Date of Revision: April 16, 2008

Submission Control No: 119412

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 7 DRUG INTERACTIONS 15 DOSAGE AND ADMINISTRATION 17 OVERDOSAGE 18 ACTION AND CLINICAL PHARMACOLOGY 18 STORAGE AND STABILITY 20 SPECIAL HANDLING INSTRUCTIONS 20 DOSAGE FORMS, COMPOSITION AND PACKAGING 20

PART II: SCIENTIFIC INFORMATION 22

PHARMACEUTICAL INFORMATION 22 CLINICAL TRIALS 23 DETAILED PHARMACOLOGY 28 MICROBIOLOGY 30 TOXICOLOGY 30 REFERENCES 33

PART III: CONSUMER INFORMATION. 34

PrTRACLEER(r) Bosentan monohydrate

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

TRACLEER is contraindicated in patients: who are hypersensitive to bosentan or to any excipient in the formulation. For a complete listing, see Dosage Forms, Composition and Packaging section of the product monograph. who are pregnant, or of childbearing potential unless adequate contraceptive measures are taken. Fetal malformations were reported in animals (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women); with moderate or severe liver impairment and/or with baseline values of liver transaminases, i.e., aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT), greater than 3 times the upper limit of normal (ULN), particularly when the total bilirubin is increased to greater than 2 times the ULN (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic); concomitant use of cyclosporine A; concomitant use of glyburide.

WARNINGS AND PRECAUTIONS

Hepatic/Biliary/Pancreatic

TRACLEER has been associated with a reversible, dose-related increase in aspartate aminotransferase (AST) and alanine aminotranferase (ALT), accompanied in some cases by elevated bilirubin. Increases in liver enzymes usually occurred within the first 26 weeks following initiation of treatment and returned to pretreatment levels without sequelae within a few days to 9 weeks, either spontaneously or after dose reduction or discontinuation. These increases may also occur late in treatment. In the post-marketing period, rare cases of unexplained hepatic cirrhosis were reported after prolonged (> 12 months) therapy with TRACLEER in patients with multiple co-morbidities and drug therapies. There have also been rare reports of liver failure. The contribution of TRACLEER in these cases could not be excluded. In at least one case the initial presentation (after > 20 months of treatment) included pronounced elevations in aminotransferases and bilirubin levels accompanied by non-specific symptoms, all of which resolved slowly over time after discontinuation of TRACLEER. This case reinforces the importance of strict adherence to the monthly monitoring schedule for the duration of treatment and the treatment algorithm, which includes stopping TRACLEER with a rise of aminotransferases accompanied by signs or symptoms of liver dysfunction.

Liver transaminase levels must be measured prior to initiation of treatment and subsequently at monthly intervals.

Pre-existing Liver Impairment:

Use in patients with baseline values of liver transaminases, i.e., aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT), greater than 3 times the upper limit of normal (ULN), particularly when the total bilirubin is increased to greater than 2 times the ULN, is contraindicated (see CONTRAINDICATIONS).

Management of Patients with Increased Liver Transaminases:

ALT/AST levels Treatment and monitoring recommendations are as follows:

> 3 and <= 5 x ULN Confirm by another liver function test; if confirmed, reduce the daily dose or stop treatment, monitor aminotransferase levels at least every 2 weeks. If the aminotransferase levels return to pretreatment values consider continuing or reintroducing TRACLEER as appropriate (see Reintroduction of treatment below).

> 5 and <= 8 x ULN Confirm by another liver function test; if confirmed, stop treatment and monitor aminotransferase levels at least every 2 weeks. Once the aminotransferase levels return to pretreatment values consider reintroducing TRACLEER (see Reintroduction of treatment below).

> 8 x ULN Treatment must be stopped and reintroduction of TRACLEER is not to be considered.

In the case of elevations of aminotransferases accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice or unusual lethargy or fatigue) or of increases in bilirubin >= 2 x ULN, treatment must be stopped and reintroduction of TRACLEER is not to be considered.

Reintroduction of treatment

Reintroduction of treatment with TRACLEER should only be considered if the potential benefits of treatment with TRACLEER outweigh the potential risks and when aminotransferase levels are within pretreatment values. TRACLEER is to be reintroduced at the starting dose and aminotransferase levels must then be checked within 3 days after reintroduction, then again after further 2 weeks, and thereafter according to the recommendations above.

General

Treatment with TRACLEER in patients with severe chronic heart failure was associated with an increased incidence of hospitalization due to worsening of chronic heart failure during the first 4 to 8 weeks of treatment with TRACLEER, which could have been the result of fluid retention. It is recommended that patients be monitored for signs of fluid retention (e.g., leg edema, weight gain). Should this occur, starting treatment with diuretics or increasing the existing dose of diuretics is recommended. Treatment with diuretics is recommended in patients with evidence of fluid retention before the start of treatment with TRACLEER.

Hematologic

Treatment with TRACLEER has been associated with dose-related decreases in hemoglobin concentration (0.9 g/dL overall average), which is likely due to hemodilution. In placebo- controlled studies TRACLEER-related decreases in hemoglobin concentration were not progressive, and stabilized after the first 4-12 weeks of treatment. It is recommended that hemoglobin concentrations be checked prior to the initiation of treatment, after 1 month and after 3 months, and quarterly thereafter. If a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and the need for specific treatment. In the post-marketing period, cases of anemia requiring red blood cell transfusion have been reported (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions).

