Bosentan (Page 5 of 8)

8.4 Pediatric Use

The efficacy of bosentan in patients <18 years is supported by data from an uncontrolled trial in which 19 pediatric patients were treated with bosentan. In this study, cardiopulmonary hemodynamic improvements were similar to those seen in adults treated with bosentan [see Pulmonary Arterial Hypertension (14.1)]. Safety in pediatric patients is supported by data from 100 pediatric patients treated with bosentan for a median of 17 months [see Clinical Studies Experience (6.1), Pulmonary Arterial Hypertension (14.1)].

Juvenile Animal Toxicity Data

In a juvenile rat toxicity study, rats were treated from Day 4 postpartum to adulthood (Day 69 postpartum). Decreased body weights, absolute weights of testes and epididymides, and reduced number of sperm in epididymides were observed after weaning. No effect on testis histology or sperm morphology and function was seen. The NOAEL was 4 times (at Day 4 postpartum) and 2 times (Day 69 postpartum) the human therapeutic exposure, respectively.

No effects on general development, sensory, cognitive function and reproductive performance were detected at the highest dose tested in juvenile rats, 7 times the therapeutic exposure in children with PAH.

8.5 Geriatric Use

Clinical studies of bosentan did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.

8.6 Hepatic Impairment

Because there is in vitro and in vivo evidence that the main route of excretion of bosentan is biliary, liver impairment could be expected to increase exposure (Cmax and AUC) of bosentan. The pharmacokinetics of bosentan have not been evaluated in patients with severe liver impairment (Child-Pugh Class C). In patients with moderate hepatic impairment (Child-Pugh Class B), the systemic exposures to bosentan and its active metabolite increased significantly. Bosentan should generally be avoided in patients with moderate or severe liver impairment. Pharmacokinetics of bosentan were not altered in patients with mild impairment of hepatic function (Child-Pugh Class A) [see Dosage and Administration (2.6), Warnings and Precautions (5.1), Pharmacokinetics (12.3)].

8.7 Renal Impairment

The effect of renal impairment on the pharmacokinetics of bosentan is small and does not require dosing adjustment [see Pharmacokinetics (12.3)].

10 OVERDOSAGE

Bosentan has been given as a single dose of up to 2,400 mg in normal volunteers, or up to 2,000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1,000 mg twice daily of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed.

In the postmarketing period, there was one reported overdose of 10,000 mg of bosentan taken by an adolescent male patient. He had symptoms of nausea, vomiting, hypotension, dizziness, sweating, and blurred vision. He recovered within 24 hours with blood pressure support.

Bosentan is unlikely to be effectively removed by dialysis due to the high molecular weight and extensive plasma protein binding.

11 DESCRIPTION

Bosentan, an endothelin receptor antagonist that belongs to a class of highly substituted pyrimidine derivatives, with no chiral centers. It is designated chemically as 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2´]-bipyrimidin-4-yl]-benzenesulfonamide monohydrate and has the following structural formula:

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C27 H29 N5 O6 S•H2 O M.W. 569.64

Bosentan is a white to yellowish powder. It is poorly soluble in water (1.0 mg/100 mL) and in aqueous solutions at low pH (0.1 mg/100 mL at pH 1.1 and 4.0; 0.2 mg/100 mL at pH 5.0). Solubility increases at higher pH values (43 mg/100 mL at pH 7.5). In the solid state, bosentan is very stable, is not hygroscopic and is not light sensitive.

Bosentan is available as 62.5 mg and 125 mg film-coated tablets for oral administration, and contains the following excipients: corn starch, ethyl cellulose, glyceryl behenate, hypromellose, iron oxide red, iron oxide yellow, magnesium stearate, pregelatinized corn starch, povidone K90, sodium starch glycolate, titanium dioxide and triacetin. Each bosentan 62.5 mg tablet contains 64.541 mg of bosentan monohydrate, equivalent to 62.5 mg of bosentan base. Each bosentan 125 mg tablet contains 129.082 mg of bosentan monohydrate, equivalent to 125 mg of bosentan base.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.3 Pharmacokinetics

General

After oral administration, maximum plasma concentrations of bosentan are attained within 3 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.

In a relative bioavailability study in healthy adults, the peak plasma concentration and area under the plasma concentration-time curve for bosentan are on an average 14% and 11%, respectively, lower following administration of the oral dispersible tablet compared to the film-coated tablet.

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.

Elimination

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 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.

Specific Populations

Pediatrics

The average plasma exposure to bosentan at steady state (AUCss) in pediatric patients with PAH aged 3 to 15 years treated with 31.25, 62.5 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. Following administration of 4 mg/kg twice daily doses of dispersible tablet in patients with PAH aged 2 to 11 years, the average systemic exposure to bosentan at steady state is similar to that observed with 2 mg/kg. 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.

The exposure to bosentan at 2 mg/kg three times daily dosing of dispersible tablet is similar to that of 2 mg/kg twice daily dosing in patients with PAH aged 3 months to 12 years.

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 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.

Drug Interactions

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.

Warfarin

Coadministration of bosentan 500 mg twice daily for 6 days in normal volunteers decreased the plasma concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A substrate) by 29 and 38%, respectively. Clinical experience with concomitant administration of bosentan and warfarin in patients with PAH did not show clinically relevant changes in INR or warfarin dose (baseline vs. end of the clinical studies), and the need to change the warfarin dose during the trials due to changes in INR or due to adverse events was similar among bosentan- and placebo-treated patients.

Digoxin, Nimodipine, and Losartan

Bosentan has no significant pharmacokinetic interactions with digoxin and nimodipine, and losartan has no significant effect on plasma levels of bosentan.

Sildenafil

In normal volunteers, coadministration of multiple doses of 125 mg twice daily bosentan and 80 mg three times daily sildenafil resulted in a reduction of sildenafil plasma concentrations by 63% and increased bosentan plasma concentrations by 50%. The changes in plasma concentrations were not considered clinically relevant and dose adjustments are not necessary. This recommendation holds true when sildenafil is used for the treatment of PAH or erectile dysfunction.

Tadalafil

Bosentan (125 mg twice daily) reduced tadalafil (40 mg once per day) systemic exposure (AUC) by 42% and Cmax by 27% following multiple dose coadministration. Tadalafil did not affect the exposure (AUC and Cmax ) of bosentan or its metabolites.

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Figure 3. CYP Induction-mediated effect of bosentan on other drugs

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Figure 4. Effects of other drugs on bosentan

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