standard error of the mean.
Figure 5 Hemodynamic ChangesInvasive hemodynamic parameters were assessed in Study 351. Treatment with TRACLEER led to a significant increase in cardiac index (CI) associated with a significant reduction in pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and mean right atrial pressure (RAP) (Table 5).
The relationship between hemodynamic effects and improvements in 6-minute walk distance is unknown.
Table 5: Change from Baseline to Week 12: Hemodynamic Parameters TRACLEER
125 mg twice dailyPlacebo Values shown are means ± SD CI (L/min/m2)n=20n=10Baseline 2.35±0.73 2.48±1.03 Absolute Change 0.50±0.46 -0.52±0.48 Treatment Effect 1.02p≤0.001; Mean PAP (mmHg)n=20n=10Baseline 53.7±13.4 55.7±10.5 Absolute Change -1.6±5.1 5.1±8.8 Treatment Effect -6.7p<0.02 PVR (dyn∙sec∙cm-5)n=19n=10Baseline 896±425 942±430 Absolute Change -223±245 191±235 Treatment Effect -415 Mean RAP (mmHg)n=19n=10Baseline 9.7±5.6 9.9±4.1 Absolute Change -1.3±4.1 4.9±4.6 Treatment Effect -6.2 Symptoms and Functional StatusSymptoms of PAH were assessed by Borg dyspnea score, WHO functional class, and rate of "clinical worsening." Clinical worsening was assessed as the sum of death, hospitalizations for PAH, discontinuation of therapy because of PAH, and need for epoprostenol. There was a significant reduction in dyspnea during walk tests (Borg dyspnea score), and significant improvement in WHO functional class in TRACLEER-treated patients. There was a significant reduction in the rate of clinical worsening (Table 6 and Figure 6). Figure 6 shows the log-rank test reflecting clinical worsening over 28 weeks.
Table 6: Incidence of Clinical Worsening, Intent To Treat Population BREATHE-1 Study 351 TRACLEER
125/250 mg twice daily
(n=144)Placebo
(n=69)TRACLEER
125 mg twice daily
(n=21)Placebo
(n=11)Note: Patients may have had more than one reason for clinical worsening. Patients with clinical worsening
[n (%)]9 (6%)p=0.0015 vs. placebo by log-rank test. There was no relevant difference between the 125 mg and 250 mg twice daily groups. 14 (20%) 0 (0%)p=0.033 vs. placebo by Fisher's exact test. 3 (27%) Death 1 (1%) 2 (3%) 0 (0%) 0 (0%) Hospitalization for PAH 6 (4%) 9 (13%) 0 (0%) 3 (27%) Discontinuation due to worsening of PAH 5 (3%) 6 (9%) 0 (0%) 3 (27%) Receipt of epoprostenolReceipt of epoprostenol was always a consequence of clinical worsening. 4 (3%) 3 (4%) 0 (0%) 3 (27%) Figure 6. Time to Clinical Worsening (BREATHE-1)
Time from randomization to clinical worsening with Kaplan-Meier estimate of the proportions of failures in BREATHE-1. All patients (n=144 in the TRACLEER group and n=69 in the placebo group) participated in the first 16 weeks of the study. A subset of this population (n=35 in the TRACLEER group and 13 in the placebo group) continued double-blind therapy for up to 28 weeks.
Figure 6 WHO Functional Class IIIn a randomized, double-blind, multicenter, placebo-controlled trial, 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.
Compared with placebo, TRACLEER treatment was associated with a reduced incidence of worsening of at least one functional class (3% TRACLEER vs. 13% placebo, p=0.03), and improvement in hemodynamic variables (PVR, mPAP, TPR, cardiac index, and SVO2; p <0.05). The +19 m mean (+14 m median) increase in 6-minute walk distance with TRACLEER vs. placebo was not significant (p=0.08). There was a significant delay in time to clinical worsening (first seen primarily as symptomatic progression of PAH) with TRACLEER compared with placebo (hazard ratio 0.2, p=0.01). Findings were consistent in strata with or without treatment with sildenafil at baseline.
Long-term Treatment of PAHLong-term follow-up of patients with Class III and IV PAH who were treated with TRACLEER in open-label extensions of trials (N=235) showed that 93% and 84% of patients were still alive at 1 and 2 years, respectively, after the start of treatment.
These uncontrolled observations do not allow comparison with a group not given TRACLEER and cannot be used to determine the long-term effect of TRACLEER on mortality.
Pediatric StudiesThe efficacy of bosentan was evaluated in an open-label, uncontrolled study in 19 pediatric patients with PAH aged 3 to 15 years. Patients had primary pulmonary hypertension (n=10) or PAH related to congenital heart diseases (9 patients) and were WHO functional class II (n=15, 79%) or class III (n=4; 21%) at baseline. Patients were dosed with bosentan at approximately 2 mg/kg twice daily (body weight adjusted dose, corresponding to the recommended adult dose)
[see Dosage and Administration (2.1)]for 12 weeks. Half of the patients in each group were already being treated with intravenous epoprostenol and the dose of epoprostenol remained constant for the duration of the study.Hemodynamics were measured in 17 patients (Table 7). The mean decrease in PVR was 389 dyn∙sec∙cm-5, which was similar to the effect seen in adults. Hemodynamic improvements from baseline were similar with or without co-administration of epoprostenol.
