Warnings and Precautions

Because of the risks associated with treatment, the use of Tracleer requires participation in the Tracleer Access Program (T.A.P.^®), a restricted distribution program. In order to receive Tracleer, prescribers and patients must enroll in T.A.P. and agree to comply with the requirements of this program.

Tracleer may cause liver damage¹

	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 liver injury, liver monitoring of all patients is essential prior to initiation of treatment and monthly thereafter.
	Elevations in aminotransferases require close attention. If elevated aminotransferase levels are seen, changes in monitoring and treatment must be initiated.
	Discontinue Tracleer if aminotransferase elevations are accompanied by signs or symptoms of liver dysfunction or injury or increases in bilirubin ≥2 × ULN.

Liver enzyme elevations: experience and management¹

	Use of Tracleer should generally be avoided in patients with elevated aminotransferases (>3 × ULN) at baseline because monitoring liver injury may be more difficult.
	It is important to adhere strictly to the monthly monitoring schedule for the duration of treatment.

Established LFT monitoring protocol¹

Tracleer aminotransferase (ALT/AST) management
ALT/AST level	Treatment and monitoring recommendations
1 to 3 × ULN	Continue to monitor; no change in monitoring schedule or dosage
>3 to ≤5 × ULN	Confirm by another test; if confirmed, reduce the dose or interrupt treatment and monitor LFT levels every 2 weeks Continue or reintroduce Tracleer if levels return to pretreatment levels
>5 to ≤8 × ULN	Confirm by another test; if confirmed, stop therapy; monitor LFTs at least every 2 weeks Consider reintroduction of therapy if LFTs return to pretreatment levels
>8 × ULN	Stop therapy; do not reintroduce

If Tracleer is reintroduced, it should be at the starting dose; aminotransferase levels should be checked within 3 days and thereafter according to the recommendations above.

If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥2 × ULN, treatment should be stopped. There is no experience with the reintroduction of Tracleer in these circumstances.

Pregnancy must be excluded and prevented¹

	Tracleer is very likely to produce major birth defects if used by pregnant females, based on animal data.
	To prevent pregnancy, females of childbearing potential must use 2 reliable methods of contraception during treatment and for 1 month after stopping Tracleer.

Hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives, should not be used as the sole means of contraception because they may not be effective in patients receiving Tracleer. Monthly pregnancy tests should be obtained.

Fluid retention¹

	Peripheral edema is a known clinical consequence of PAH and worsening PAH, and is also a known effect of other endothelin receptor antagonists.
	In PAH clinical trials with Tracleer, combined adverse events of fluid retention or edema were reported in 1.7% (placebo-corrected) of patients.
	There have been postmarketing reports of fluid retention in patients with pulmonary hypertension occurring within weeks after starting Tracleer.
	If clinically significant fluid retention develops, further evaluation should be undertaken to determine the cause, and the possible need for treatment or discontinuation of Tracleer therapy.

Decreased sperm counts¹

	In an open-label study (N=25), a decline in sperm count of at least 50% in 25% of Tracleer-treated patients was observed after 3 or 6 months. Sperm count remained in normal range after 6 months, with no changes in sperm morphology, sperm motility, or hormone levels.
	It cannot be excluded that endothelin receptor antagonists such as Tracleer have an adverse effect on spermatogenesis.
	Decreases in hemoglobin concentration:

Monitoring of hemoglobin concentrations is recommended after 1 and 3 months, and quarterly thereafter.

Associated with dose-related decreases in hemoglobin¹

Decreases in hemoglobin concentration:

Monitoring of hemoglobin concentrations is recommended after 1 and 3 months, and quarterly thereafter.

Pulmonary veno-occlusive disease (PVOD)¹

If signs of pulmonary edema occur when Tracleer is administered, the possibility of associated PVOD should be considered and Tracleer should be discontinued.

Tracleer is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) in patients with WHO Class II-IV symptoms, to improve exercise ability and decrease the rate of clinical worsening. 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 potential benefits are sufficient to offset liver injury in WHO Class II patients, which may preclude future use as their disease progresses.

Important safety information

Because of the associated risks, Tracleer may be prescribed only through the Tracleer Access Program.

Potential for serious liver injury (including, after prolonged treatment, rare cases of liver failure and unexplained hepatic cirrhosis in a setting of close monitoring)—Liver monitoring of all patients is essential prior to initiation of treatment and monthly thereafter.

High potential for major birth defects—Pregnancy must be excluded and prevented through the use of reliable forms of birth control; monthly pregnancy tests should be obtained.

Contraindicated for use with cyclosporine A and glyburide.

Please see full prescribing information including BOXED WARNING.

Review the safety profile of Tracleer

1. Tracleer (bosentan) full prescribing information. Actelion Pharmaceuticals US, Inc. August 2009.