Bosentan (Tracleer®)
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Indications: Bosentan is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1)
to improve exercise ability and to decrease clinical worsening.
Mechanism: Bosentan works by binding specifically to two different endothelin receptors (ETa and ETb) and blocking the effects of endothelin at these receptors. Bosentan binds with more specificity for ETa receptors than for ETb receptors. Endothelin-1 (ET-1) is a substance in the body which is elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a clinical role in this disease.
Dosing: Start treatment with bosentan at 62.5 mg twice daily for 4 weeks, then increase the dose to the maintenance dose of 125 mg twice daily. Doses above 125 mg twice daily offer no additional benefit and
are offset by an increased risk of hepatotoxicity. Bosentan should be given in the morning and evening with or without food.
Efficacy: Bosentan was shown effective in two randomized, double-blind, multi-center, placebo-controlled trials that were conducted in 32 and 213 patients, respectively. The larger study, named BREATHE-1, compared two doses of bosentan with placebo. The two studies evaluated 6-minute walk distance, either at 3 months (Study 351) or 4 months (BREATHE-1). Results are shown in Table 1.
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In both trials, treatment with bosentan resulted in a significant increase in exercise ability. The improvement in walk distance was apparent after 1 month of treatment (with 62.5 mg twice daily) and fully developed by about 2 months of treatment. It was maintained for up to 7 months of double-blind treatment (Figure 1).
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Clinical worsening was evaluated as the sum of death, hospitalizations for PAH, discontinuation of therapy because of PAH, and need for epoprostenol. There was a significant reduction in shortness of breath during walk tests. There was also a significant improvement noted in WHO functional class in bosentan-treated patients accompanied by a significant reduction in the rate of clinical worsening (Figure 2).
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Adverse Events: The most common adverse reactions seen with bosentan are respiratory tract infection and anemia. Bosentan may increase the risk of liver toxicity (as noted in ALT/AST elevations), in some cases with at least a 3-fold upper limit of normal elevation of ALT/AST accompanied by elevated bilirubin. Because these changes indicate the potential for serious hepatotoxicity, serum AST/ALT levels must be measured prior to initiation of treatment and then monthly.
Warnings:
- Pre-existing hepatic impairment: Avoid use in patients with moderate and severe impairment.
- Fluid retention: May require intervention.
- Pulmonary veno-occlusive disease (PVOD): If signs of pulmonary edema occur, consider the diagnosis of associated PVOD and consider discontinuing bosentan.
- Decreased sperm counts.
- Decreases in hemoglobin and hematocrit: Therefore it is necessary to monitor hemoglobin levels after and 3 months of treatment, then every 3 months thereafter.
Contraindications:
- Pregnancy-Bosentan is likely to cause major birth defects if used during pregnancy.
- Do not use with Cyclosporine A
- Do not use with Glyburide
- Hypersensitivity
Metabolism/Drug interactions:
Bosentan is metabolized by the liver using the cytochrome P450 system. Specifically, CYP2C9 and CYP3A metabolize bosentan. Bosentan may also act as an inducer of other isoenzymes, specifically CYP3A and CYP2C9. This means that drugs that are metabolized by CYP3A4 and 2C9 will have decreased blood levels as a result of increased metabolism induced by bosentan.
- Ritonavir
– Discontinue bosentan 36 hours prior to initiation of ritonavir.
– Patients on ritonavir: Initiate bosentan at 62.5 mg once daily or every other day.
- Hormonal contraceptives and simvastatin exposure and effectiveness are reduced when administered along with bosentan.
Tracleer Access Program (T.A.P.): Because of the risks of hepatotoxicity and birth defects, healthcare professionals who prescribe bosentan must enroll in the Tracleer Access Program (T.A.P.) and must comply with the required monitoring to minimize the risks associated with Tracleer.
T.A.P. Patient/Prescriber Enrollment Form: http://www.tracleer.com/docs/Tracleer_Enrollment_Form.pdf
Tracleer Prescriber Certification Form: http://www.tracleerrems.com/docs/Prescriber_Certification_Form.pdf
Full US Prescribing Information can be found here: http://www.tracleer.com/docs/Tracleer_Full_Prescribing_Information.pdf
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