Cardiovascular

TRACLEER should be initiated with caution if the patient has a systemic systolic blood pressure lower than 85 mm Hg.

Carcinogenesis and Mutagenesis (See Toxicology)

Special Populations

Pregnant Women: TRACLEER should be considered a potential human teratogen. TRACLEER has been shown to be teratogenic in rats when given at doses >= 60 mg/kg/day (twice the human oral therapeutic dose of 125 mg b.i.d., on an mg/m2 basis). In an embryo-fetal toxicity study in rats, TRACLEER showed dose-dependent teratogenic effects including malformations of the head and face and of the major vessels. No birth defects were observed in rabbits at doses of up to 1500 mg/kg/day; however, the plasma concentrations were lower than those reached in rats. The similarity of malformations induced by TRACLEER and those observed in endothelin-1 knockout mice and in animals treated by other endothelin receptor antagonists indicates that teratogenicity is a class effect of these drugs. There are no studies in pregnant women. TRACLEER treatment must not be initiated in women of childbearing potential unless they practice reliable contraception and the result of the pretreatment pregnancy test is negative. Before the initiation of TRACLEER treatment in women of childbearing potential, the absence of pregnancy should be checked, appropriate advice on reliable method of contraception provided, and reliable contraception initiated. Patients and prescribers must be aware that, due to potential pharmacokinetic interactions, TRACLEER may render hormonal contraceptives ineffective (see DRUG INTERACTIONS, Drug-Drug Interactions, Hormonal contraceptives). Therefore, women of childbearing potential must not use hormonal contraceptives (including oral, injectable, transdermal, and implantable forms) as the sole method of contraception but should use an additional or an alternative reliable method of contraception. If there is any doubt on what contraceptive advice should be given to the individual patient, consultation with a gynecologist is recommended. Because of possible hormonal contraception failure during TRACLEER treatment and also bearing in mind the risk that pulmonary hypertension severely deteriorates with pregnancy, monthly pregnancy tests during treatment with TRACLEER are recommended to allow early detection of pregnancy.

Nursing Women:

It is not known whether TRACLEER is excreted in human milk. Because many drugs are excreted in human milk, nursing women taking TRACLEER should be advised to discontinue breastfeeding.

Pediatrics (3-18 years of age)(r)

: The safety and efficacy of TRACLEER in children was studied in a group of 19 patients ages 3-15 years with PAH either primary or secondary to various congenital heart defects, in WHO functional class II or III. Of the 19 patients, 10 were receiving concomitant Flolan

(epoprostenol). After 12 weeks of treatment with TRACLEER, efficacy could not be demonstrated based on increased exercise capacity. However, statistically significant improvements in certain hemodynamic indices were noted (mean pulmonary artery pressure, mean systemic artery pressure, pulmonary vascular resistance and pulmonary vascular resistance index, systemic vascular resistance and systemic vascular resistance index, cardiac

output and stroke index). No statistically significant improvement in respiratory parameters (oxygen and CO2) or cardiac index was present. By treatment end, five patients had improved by one functional class and one deteriorated. No new safety concerns arose during the study, though one patient was withdrawn from treatment due to increased liver transaminases. The dosing regimen used in the study was based on body-weight:

Geriatrics (> 65 years of age)DOSAGE AND ADMINISTRATION

: Limited clinical experience with TRACLEER in patients aged 65 years or older has not identified any difference in response between elderly and younger patients, but the possibility of decreased hepatic function in the elderly should be considered (see

).

Monitoring and Laboratory Tests

Liver abnormalities management:

Liver transaminase levels must be measured prior to initiation of treatment and subsequently at monthly intervals. For liver abnormalities management (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

Hemoglobin concentrations management:

Hemoglobin concentrations should be checked prior to the initiation of treatment, after 1 month and after 3 months, and quarterly thereafter. If a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and the need for specific treatment. (See WARNINGS AND PRECAUTIONS, Hematologic)

DRUG INTERACTIONS

Overview

Cytochrome P450 System450

: Bosentan had no relevant inhibitory effect on cytochrome P

isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1,

and CYP3A4. Consequently, TRACLEER is not expected to increase plasma concentrations of drugs metabolized by these enzymes. Bosentan is an inducer of CYP3A4 and CYP2C9. Consequently, plasma concentrations of drugs metabolized by these two isoenzymes may be decreased when TRACLEER is co-administered. Concomitant administration of both a CYP2C9 inhibitor (such as fluconazole or voriconazole) and a CYP3A4 inhibitor (such as ketoconazole, itraconazole or ritonavir) with bosentan may theoretically lead to large increases in plasma concentrations of bosentan. Co-administration of such combinations of a potent CYP2C9 inhibitor plus a CYP3A4 inhibitor with TRACLEER is not recommended.

Drug-Drug Interactions

Warfarin:

Co-administration of TRACLEER 500 mg twice daily decreased plasma concentrations of both S-warfarin and R-warfarin by approximately 30%. In patients with

pulmonary arterial hypertension, TRACLEER 125 mg b.i.d. had no clinically significant effect on prothrombin time/INR when administered to patients receiving chronic warfarin therapy. No additional dose adjustment should be needed for warfarin, but routine INR monitoring is recommended.

