BREATHE-5 was the first randomized, double-blind, placebo-controlled trial in adult patients with PAH* associated with Eisenmenger syndrome (N=54)1
Design
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Dosing and duration
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Randomized, double-blind, placebo-controlled study
of 54 patients with PAH* associated
with Eisenmenger syndrome. Patients were randomized to Tracleer (n=37) or placebo
(n=17).
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Tracleer 62.5 BID first 4 weeks
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Tracleer 125 mg BID following 12 weeks
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Primary endpoints
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Secondary endpoints
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PVRi
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Change in oxygen saturation at week 16
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Change in exercise ability
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Change in hemodynamics
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Change in functional class
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PAH* etiology (Tracleer treatment group)
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Background therapies
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CHD: 37 (100%)
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—
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ASD: 8 (22%)
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—
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VSD: 24 (65%)
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ASD + VSD: 5 (14%)
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Anticoagulants
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Vasodilators
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Diuretics
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Supplemental oxygen
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Baseline functional class status
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Baseline characteristics
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FC III: 100%
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Atrial septal defect (ASD) ≥2 cm (n=13); ventricular septal defect (VSD) ≥1 cm (n=36);
ASD + VSD (n=5)
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Results
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Reduces PVRi1
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Improved exercise ability1
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No increase in shunting
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Results confirm that Tracleer did not worsen the shunt, an important safety consideration
in Eisenmenger syndrome.1
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No significant change in oxygen saturation from baseline to 16 weeks (82.4% ± 5.3%,
baseline; 83.8% ± 5.5%, week 16)2
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*INDICATION
Tracleer is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve
exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly
patients with NYHA 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 systemic-to-pulmonary shunts (18%).
Considerations for use
Patients with WHO class II symptoms showed reduction in the rate of clinical deterioration and a trend for
improvement in walk distance. Physicians should consider whether these benefits are sufficient to offset the
risk of liver injury in WHO class II patients, which may preclude future use as their disease progresses.
IMPORTANT SAFETY INFORMATION
Because of the risks of liver injury and birth defects, Tracleer may be prescribed and dispensed only
through the Tracleer Access Program (T.A.P.), a restricted distribution program, by calling 1-866-228-3546.
Only prescribers and pharmacies registered with T.A.P. may prescribe and distribute Tracleer. Tracleer
may be dispensed only to patients who are enrolled in and meet all conditions of T.A.P.
Liver injury
Elevations of liver aminotransferases (ALT, AST) and liver failure have been reported with Tracleer.
In a setting of close monitoring, rare cases of liver failure and unexplained hepatic cirrhosis were
observed after prolonged treatment. In general, avoid using Tracleer in patients with elevated
aminotransferases
(>3 × ULN). Measure liver aminotransferases prior to initiation of treatment and
then monthly. Discontinue Tracleer if aminotransferase elevations are accompanied by signs or symptoms
of liver dysfunction or injury or increases in bilirubin ≥2 × ULN.
Teratogenicity
Based on animal data, Tracleer is likely to cause major birth defects if used during pregnancy. Exclude pregnancy before and during treatment. To prevent pregnancy, females of childbearing potential must use 2 reliable forms of contraception during treatment and for 1 month after stopping Tracleer unless the patient has a tubal sterilization or Copper T 380A IUD or LNg 20-IUS inserted, in which case no other contraception is needed. Monthly pregnancy tests should be obtained.
CONTRAINDICATIONS
Tracleer is contraindicated with cyclosporine A, glyburide, in females who are or may become pregnant,
or in patients who are hypersensitive to bosentan or any component of Tracleer.
WARNINGS AND PRECAUTIONS
In clinical trials, Tracleer caused ALT/AST elevations (>3 × ULN) in 11% of patients accompanied by elevated
bilirubin in a few cases. The combination of hepatocellular injury (increases in aminotransferases of >3 × ULN)
and increases in total bilirubin (≥3 × ULN) is a marker for potential serious liver injury. Liver aminotransferase
levels must be measured prior to initiation of treatment and then monthly. Avoid using Tracleer in patients
with moderate or severe liver impairment or elevated ALT/AST >3 × ULN.
If clinically significant fluid retention develops, with or without associated weight gain, the cause,
such as Tracleer or underlying heart failure, must be determined. Patients may require treatment or
Tracleer therapy may need to be discontinued.
Preclinical data and an open-label safety study (N=25) showed a decline in sperm count of ≥50% in 25% of
Tracleer-treated patients after 3 or 6 months. After 6 months, sperm count remained in normal range, with
no changes in sperm morphology or motility, or hormone levels. Endothelin receptor antagonists such as
Tracleer may adversely affect spermatogenesis.
Treatment with Tracleer can cause a dose-related decrease in hemoglobin (Hgb) and hematocrit. Hgb should be
checked after 1 and 3 months, and then every 3 months. Upon marked decrease in Hgb, determine the cause and
need for specific treatment.
If signs of pulmonary edema occur, the possibility of associated pulmonary veno-occlusive disease should
be considered. Tracleer should be discontinued.
ADVERSE EVENTS
In Tracleer pivotal trials, the most common adverse events occurring more often in Tracleer-treated
patients than in patients taking placebo (≥2%) were respiratory tract infection, edema, hypotension,
sinusitis, arthralgia, liver function test abnormal, palpitations, and anemia.
Please see full
Prescribing Information, including
BOXED WARNING about liver injury and pregnancy.
- Galiè N, Beghetti M, Gatzoulis MA, et al, for the Bosentan Randomized Trial of Endothelin
Antagonist Therapy-5 (BREATHE-5) Investigators. Bosentan therapy in patients with
Eisenmenger syndrome: a multicenter, double-blind, randomized, placebocontrolled
study. Circulation. 2006;114:48-54.
- Data on file, Actelion Pharmaceuticals.
