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Important Safety Information
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- In the Tracleer pivotal clinical trials, 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.
- Discontinue Tracleer if aminotransferase elevations are accompanied by signs or symptoms of liver dysfunction or injury or increases in bilirubin ≥ 2 x ULN.
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- 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 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.
- Please remember that a patient receiving Tracleer can transition into a female of childbearing potential during the course of therapy.
For complete safety information, including boxed warning, please see full prescribing information.
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- Patients receiving Tracleer continued other medications, including anticoagulants, digoxin, diuretics, and vasodilators such as calcium channel blockers and ACE inhibitors.2,4,5
- Patients receiving epoprostenol within 3 months of study screening were ineligible for participation.2,4,5
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- Tracleer is contraindicated for use with cyclosporine A and glyburide.1
- Tracleer is metabolized by CYP2C9 and CYP3A.1
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Co-administration with agents that are metabolized by these pathways may affect plasma concentrations of one or both agents. |
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When initiating lopinavir/ritonavir and other ritonavir-containing HIV regimens, dosage adjustment of Tracleer is necessary.
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When co-administered with simvastatin, or other statins that are CYP3A substrates, dosage adjustment of such statins may need to be considered.
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When co-administered with rifampicin, a CYP3A inducer, liver function should be monitored weekly for the first 4 weeks before reverting to normal monitoring.
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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.
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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.
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- There are no clinically relevant interactions between Tracleer and warfarin, digoxin, nimodipine, losartan, or sildenafil.1
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Dose adjustments are not necessary when Tracleer and sildenafil are co-administered. |
- Tracleer has no significant interaction with iloprost.1
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- Decreases in hemoglobin concentration:1
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Measured 0.9 g/dL (overall mean decrease) for Tracleer-treated patients
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Were detected during the first few weeks of treatment
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Stabilized by 4–12 weeks of treatment
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- Monitoring of hemoglobin concentrations recommended after 1
and 3 months, and quarterly thereafter1
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- 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 levels1
- It cannot be excluded that endothelin receptor antagonists such
as Tracleer have an adverse effect on spermatogenesis1
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- 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.
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- 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) 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 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 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.
REFERENCES
1. Tracleer (bosentan) full prescribing information. Actelion Pharmaceuticals US, Inc. August 2009.
2. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial
hypertension. N Engl J Med. 2002;346:896–903.
3. Data on file, Actelion Pharmaceuticals.
4. 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.
5. Galič 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.
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Important Safety Information