Simvastatin and other statins:

Co-administration of TRACLEER decreased the plasma concentrations of simvastatin, and of its active ss-hydroxy acid metabolite, by approximately 50%. The plasma concentrations of TRACLEER were not affected. TRACLEER is also expected to reduce plasma concentrations of other statins that have significant metabolism by CYP3A4. The possibility of reduced efficacy should be considered for these statins.

Glyburide: CONTRAINDICATIONS

An increased risk of elevated transaminases was observed in patients receiving concomitant therapy with glyburide. Therefore, the concomitant administration of TRACLEER and glyburide is contraindicated, and alternative hypoglycemic agents should be considered (see

).

Co-administration of TRACLEER decreased the plasma concentrations of glyburide by approximately 40%. The plasma concentrations of TRACLEER were also decreased by approximately 30%. TRACLEER is also expected to reduce plasma concentrations of other oral hypoglycemic agents that are predominantly metabolized by CYP2C9 or CYP3A4. The possibility of worsened glucose control in patients using these agents should be considered.

Ketoconazole:

Co-administration of TRACLEER and ketoconazole increased the plasma concentrations of TRACLEER by approximately 2-fold. No dose adjustment is necessary. However, increased effects of TRACLEER should be considered.

Nimodipine, Digoxin, and Losartan:

TRACLEER has been shown to have no pharmacokinetic interactions with digoxin and nimodipine. Losartan has no effect on plasma levels of TRACLEER.

Cyclosporine A: CONTRAINDICATIONS

Co-administration of TRACLEER decreased the blood concentrations of cyclosporine A by approximately 50%. Initial trough concentrations of TRACLEER were approximately 30-fold higher than those measured after TRACLEER alone. However, at steady state, TRACLEER plasma concentrations were only 3- to 4-fold higher. The concomitant administration of TRACLEER and cyclosporine A is contraindicated (see

).

Tacrolimus and sirolimus:

No drug-interaction study was performed with tacrolimus or sirolimus but a similar interaction with cyclosporine A can be expected. It is recommended to exclude concomitant administration of TRACLEER and tacrolimus or sirolimus.

Hormonal ContraceptivesWARNINGS AND PRECAUTIONS, Pregnant Women

: Co-administration of bosentan decreased the plasma concentrations of ethinyl estradiol and norethindrone by 31 and 14% respectively. However, decreases in exposure were as much as 56% and 66%, respectively, in individual subjects. Bosentan is also expected to reduce plasma concentrations of other contraceptive steroids that have significant metabolism by CYP3A4. Therefore, hormone-based contraceptives alone, regardless of the route of administration (i.e. oral, injectable, transdermal, and implantable forms), are not considered as reliable methods of contraception (see

).

Sildenafil:

In healthy volunteers co-administration of TRACLEER 125 mg twice daily (steady state) with sildenafil 80 mg three times a day (steady state) resulted in a 63% decrease of the sildenafil AUC and a 50% increase of the bosentan AUC. The combination was well tolerated. A dose adjustment of neither drug is considered necessary.

Rifampicin:

Co-administration of TRACLEER 125 mg twice daily for 7 days and rifampicin, a potent inducer of CYP2C9 and CYP3A4, decreased the plasma concentrations of bosentan by 58%, and this decrease could achieve almost 90% in an individual case. Therefore a significantly reduced effect of bosentan is expected when it is co-administered with rifampicin. Data on other CYP3A4 inducers, e.g. carbamazepine, phenobarbital, phenytoin and St John's wort are lacking, but their concomitant administration is expected to lead to reduced systemic exposure to bosentan. A clinically significant reduction of efficacy cannot be excluded.

Epoprostenol: Data obtained in a study in pediatric PAH patients (refer to clinical section) show that after both single- and multiple-dose administration, the Cmax and AUC values of bosentan were similar in patients with or without continuous infusion of epoprostenol.

Drug-Food Interactions

Co-administration of TRACLEER with food results in small clinically irrelevant increases in Cmax (22%) and AUC (10%). Bosentan can be given with or without food.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established (see ADVERSE REACTIONS, Abnormal Hematologic and Clinical Chemistry Findings).

DOSAGE AND ADMINISTRATION

Dosing Considerations

Dosage in Patients with Hepatic Impairment: ACTION AND CLINICAL PHARMACOLOGY, CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS

No dose adjustment of TRACLEER is needed in patients with mild hepatic impairment (i.e., Child-Pugh class A). Use of TRACLEER in patients with moderate or severe liver impairment is contraindicated (see

).

Recommended Dose and Dosage Adjustment

TRACLEER should be initiated at a dose of 62.5 mg twice daily for 4 weeks and then increased to the recommended maintenance dose of 125 mg twice daily. Doses above 125 mg twice daily do not confer additional benefit sufficient to offset the increased risk of liver injury. TRACLEER should be taken morning and evening, consistently, with or without food.

Dosage in Pediatric Patients: WARNINGS AND PRECAUTIONS, Pediatrics

There is only limited experience with TRACLEER in patients under the age of 18 years (see

)

Dosage in the Elderly:

Clinical studies of TRACLEER did not include a sufficient number of patients aged 65 and over to determine if they respond differently than younger patients with pulmonary arterial hypertension. In general, dose selection for an elderly patient should be made cautiously, reflecting a possible decrease in renal and/or cardiac function, concomitant disease, other drug therapy, and, particularly, decrease in hepatic function.

