TRACLEER®
[bosentan]

62.5 mg and 125 mg film-coated tablets

DESCRIPTION

Bosentan is the first of a new drug class, an endothelin receptor antagonist.

TRACLEER® (bosentan) 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:

Bosentan has a molecular weight of 569.64 and a molecular formula of C27H29N5O6S•H2O. 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.

TRACLEER® is available as 62.5 mg and 125 mg film-coated tablets for oral administration, and contains the following excipients: corn starch, pregelatinized starch, sodium starch glycolate, povidone, glyceryl behenate, magnesium stearate, hydroxypropylmethylcellulose, triacetin, talc, titanium dioxide, iron oxide yellow, iron oxide red, and ethylcellulose. Each TRACLEER® 62.5 mg tablet contains 64.541 mg of bosentan, equivalent to 62.5 mg of anhydrous bosentan. Each TRACLEER® 125 mg tablet contains 129.082 mg of bosentan, equivalent to 125 mg of anhydrous bosentan.

CLINICAL PHARMACOLOGY

Mechanism of Action

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 pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease. 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.

Pharmacokinetics

General

After oral administration, maximum plasma concentrations of bosentan are attained within 3–5 hours and the terminal elimination half-life (t1/2) is about 5 hours in healthy adult subjects. The exposure to bosentan after intravenous and oral administration is about 2-fold greater in adult patients with pulmonary arterial hypertension than in healthy adult subjects.

Absorption and Distribution

The absolute bioavailability of bosentan in normal volunteers is about 50% and is unaffected by food. The volume of distribution is about 18 L. Bosentan is highly bound (> 98%) to plasma proteins, mainly albumin. Bosentan does not penetrate into erythrocytes.

Metabolism and Elimination

Bosentan has three metabolites, one of which is pharmacologically active and may contribute 10%–20% of the effect of bosentan. Bosentan is an inducer of CYP2C9 and CYP3A4 and possibly also of CYP2C19. Total clearance after a single intravenous dose is about 4 L/hr in patients with pulmonary arterial hypertension. Upon multiple oral dosing, plasma concentrations in healthy adults decrease gradually to 50-65% of those seen after single dose administration, probably the effect of auto-induction of the metabolizing liver enzymes. Steady-state is reached within 3-5 days. Bosentan is eliminated by biliary excretion following metabolism in the liver. Less than 3% of an administered oral dose is recovered in urine.

Special Populations

It is not known whether bosentan's pharmacokinetics is influenced by gender, body weight, race, or age.

Liver Function Impairment

In vitro and in vivo evidence showing extensive hepatic metabolism of bosentan suggests that liver impairment could significantly increase exposure of bosentan. In a study comparing 8 patients with mild liver impairment (as indicated by the Child-Pugh method) to 8 controls, the single- and multiple-dose pharmacokinetics of bosentan were not altered in patients with mild hepatic impairment. The influence of moderate or severe liver impairment on the pharmacokinetics of bosentan has not been eva luated. Bosentan should generally be avoided in patients with moderate or severe liver abnormalities and/or elevated aminotransferases >3 × ULN (See DOSAGE AND ADMINISTRATION and WARNINGS).

Renal Impairment

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

Clinical Studies

Pulmonary Arterial Hypertension

Two randomized, double-blind, multi-center, placebo-controlled trials were conducted in 32 and 213 patients. The larger study (BREATHE-1) compared 2 doses (125 mg b.i.d. and 250 mg b.i.d.) of TRACLEER® with placebo. The smaller study (Study 351) compared 125 mg b.i.d. with placebo. Patients had severe (WHO functional Class III–IV) pulmonary arterial hypertension: primary pulmonary hypertension (72%) or pulmonary hypertension secondary to scleroderma or other connective tissue diseases (21%), or to autoimmune diseases (7%). There were no patients with pulmonary hypertension secondary to other conditions such as HIV disease, or recurrent pulmonary emboli.

In both studies, TRACLEER® or placebo was added to patients' current therapy, which could have included a combination of digoxin, anticoagulants, diuretics, and vasodilators (e.g., calcium channel blockers, ACE inhibitors), but not epoprostenol. TRACLEER® was given at a dose of 62.5 mg b.i.d. for 4 weeks and then at 125 mg b.i.d. or 250 mg b.i.d. for either 12 (BREATHE-1) or 8 (Study 351) additional weeks. The primary study endpoint was 6-minute walk distance. In addition, symptoms and functional status were assessed. Hemodynamic measurements were made at 12 weeks in Study 351.

The mean age was about 49 years. About 80% of patients were female, and about 80% were Caucasian. Patients had been diagnosed with pulmonary hypertension for a mean of 2.4 years.

Submaximal Exercise Capacity

Results of the 6-minute walk distance at 3 months (Study 351) or 4 months (BREATHE-1) are shown in Table 1.

