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EARLY (FC II) Significantly improved in PVR, CI, and mPAP2,3
–197 dyn•sec/cm5 (2.46 Wood units) treatment effect. Comparable treatment effect also observed in subgroup of patients receiving sildenafil at baseline (n=28).2,4
PVR was a coprimary endpoint along with 6MWD.
No formal hypothesis testing was planned for these exploratory comparisons. The relationship between hemodynamic effects and 6MWD is unknown. Study 351 (FC III) Significantly improved 4 key hemodynamic parameters3,5
BREATHE-5 (Eisenmenger syndrome FC III) Significantly improved PVRi6
Baseline values: 2870 ± 1209.3, placebo; 3425.1 ± 1410.5, Tracleer.
‡–472 dyn•sec/cm5 = –5.9 Wood units. Change in systemic pulse oximetry and PVRi were coprimary endpoints in BREATHE-5. Note: In clinical studies of Tracleer, hemodynamics were not studied in FC IV patients. CI cardiac index; FC functional class: mPAP mean pulmonary arterial pressure; PAP pulmonary arterial pressure; PVR pulmonary vascular resistance; RAP right atrial pressure. *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.
EARLY Endothelin Antagonist tRial in miLdlY symptomatic PAH* patients. The first and only randomized, double-blind, placebo-controlled trial conducted solely in mildly symptomatic (functional class II) patients with PAH* (N=185). Patients were randomized to Tracleer (62.5 mg BID, 125 mg BID) or placebo. Trial duration was 6 months. Concomitant use of anticoagulants and calcium channel blockers was allowed. Baseline PVR: 839 ± 531 dyn•sec/cm5, Tracleer; 805 ± 531 dyn•sec/cm5, placebo. Baseline CI: 2.7 ± 0.8 L/min/m2, Tracleer; 2.7 ± 0.6 L/min/m2, placebo. Baseline mPAP: 52.5 ± 18.9 mm Hg, Tracleer; 52.3 ± 16.0 mm Hg, placebo. Both the Tracleer group and the placebo group included some patients on sildenafil at baseline (Tracleer, n=14; placebo, n=15).2 Study 351 Randomized, double-blind, placebo-controlled study of Tracleer 125 mg BID vs placebo in patients with WHO functional class III or IV pulmonary arterial hypertension* (N=32).5 BREATHE-5 Randomized, double-blind, placebo-controlled trial in adults with PAH* associated with Eisenmenger syndrome (N=54). Patients were randomized to Tracleer (62.5 mg BID, 125 mg BID) or placebo. Background therapies included anticoagulants, vasodilators, diuretics, and supplemental oxygen.6
* Please see Indication above. |
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