Dosage in Patients with Renal Impairment:

The effect of renal impairment on the pharmacokinetics of TRACLEER is small. No dosing adjustment is required including patients undergoing dialysis.

Missed Dose

If a scheduled dose of TRACLEER is missed, a double dose should not be taken to make up for the forgotten individual dose. The patient should take the next tablet at the usual scheduled time.

Discontinuation of Treatment

There is no experience with abrupt discontinuation of TRACLEER at the recommended doses in pulmonary arterial hypertension patients. However, to avoid the possible occurrence of sudden clinical deterioration as has been seen with the discontinuation of other medications for this disease, patients should be monitored closely and reducing the dose by half for 3 to 7 days prior to discontinuation should be considered.

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

TRACLEER has been given as a single dose of up to 2,400 mg in normal volunteers, or up to 2,000 mg/day for two months in patients, without any major clinical consequences. The most common side effect was headaches of mild-to-moderate intensity. In the cyclosporine A interaction study, where doses of 500 and 1,000 mg of TRACLEER were given concomitantly with cyclosporine A, initial trough plasma concentrations of TRACLEER increased 30-fold resulting in severe headaches, nausea, and vomiting, but no serious adverse events occurred. Mild decreases in blood pressure and increases in heart rate were observed. Massive overdosage may result in pronounced hypotension requiring active cardiovascular support. In the post-marketing period there was one reported overdose of 10,000 mg of TRACLEER taken by an adolescent male patient. He had symptoms of nausea, vomiting, hypotension, dizziness, sweating, blurred vision. He recovered completely within 24 hours with blood pressure support. Note: bosentan is not removed through dialysis.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action/Pharmacodynamics

Bosentan is a dual endothelin receptor antagonist with affinity for both ETA and ETB receptors. Bosentan decreases both pulmonary and systemic vascular resistance, resulting in increased cardiac output without increasing heart rate. The neurohormone endothelin is a potent vasoconstrictor with the ability to promote fibrosis, cell proliferation, and tissue remodeling. Endothelin concentrations in plasma and tissues are increased in a number of cardiovascular disorders, including pulmonary hypertension, suggesting a pathological role for endothelin in these diseases. In pulmonary arterial hypertension, endothelin plasma concentrations strongly correlate with poor prognosis. Bosentan is specific for endothelin receptors. Bosentan competes with the binding of endothelin for both ETA and ETB receptors with a slightly higher affinity for ETA receptors. In animal models of pulmonary hypertension, chronic oral administration of bosentan reduced pulmonary vascular resistance and reversed pulmonary vascular and right ventricular hypertrophy. In an animal model of pulmonary fibrosis, bosentan reduced collagen deposition.

Pharmacokinetics

Table 3 - Summary of bosentan's pharmacokinetic parameters in patients with pulmonary arterial hypertension

Data are expressed as arithmetic mean (and 95% confidence limits) or, for tmax, as median (and range). Data were obtained from PAH patients treated for at least two weeks with the maintenance dose of 125 mg b.i.d..

Absorption:

The absolute bioavailability of bosentan is approximately 50% and is unaffected by food. Maximum plasma concentrations are attained within 3-5 hours after oral administration. Pharmacokinetic data following both oral and intravenous administration in adult patients with pulmonary arterial hypertension have been obtained. The data show that the exposure to bosentan in adult pulmonary arterial hypertension patients is about 2-fold greater than in healthy adult subjects.

Distribution:

The volume of distribution is about 18 L and the clearance is about 8 L/h. Bosentan is highly bound (> 98%) to plasma proteins, mainly albumin. Bosentan does not penetrate into erythrocytes.

Metabolism: Bosentan is metabolized in the liver by the cytochrome P450 isoenzymes, CYP3A4 and CYP2C9. Three metabolites of bosentan were identified in human plasma. Only one metabolite, Ro 48-5033, is pharmacologically active. In adult patients, the exposure to this active metabolite is greater than in healthy subjects and it may contribute up to 25% to the effect of bosentan. In patients with evidence of the presence of cholestasis, the exposure to the active metabolite may be increased. Excretion: Bosentan is eliminated by biliary excretion. The apparent elimination half-life (t1/2) is 5.4 hours.

Special Populations and Conditions

Pediatrics: The pharmacokinetics of single and multiple oral doses of bosentan have been studied (see WARNINGS AND PRECAUTIONS, Pediatric Patients) in pediatric patients with pulmonary arterial hypertension. The exposure to bosentan decreased with time in a manner consistent with the known auto-induction properties of bosentan. The mean AUC (CV%) values of bosentan in pediatric patients treated with 31.25, 62.5 or 125 mg b.i.d. were 3496 (49), 5428 (79), and 6124 (27) ng *h/ml, respectively, and were lower than the value of 8149 (47) ng *h/ml observed in adult patients receiving 125 mg b.i.d.

Geriatrics:

The pharmacokinetics of bosentan have not been evaluated in patients over the age

of 65 years.

Gender:

No significant relationship or trend was noted between bosentan pharmacokinetic parameters and gender.