In both trials, treatment with TRACLEER® resulted in a significant increase in exercise capacity. The improvement in walk distance was apparent after 1 month of treatment (with 62.5 mg b.i.d.) and fully developed by about 2 months of treatment (Figure 1). It was maintained for up to 7 months of double-blind treatment. Walking distance was somewhat greater with 250 mg b.i.d., but the potential for increased liver injury causes this dose not to be recommended (See DOSAGE AND ADMINISTRATION). There were no apparent differences in treatment effects on walk distance among subgroups analyzed by demographic factors, baseline disease severity, or disease etiology, but the studies had little power to detect such differences.

Change from baseline in 6-minute walking distance from start of therapy to week 16 in the placebo and combined bosentan (125 mg b.i.d. and 250 mg b.i.d.) groups. Values are expressed as mean ± standard error of the mean.

Hemodynamic Changes

Invasive hemodynamic parameters were assessed in Study 351. Treatment with TRACLEER® led to a significant increase in cardiac index (CI) associated with a significant reduction in pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and mean right atrial pressure (RAP) (Table 2).

Symptoms and Functional Status

Symptoms of pulmonary arterial hypertension were assessed by Borg dyspnea score, WHO functional class, and rate of "clinical worsening." Clinical worsening was assessed as the sum of death, hospitalizations for PAH, discontinuation of therapy because of PAH, and need for epoprostenol. There was a significant reduction in dyspnea during walk tests (Borg dyspnea score), and significant improvement in WHO functional class in TRACLEER®-treated patients. There was a significant reduction in the rate of clinical worsening (Table 3 and Figure 2). Figure 2 shows the Log-rank test reflecting clinical worsening over 28 weeks.

Time from randomization to clinical worsening with Kaplan-Meier estimate of the proportions of failures in BREATHE-1. All patients (N=144 in the bosentan group and N=69 in the placebo group) participated in the first 16 weeks of the study. A subset of this population (N=35 in the bosentan group and 13 in the placebo group) continued double-blind therapy for up to 28 weeks.

Pulmonary Arterial Hypertension related to Congenital Heart Defect

A small study with patients with Eisenmenger physiology demonstrated effects of bosentan on exercise and safety that were similar to those seen in other trials in patients with PAH (WHO Group I).

Congestive Heart Failure (CHF)

In a pair of studies, 1613 subjects with NYHA Class III-IV heart failure, left ventricular ejection fraction <35%, on diuretics, ACE inhibitor, and other therapies, were randomized to placebo or TRACLEER® (62.5 mg b.i.d. titrated as tolerated to 125 mg b.i.d.) and followed for up to 70 weeks. Use of TRACLEER® was associated with no benefit on patient global assessment (the primary end point) or mortality. However, hospitalizations for heart failure were more common during the first 4 to 8 weeks after bosentan was initiated. Based on these results, bosentan is not effective in the treatment of congestive heart failure with left ventricular dysfunction.

Long-term Treatment

The long-term follow-up of the patients who were treated with TRACLEER® in the two pivotal studies and their open-label extensions (N=235) shows that 93% and 84% of patients were still alive at 1 and 2 years, respectively, after the start of treatment with TRACLEER®. These uncontrolled observations do not allow comparison with a group not given TRACLEER® and cannot be used to determine the long-term effect of TRACLEER® on mortality.

INDICATIONS AND USAGE

TRACLEER® is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in patients with WHO Class III or IV symptoms, to improve exercise ability and decrease the rate of clinical worsening (see Clinical Studies).

CONTRAINDICATIONS

See BOX WARNING for CONTRAINDICATION to use in pregnancy.

Pregnancy Category X

TRACLEER® is expected to cause fetal harm if administered to pregnant women. Bosentan was teratogenic in rats given oral doses ≥ 60 mg/kg/day (twice the maximum recommended human oral dose of 125 mg, b.i.d., on a mg/ m2 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 of 60 and 300 mg/kg/day (2 and 10 times, respectively, the maximum recommended human dose on a mg/m2 basis). Although birth defects were not observed in rabbits given oral doses of up to 1500 mg/kg/day, 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 teratogenicity is a class effect of these drugs. There are no data on the use of TRACLEER® in pregnant women.

Pregnancy must be excluded before the start of treatment with TRACLEER® and prevented thereafter by use of reliable contraception. It has been demonstrated that hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives may not be reliable in the presence of TRACLEER® and should not be used as the sole contraceptive method in patients receiving TRACLEER® (see Drug Interactions: Hormonal Contraceptives, Including Oral, Injectable, Transdermal and Implantable Contraceptives). Input from a gynecologist or similar expert on adequate contraception should be sought as needed.

TRACLEER® should be started only in patients known not to be pregnant. For female patients of childbearing potential, a prescription for TRACLEER® should not be issued by the prescriber unless the patient assures the prescriber that she is not sexually active or provides negative results from a urine or serum pregnancy test performed during the first 5 days of a normal menstru