Table 7: Change from Baseline to Week 12: Hemodynamic Parameters TRACLEER
2 mg/kg twice dailyValues shown are means ± SD CI (L/min/m2)n=17Baseline 4.0±1.5 Absolute Change 0.5±1.4 Mean PAP (mmHg)n=18Baseline 60±18 Absolute Change -8±9 PVR (dyn∙sec∙cm-5)n=17Baseline 1195±755 Absolute Change -389±616 Mean RAP (mmHg)n=18Baseline 6.1±2.7 Absolute Change -0.5±2.3 Pulmonary Arterial Hypertension in Adults related to Congenital Heart Disease with Left-to-Right ShuntsA small study (N=54) and its open-label extension (N=37) of up to 40 weeks in adult patients with Eisenmenger physiology demonstrated effects of TRACLEER on exercise and safety that were similar to those seen in other trials in patients with PAH (WHO Group 1).
- in pediatric patients aged 3 years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability.
- Patients older than 12 years of age: initiate at 62.5 mg orally twice daily; for patients weighing greater than 40 kg, increase to 125 mg orally twice daily after 4 weeks ().
2.2 Recommended DosageAdminister TRACLEER orally following the dosing recommendations in Table 1. Doses above 125 mg twice daily did not appear to confer additional benefit sufficient to offset the increased risk of hepatotoxicity.
Table 1: Dosing Recommendations Initial 4 weeks Maintenance (after 4 weeks) Patients >12 years of age and >40 kg 62.5 mg twice daily 125 mg twice daily Patients >12 years of age and <40 kg 62.5 mg twice daily 62.5 mg twice daily Patients ≤12 years of age ≥4–8 kg 16 mg twice daily 16 mg twice daily >8–16 kg 32 mg twice daily 32 mg twice daily >16–24 kg 48 mg twice daily 48 mg twice daily >24–40 kg 64 mg twice daily 64 mg twice daily - Patients 12 years of age and younger: dosage is based on weight, see(
Table 1: Dosing Recommendations Initial 4 weeks Maintenance (after 4 weeks) Patients >12 years of age and >40 kg 62.5 mg twice daily 125 mg twice daily Patients >12 years of age and <40 kg 62.5 mg twice daily 62.5 mg twice daily Patients ≤12 years of age ≥4–8 kg 16 mg twice daily 16 mg twice daily >8–16 kg 32 mg twice daily 32 mg twice daily >16–24 kg 48 mg twice daily 48 mg twice daily >24–40 kg 64 mg twice daily 64 mg twice daily ).2.2 Recommended DosageAdminister TRACLEER orally following the dosing recommendations in Table 1. Doses above 125 mg twice daily did not appear to confer additional benefit sufficient to offset the increased risk of hepatotoxicity.
Table 1: Dosing Recommendations Initial 4 weeks Maintenance (after 4 weeks) Patients >12 years of age and >40 kg 62.5 mg twice daily 125 mg twice daily Patients >12 years of age and <40 kg 62.5 mg twice daily 62.5 mg twice daily Patients ≤12 years of age ≥4–8 kg 16 mg twice daily 16 mg twice daily >8–16 kg 32 mg twice daily 32 mg twice daily >16–24 kg 48 mg twice daily 48 mg twice daily >24–40 kg 64 mg twice daily 64 mg twice daily - Reduce the dose and closely monitor patients developing aminotransferase elevations more than 3×Upper Limit of Normal (ULN) ().
2.4 Dosage Adjustments for Aminotransferase ElevationsIf aminotransferase levels increase, adjust monitoring and treatment plan according to Table 2.
Discontinue TRACLEER 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 bilirubin ≥2
×Upper Limit of Normal (ULN). There is no experience with the reintroduction of TRACLEER in these circumstances.Table 2: Dosage Adjustment and Monitoring in Patients Developing Aminotransferase Elevations >3×ULN ALT/AST levels Treatment and monitoring recommendations >3 and ≤5 ×ULNConfirm by another aminotransferase test; if confirmed, - in adults and pediatric patients >12 years and >40 kg, reduce the daily dose to 62.5 mg twice daily or interrupt treatment, and monitor aminotransferase levels at least every 2 weeks. If the aminotransferase levels return to pretreatment values, treatment may continue or be reintroduced at 62.5 mg twice daily, with reassessment of aminotransferase levels within 3 days.
- in all other pediatric patients, interrupt treatment with no prior dose reduction. If the aminotransferase levels return to pretreatment values, reintroduce at the dose used prior to treatment interruption, with reassessment of aminotransferase levels within 3 days.
>5 and ≤8 ×ULNConfirm by another aminotransferase test; if confirmed, stop treatment and monitor aminotransferase levels at least every 2 weeks. Once the aminotransferase levels return to pretreatment values, - in adults and pediatric patients >12 years and >40 kg, consider reintroduction of treatment at 62.5 mg twice daily, with reassessment of aminotransferase levels within 3 days.
- in all other pediatric patients, consider reintroduction at the dose used prior to treatment interruption, with reassessment of aminotransferase levels within 3 days.
>8 ×ULNStop treatment permanently. There is no experience with reintroduction of TRACLEER in these circumstances.
- Nursing mothers: Choose breastfeeding or TRACLEER ().
8.2 LactationRisk SummaryData from a case report describe the presence of bosentan in human milk. There is insufficient information about the effects of bosentan on the breastfed infant and no information on the effects of bosentan on milk production. Because of the potential for serious adverse reactions, such as fluid retention and hepatotoxicity, in breastfed infants from TRACLEER, advise women not to breastfeed during treatment with TRACLEER.