Race:

The pharmacokinetics of bosentan were compared between Caucasian and Japanese subjects both after single- and multiple-dose administration. The bosentan pharmacokinetics were similar and dose-proportional in Caucasian and Japanese subjects. Other ethnic differences in bosentan pharmacokinetics have not been evaluated.

Hepatic Insufficiency: CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS

In patients with mildly impaired liver function (Child-Pugh class A) no relevant changes in the pharmacokinetics have been observed and no dose adjustment is required in these patients. The steady-state AUC of bosentan was 9% greater and the AUC of the major metabolite, Ro 48-5033, was 33% greater in patients with mild hepatic impairment than in healthy volunteers. The pharmacokinetics of bosentan have not been studied in patients with Child-Pugh class B or C hepatic impairment and bosentan is contra-indicated in this patient population. (see

).

Renal Insufficiency:

In patients with severe renal impairment (creatinine clearance 15-30 ml/min), plasma concentrations of bosentan decreased by approximately 10%, and plasma concentrations of the three metabolites increased about 2-fold as compared to volunteers with normal renal function. No dose adjustment is required in patients with renal impairment, as less than 3% of an administered dose is excreted in urine. The degree to which bosentan is removed by hemodialysis has not been established.

STORAGE AND STABILITY

TRACLEER should be stored at room temperature between 15oC and 30oC.

SPECIAL HANDLING INSTRUCTIONS

There are no special handling requirements for TRACLEER.

DOSAGE FORMS, COMPOSITION AND PACKAGING

TRACLEER is available as 62.5 mg and 125 mg bosentan (from bosentan monohydrate) tablets for oral administration containing the following excipients: corn starch, glyceryl behenate, magnesium stearate, povidone, pregelatinized starch, and sodium starch glycolate. The film- coating is composed of ethylcellulose, hydroxypropylmethylcellulose, iron oxide red, iron oxide yellow, talc, titanium dioxide and triacetin. TRACLEER is supplied as follows:

• 62.5 mg film-coated, round, biconvex, orange-white tablets embossed with '62,5' on one side - carton box containing 4 blisters of 14 tablets each (56 tablets in total).

• 125 mg film-coated, oval, biconvex, orange-white tablets embossed with '125' on one side - carton box containing 4 blisters of 14 tablets each (56 tablets in total).

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:

Bosentan monohydrate

Chemical name:

TRACLEER (bosentan monohydrate) belongs to a class of highly substituted pyrimidine derivatives, with no chiral centers. Its chemical designation is 4- tert-butyl-N - [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2'] bipyrimidin-4-yl] - benzenesulfonamide monohydrate.

Molecular formula: The molecular formula is C27H29N5O6S *H2O.

Molecular weight:

Bosentan monohydrate has a molecular weight of 569.64.

Structural formula:

Physicochemical properties:

Bosentan monohydrate is a white to yellowish powder.

Solubility:

It is poorly soluble in water (1 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.

CLINICAL TRIALS

Study demographics and trial design

Table 4 - Summary of patient demographics for clinical trials in specific indication

Study results

Two randomized, double-blind, multi-center, placebo-controlled trials were conducted in 32 (Study AC-052-351) and 213 patients (Study AC-052-352 - BREATHE-1) respectively, with WHO functional class III or IV primary pulmonary hypertension (PPH) or pulmonary arterial hypertension secondary to scleroderma or other connective tissue diseases. The BREATHE-1 study compared 2 doses (125 mg b.i.d. and 250 mg b.i.d.) of TRACLEER with placebo. Study AC-052-351 compared 125 mg b.i.d. with placebo. In both studies, TRACLEER or placebo was added to patients' existing therapy (oral vasodilators, anticoagulants, diuretics, cardiac glycosides and/or supplemental oxygen, but not epoprostenol). Patients received TRACLEER 62.5 mg or matching placebo twice daily for 4 weeks and then TRACLEER 125 mg or 250 mg b.i.d. or matching placebo twice daily for either 8 (Study AC-052-351) or 12 (BREATHE-1) 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 AC-052-351. At week 12 (study AC-052-351) or week 16 (BREATHE-1) the main evaluations were performed and patients were followed for up to 28 weeks. In both trials, treatment with TRACLEER was associated with a significant increase in walking distance. The placebo- corrected increases in the primary efficacy parameter, distance in the 6-minute walk test, compared to baseline were 75.9 +- 31.0 m (95% CL = 12.5, 139.2; t-test, p = 0.0205) and 44.2 +- 11.6 (95% CL = 21.4, 67.0; Mann-Whitney U-test, p = 0.0002). 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. It was maintained for up to 7 months of double-blind treatment. (see DOSAGE AND ADMINISTRATION). Invasive hemodynamic parameters were assessed in Study AC-052-351. As compared to placebo significant improvement from baseline to week 12 was observed with TRACLEER in pulmonary arterial pressure (PAP), cardiac index (CI), pulmonary vascular resistance (PVR), right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP).

