Safety profile

Adverse events occurring in ≥3% of patients treated with Tracleer
and more frequently than the placebo group¹

Adverse event	Tracleer (n=258)	Placebo (n=172)
Respiratory tract infection	56 (22%)	30 (17%)
Headache	39 (15%)	25 (14%)
Edema	28 (11%)	16 (9%)
Chest pain	13 (5%)	8 (5%)
Syncope	12 (5%)	7 (4%)
Flushing	10 (4%)	5 (3%)

Adverse event	Tracleer (n=258)	Placebo (n=172)
Hypotension	10 (4%)	3 (2%)
Sinusitis	9 (4%)	4 (2%)
Arthralgia	9 (4%)	3 (2%)
Liver function test abnormal	9 (4%)	3 (2%)
Palpitations	9 (4%)	3 (2%)
Anemia	8 (3%)	—

Safety profile when administered with other standard medication in pivotal trials

	Patients receiving Tracleer continued other medications, including anticoagulants, digoxin, diuretics, and vasodilators such as calcium channel blockers and ACE inhibitors.^2,3
	Patients receiving epoprostenol within 3 months of study screening were ineligible for participation.^2,3
	In the EARLY trial, both the Tracleer group and the placebo group included some patients on sildenafil at baseline (Tracleer, n=14; placebo, n=15).⁴

Drug-drug interactions¹

Tracleer's DDI profile is well-studied, meeting all postapproval commitments from the FDA

	Tracleer is contraindicated for use with cyclosporine A and 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.
—	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 rifampicin, a CYP3A inducer, liver function should be monitored weekly for the first 4 weeks before reverting to normal (monthly) monitoring.
—	Co-administration of tacrolimus and bosentan resulted in markedly increased plasma concentrations of bosentan in animals; caution should be exercised if they are used together.
—	When co-administered with ketoconazole, a potent CYP3A inhibitor, no dose adjustment of bosentan 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.
	Tracleer has no significant interaction with iloprost.

*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.

Review how to prescribe Tracleer

Tracleer (bosentan) full prescribing information. Actelion Pharmaceuticals US, Inc. February 2011.
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.
Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896-903.
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.

Safety profile

Adverse events occurring in ≥3% of patients treated with Tracleerand more frequently than the placebo group1

Safety profile when administered with other standard medication in pivotal trials

Drug-drug interactions1

Adverse events occurring in ≥3% of patients treated with Tracleer
and more frequently than the placebo group¹

Drug-drug interactions¹