Bosentan 62.5 mg · Tablets

Bosentan is a specific and competitive antagonist at endothelin receptor types ETA and ETB. Bosentan has a slightly higher affinity for ETA receptors than for ETB receptors. The clinical impact of dual endothelin blockage is unknown.

Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ETA and ETB receptors in the endothelium and vascular smooth muscle. ET-1 concentrations are elevated in plasma and lung tissue of patients with PAH, suggesting a pathogenic role for ET-1 in this disease.

General — After oral administration, maximum plasma concentrations of bosentan are attained within 3 hours to 5 hours and the terminal elimination half-life is about 5 hours in healthy adult subjects. The exposure to bosentan after intravenous and oral administration is about twice as high in adult patients with PAH as it is in healthy adult subjects.

Absorption — The absolute bioavailability of bosentan in normal volunteers is about 50% and is unaffected by food.

Bosentan is highly bound (> 98%) to plasma proteins, mainly albumin. Bosentan does not penetrate into erythrocytes. The volume of distribution is about 18 L.

Metabolism — Bosentan has three metabolites, one of which is pharmacologically active and may contribute 10% to 20% of the effect of bosentan. Bosentan is an inducer of CYP2C9 and CYP3A and possibly also of CYP2C19. Upon multiple oral dosing, plasma concentrations in healthy adults decrease gradually to 50% to 65% of those seen after single dose administration, probably the effect of auto-induction of the metabolizing liver enzymes. Steady-state is reached within 3 days to 5 days.

Excretion — Bosentan is eliminated by biliary excretion following metabolism in the liver. Less than 3% of an administered oral dose is recovered in urine. Total clearance after a single intravenous dose is about 4 L/h in patients with PAH.

Pediatrics — The average plasma exposure to bosentan at steady state (AUCss) in pediatric patients with PAH aged 3 years to 15 years treated with 31.25 mg, 62.5 mg or 125 mg (approximately 2 mg/kg) film-coated tablet twice daily is 37% lower than that observed in adult patients with PAH receiving 125 mg film-coated tablet twice daily. The average exposure to bosentan in these pediatric patients was approximately half the exposure in adult patients treated with 125 mg film-coated tablets twice daily.

Based on these findings, exposure to bosentan reaches a plateau at lower doses in pediatric patients than in adults, and doses higher than 2 mg/kg twice daily do not increase the exposure to bosentan in pediatric patients.

Hepatic Impairment — In vitro and in vivo evidence showing extensive hepatic metabolism of bosentan suggests that liver impairment could significantly increase exposure to bosentan. In a study comparing 8 patients with mild liver impairment (Child-Pugh Class A) to 8 controls, the single-and multiple-dose pharmacokinetics of bosentan were not altered in patients with mild hepatic impairment.

In another small (N=8) pharmacokinetic study, the steady-state AUC of bosentan was on average 4.7 times higher and the active metabolite Ro 48-5033 was 12.4 times higher in 5 patients with moderately impaired liver function (Child-Pugh Class B) and PAH associated with portal hypertension than in 3 patients with normal liver function and PAH of other etiologies.

The pharmacokinetics of bosentan have not been evaluated in patients with severe liver impairment (Child-Pugh Class C) [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Use in Specific Populations (8.6)].

Renal Impairment — In patients with severe renal impairment (creatinine clearance 15 mL/min to 30 mL/min), plasma concentrations of bosentan were essentially unchanged and plasma concentrations of the three metabolites were increased about 2-fold compared to subjects with normal renal function. These differences do not appear to be clinically important.

Ketoconazole — Coadministration of bosentan 125 mg twice daily and ketoconazole, a potent CYP3A inhibitor, increased the plasma concentrations of bosentan by approximately 100% in normal volunteers. No dose adjustment of bosentan is necessary, but increased effects of bosentan should be considered.