Table 5 - Change from baseline to week 12 in hemodynamic parameters in study AC-052-351

Values are mean +- SD

* p < 0.05

* * p < 0.001

Symptoms of pulmonary arterial hypertension were assessed by WHO functional class, Borg dyspnea score and rate of "clinical worsening". There was a reduction in dyspnea during walk test (Borg dyspnea score), an improvement in WHO functional class and a significant reduction in the rate of clinical worsening in TRACLEER-treated patients. In study AC-052-351, 9 patients (42.8%) treated with TRACLEER, had their WHO functional class of pulmonary hypertension improved from class III to class II. In the placebo group, 1 patient (9.1%) improved from class III to class II, and 2 patients (18.1%) deteriorated from class III to class IV. In trial AC-052-352 (BREATHE 1) 92% of the 213 patients were classified at baseline as WHO functional class III and 8% as class IV. Treatment with TRACLEER led to a WHO functional class improvement in 42.4% of patients (placebo 30.4%). Clinical worsening was assessed as the time to death or hospitalizations for PAH or discontinuation of therapy because of PAH or need for epoprostenol. Figure 1 below shows the Log-rank test reflecting clinical worsening over 28 weeks and the incidences of each component of the clinical worsening endpoint are described in the Table 6 below.

Table 6 - Incidence of clinical worsening *

BREATHE-1 Study AC-052-351

Patients with clinical worsening [n (%)] Death

Hospitalization for PAH Discontinuation due to Worsening of PAH Receipt of epoprostenol

(c)

Bosentan 125 mg b.i.d.

(n=74)

5 (7%)

(a)

1 (1%)

3 (4%)

3 (4%)

2 (3%)

Placebo (n=69)

14 (20%)

2 (3%)

9 (13%)

6 (9%)

3 (4%)

Bosentan 125 mg b.i.d.

(n=21)

0 (0%)

(b)

0 (0%)

0 (0%)

0 (0%)

0 (0%)

Placebo (n=11)

3 (27%)

0 (0%)

3 (27%)

3 (27%)

3 (27%)

Note: Patients may have had more than one reason for clinical worsening.

(a)

p=0.015 vs. placebo by log-rank test.

(b)

p=0.033 vs. placebo by Fisher's exact test.

Receipt of epoprostenol was always a consequence of clinical worsening.

*shortest time to death, premature withdrawal or hospitalization due to PHT worsening, or initiation of epoprostenol therapy

Figure 1 - Time from randomization to clinical worsening up to Week 28 in BREATHE-1 Study

Time to Clinical Worsening

88%

Event-Free (%)

Bosentan (n = 74)

Placebo (n = 69)

Bosentan (n = 19) Placebo (n = 13)

0 4 8 12 16 20 24 28

Time (Weeks)

Time from randomization to clinical worsening with Kaplan-Meier estimate of the proportions of failures in BREATHE-1. All patients (n=74 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=19 in the bosentan group and 13 in the placebo group) continued double-blind therapy for up to 28 weeks.

Long-term treatment

The long-term effect of TRACLEER was further assessed in two open-label studies (open-label extensions of study AC-052-351 and AC-052-352) with 229 patients treated with TRACLEER for up to 2.5 years with a mean treatment duration of 1.9 +- 0.7 years. During this period, the effects of TRACLEER were maintained in the patients previously treated with TRACLEER. Treatment with TRACLEER in those patients previously on placebo, resulted in an improvement in exercise capacity. Improvement in functional class observed in the initial period of the study tended to decline later.

Long-term survival

Long-term survival was recorded for all 235 patients who were treated with TRACLEER in the two pivotal placebo-controlled trials and their open-label extension studies. The results show that 93% and 84% of patients were still alive after 1 and 2 years, respectively, after the start of treatment with TRACLEER. These estimates may be influenced by the initiation of epoprostenol treatment in 43/235 patients. In a subset of primary pulmonary hypertension (PPH) patients (n=169) the Kaplan-Meier survival estimates were 96% at 1 year and 89% at 2 years as compared to the predicted survival (calculated by the NIH registry formula) of 69% and 57% respectively.

Patients with Pulmonary Arterial Hypertension associated with Congenital Heart Disease

A randomized, double-blind, multi-center, placebo-controlled study were conducted in 54 patients with WHO functional class III pulmonary arterial hypertension associated with Eisenmenger physiology associated with congenital heart disease (resulting in right to left shunt). Patients received TRACLEER 62.5 mg (n=37) or matching placebo (n=17) twice daily for 4 weeks and then TRACLEER 125 mg b.i.d. or matching placebo twice daily for 12 additional weeks.

In this study there were two primary endpoints. The first primary endpoint was to show that TRACLEER did not worsen the shunt or increase hypoxemia. The second primary endpoint was the mean change from baseline versus placebo in pulmonary vascular resistance indexed (PVRi) at Week 16. In addition 6-minute walk distance was assessed. After 16 weeks, TRACLEER increased mean oxygen saturation by 1.0% (95% CL = -0.7; 2.8) as compared to placebo, demonstrating that bosentan did not relevantly worsen hypoxemia. In comparison with placebo, treatment with TRACLEER statistically significantly decreased the indexed pulmonary vascular resistance by -472.0 +- 221.9 dyn *sec *cm-5 compared with placebo (95% CL = -917.6, -26.5; t-test, p = 0.0383). Treatment with TRACLEER was associated with a statistically significant improvements in walk distance with a placebo-corrected increases of 53.1 +- 19.2 m (95% CL = 14.5, 91.7; t-test, p = 0.0079) compared to placebo.

