Bosentan

Cytochrome P450: Coadministration of TRACLEER with drugs metabolized by CYP2C9 and CYP3A can increase exposure to TRACLEER and/or the coadministered drug ( 4.2 , 4.3 , 7.1 ). Hormonal contraceptives: TRACLEER use decreases contraceptive exposure and reduces effectiveness ( 7.2 ).

7.1 Cytochrome P450 Drug Interactions Bosentan is metabolized by CYP2C9 and CYP3A. Inhibition of these enzymes may increase the plasma concentration of bosentan [see Clinical Pharmacology (12.3) ] . Concomitant administration of both a CYP2C9 inhibitor (such as fluconazole or amiodarone) and a strong CYP3A inhibitor (e.g., ketoconazole, itraconazole) or a moderate CYP3A inhibitor (e.g., amprenavir, erythromycin, fluconazole, diltiazem) with TRACLEER will likely lead to large increases in plasma concentrations of bosentan. Co-administration of such combinations of a CYP2C9 inhibitor plus a strong or moderate CYP3A inhibitor with TRACLEER is not recommended.

Bosentan is an inducer of CYP3A and CYP2C9. Consequently plasma concentrations of drugs metabolized by these two isozymes will be decreased when TRACLEER is co-administered. Bosentan had no relevant inhibitory effect on any CYP isozyme in vitro (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A). Consequently, TRACLEER is not expected to increase the plasma concentrations of drugs metabolized by these enzymes. Figure 1. CYP3A induction-mediated effect of bosentan on other drugs Figure 2. Effect of other drugs on bosentan Figure 1 Figure 2

7.2 Hormonal Contraceptives Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when TRACLEER is co-administered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking TRACLEER [see Use in Specific Populations (8.3) ] . An interaction study demonstrated that co-administration of bosentan and a combination oral hormonal contraceptive produced average decreases of norethindrone and ethinyl estradiol levels of 14% and 31%, respectively. However, decreases in exposure were as much as 56% and 66%, respectively, in individual subjects.

8.1 Pregnancy Risk Summary Based on data from animal reproduction studies, TRACLEER may cause fetal harm, including birth defects and fetal death, when administered to a pregnant female and is contraindicated during pregnancy [see Contraindications (4.1) ] . Available data from postmarketing reports and published literature over decades of use with endothelin receptor antagonists (ERA) in the same class as TRACLEER have not identified an increased risk of major birth defects; however, these data are limited.

Methodological limitations of these postmarketing reports and published literature include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and missing data. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal ERA use. In animal reproduction studies, oral administration of bosentan to pregnant rats at 2-times the maximum recommended human dose (MRHD) on a mg/m 2 basis caused teratogenic effects in rats, including malformations of the head, mouth, face, and large blood vessels [see Animal Data ] . Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Animal Data Bosentan was teratogenic in rats given oral doses two times the MRHD (on a mg/m 2 basis). In an embryo-fetal toxicity study in rats, bosentan showed dose-dependent teratogenic effects, including malformations of the head, mouth, face and large blood vessels.

Bosentan increased stillbirths and pup mortality at oral doses 2 and 10 times the MRHD (on a mg/m 2 basis). Although birth defects were not observed in rabbits given oral doses of up to the equivalent of 10.5 g/day in a 70 kg person, plasma concentrations of bosentan in rabbits were lower than those reached in the rat. The similarity of malformations induced by bosentan and those observed in endothelin-1 knockout mice and in animals treated with other endothelin receptor antagonists indicates that embryo-fetal toxicity is a class effect of these drugs.