Patients with Pulmonary Arterial Hypertension associated with human immunodeficiency virus In an open-label study without a control group 16 epoprostenol-naive patients with pulmonary arterial hypertension associated with human immunodeficiency virus (HIV) infection (stable, with CD4 cell > 100 cells/mm3) with WHO functional class III and IV were treated with TRACLEER 62.5 mg b.i.d. for 4 weeks and then up-titrated to 125 mg b.i.d. for the remaining 12 weeks of the study. The distance in 6-minute walk test after 16 weeks of treatment with TRACLEER improved significantly by 91.4 +- 59.5 m from baseline (95% CL = 59.7, 123.3; t-test, p<0.001). Improvement in Borg dyspnea index was also observed and was significantly reduced at week 16 (1.5 +- 1.6) compared with baseline (3.4 +- 2.5) (95% CL = -3.3, -0.5; t-test, p<0.013) . At baseline, 15 of the 16 patients were functional class III and one patient was class IV. After 4 weeks of treatment with TRACLEER at the 62.5-mg b.i.d. dose, 9 (56.3%) patients showed improvement in functional class. After an additional 12 weeks of treatment at the 125 mg b.i.d. dose, 14 of 16 patients (87.5%) improved from their baseline class including the one patient in class IV. Three patients improved from class III at baseline to class I and no patients deteriorated in functional class. One patient experienced clinical worsening in pulmonary arterial hypertension and was hospitalized. Improvement from baseline to week 16 was observed with TRACLEER with a mean increase in cardiac index (0.88 L/min/m2 +- 0.72; 95% CL = 0.49, 1.26; t-test, p <0.001) and mean decreases in mean PAP (-11.0 mmHg; 95% CL = -17.4, -4.7; t-test, p = 0.0002), and PVR (-339 dyn *sec /cm5; 95% CL = -454, -223; t-test, p < 0.001). This was an open-label study without a control group. These data should be interpreted cautiously.

Patients Treated with Epoprostenol

The combination of TRACLEER and epoprostenol has been investigated in two studies: AC- 052-355 (BREATHE-2) and AC-052-356 (BREATHE-3). AC-052-355 was a multicentre, randomized, double-blind, parallel-group trial of TRACLEER versus placebo in 33 patients with severe pulmonary arterial hypertension who were receiving concomitant epoprostenol therapy. AC-052-356 was an open-label, non-control trial in pediatric patients. Ten of the 19 pediatric patients were on concomitant TRACLEER and epoprostenol therapy during the 12-week trial. Combination therapy with TRACLEER and epoprostenol was safe and well tolerated in children and adults. In children, TRACLEER treatment, with or without epoprostenol, resulted in significantly improved hemodynamics. In adults, combination therapy was associated with a larger improvement in hemodynamics compared to epoprostenol alone, although in no case did the differences between the groups reached statistical significance.

DETAILED PHARMACOLOGY

In vivo

Animal Studies:

Bosentan has an effect not only on hemodynamic variables but also on structural changes and disease progression in rat models of pulmonary hypertension. In chronic hypoxia and monocrotaline rat models, bosentan at doses of 100 mg/kg/day for up to four weeks decreases pulmonary vascular resistance and reverses pulmonary vascular and right ventricular hypertrophy. In a rat model of bleomycin-induced pulmonary fibrosis, bosentan at doses of 100 mg/kg/day for up to four weeks decreases pulmonary interstitial fibrosis by reducing collagen deposition in the lungs. In acute pulmonary hypertension pig models, i.v. administration of bosentan at doses of 3-10 mg/kg prevents acute pulmonary hypertension.

In Vivo

Human Studies:

The clinical pharmacology program for bosentan included 23 studies of < 14 days duration, involving 350 healthy subjects and 221 patients, with a total of 434 individuals receiving bosentan.

Pharmacokinetics

The pharmacokinetics of bosentan have mainly been documented in healthy subjects. Limited data in patients show that the exposure to bosentan in adult pulmonary arterial hypertension patients is approximately 2-fold greater than in healthy adult subjects. In healthy subjects, bosentan displays dose- and time-dependent pharmacokinetics. Clearance and volume of distribution decrease with increased intravenous doses and increase with time. After oral administration, the systemic exposure is proportional to dose up to 500 mg. At higher oral doses Cmax and AUC increase less than proportionally to the dose. Upon multiple dosing, plasma concentrations of bosentan decrease gradually to 50%-65% of those seen after single dose administration. This decrease is probably due to auto-induction of metabolizing liver enzymes. Steady-state conditions are reached within 3-5 days. Bosentan is highly bound (> 98%) to plasma proteins, mainly albumin. Bosentan does not penetrate into erythrocytes. Based on the available data it is not expected that the pharmacokinetics of bosentan will be influenced by gender, body weight, race, or age in the adult population to any relevant extent. No kinetic data are available in children under 3 years.

Pharmacodynamics

In healthy subjects, oral administration of bosentan has no clinically relevant effect on heart rate and blood pressure in single and multiple-dose studies at doses up to 1,000 mg. Plasma endothelin levels increase in a dose- and concentration-dependent manner after i.v. and oral doses of bosentan are administered in healthy subjects. No consistent changes in the plasma levels of other hormonal parameters are found. In these subjects, dose-related headaches of mostly mild-to-moderate intensity are the most frequent adverse event. In patients with primary pulmonary arterial hypertension and pulmonary arterial hypertension secondary to scleroderma or human immunodeficiency virus, oral bosentan significantly decreases pulmonary arterial pressure (PAP), pulmonary vascular resistance (PVR), right atrial pressure (RAP), and pulmonary capillary wedge pressure (PCWP) and significantly increases cardiac index (CI) as compared to placebo.

MICROBIOLOGY

Not applicable. TRACLEER does not have antimicrobial potential.

TOXICOLOGY

Animal toxicity studies

Bosentan had a low order of acute toxicity. The highest non-lethal doses were in the 125 to 250 mg/kg range by the i.v. and intraperitoneal routes of administration, 1,000 mg/kg or more by the subcutaneous route and 2,000 to > 4,000 mg/kg by the oral route.

Repeated-dose toxicity - oral administration

Oral repeated-dose toxicity studies were conducted with bosentan in rats, dogs, and marmosets. Three repeated-dose toxicity studies of up to 6 months duration in rats and four studies of up to 12 months duration in dogs were conducted. There was no substantial toxicity observed in any of the rat studies. Mild decreases (within normal limits) in red blood cell (RBC) parameters were noted that may be due to the vasodilating effects of bosentan and to the associated increase in plasma volume. Increases in liver weight were observed in rat studies; however, there was no histopathological evidence of hepatotoxicity in any of the repeated-dose studies in rats. In most of the dog studies, a mild decrease in RBC parameters was also observed. In a 4-week study conducted at very high doses (500 and 1,000 mg/kg), increased serum liver enzymes and, histologically, bile duct proliferation and single cell necrosis were observed. In the 6-month study (10, 60 and 400 mg/kg), no significant toxicity was observed at doses up to 400 mg/kg. In the 12-month study (60, 180, and 500 mg/kg), histological changes indicative of a mild cholestasis and increased serum bile salts were observed at high doses. Mild increases in alkaline phosphatase, along with increased liver weights and hepatocellular hypertrophy, are compatible with the microsomal enzyme inducing properties of the drug in dogs. There were no signs of centrolobular necrosis in any studies. Oral administration (10, 80, and 500 mg/kg/day) to marmosets was generally well tolerated. No signs of systematic toxicity were observed.

Mutagenicity

The mutagenic and clastogenic potential of bosentan was evaluated in a comprehensive battery of tests in vitro and in vivo. In these tests, there was no evidence for any mutagenic or clastogenic activity with bosentan, including the lots with a higher level of impurities.

Carcinogenicity

Two years of dietary administration of bosentan to mice produced an increased incidence of hepatocellular adenomas and carcinomas in males at doses as low as 450 mg/kg/day (about 8 times the maximum recommended human dose (MRHD) of 125 mg b.i.d., on a mg/m2 basis). In the same study, doses greater than 2,000 mg/kg/day (about 32 times the [MRDH]) were associated with an increased incidence of colon adenomas in both males and females. In rats, oral administration of bosentan for 2 years produced a small, significant increase in the combined incidence of thyroid follicular cell adenomas and carcinomas in male rats treated at doses of 3,000 mg/kg/day, about 600 times the human oral therapeutic dose in a 50-kg patient. There was no significant increase in the incidence of tumors in female rats or at sites other than the thyroid gland in male rats. There was evidence for a mild thyroid hormonal imbalance induced by bosentan in rats. There was no increase in mortality at any dose in mice and rats. Bosentan is a microsomal enzyme inducer in mice; therefore the formation of liver tumors is not unexpected. Likewise, rats, particularly males, are susceptible to the development of thyroid follicular tumors secondary to thyroid hormone imbalance. No other rat or mouse tumor was considered related to bosentan treatment. The thyroid in rats and the liver in mice are among the most common tumor sites in carcinogenicity studies with pharmaceutical agents and this combination of tumors is found with many other drugs. Since an extensive battery of tests showed bosentan has no genotoxic potential, these findings are considered not to represent a relevant cancer risk.

Testicular findings in bosentan-treated rats

In the 2-year carcinogenicity study in rats, an increase in the incidence of testicular tubular atrophy was observed in the treated groups as compared to the control groups. There was no increase in the incidence of testicular tubular atrophy in rats treated for 6 months or in dogs treated up to 12 months. An increased incidence of tubular atrophy was not observed in mice treated for 2 years at doses up to 4,500 mg/kg/day. In various fertility studies, fertility was normal and sperm parameters (motility and counts), testis and epididymal weights, and histopathology were normal.

Reproductive toxicity

In the fertility studies in rats, no effects were observed on mating performance or fertility, on the development of the preimplantation embryo, or on implantation. There were no changes in sperm count, motility, or viability or on testis weights. Bosentan has been shown to be teratogenic in rats when given at doses about 6 times the human oral therapeutic dose in a 50-kg patient. In an embryo-fetal toxicity study in rats, bosentan showed dose-dependent teratogenic effects, including malformations of the head and face and of the major vessels. No birth defects were observed in rabbits at doses of up to 1,500 mg/kg/day. Similarities in the pattern of malformations observed with other endothelin receptor antagonists and in endothelin knock-out mice indicate a class effect.

REFERENCE

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