Tracleer bosentan 125 mg Tablet, Film Coated — NDC 66215-102-03 (Billing 66215-0102-03)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Bosentan is a specific and competitive antagonist at endothelin receptor types ET A and ET B . Bosentan has a slightly higher affinity for ET A receptors than for ET B 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 ET A and ET B 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.

12.3Pharmacokinetics General After oral administration, maximum plasma concentrations of bosentan are attained within 3–5 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%–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 50–65% 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. 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 (AUC ss ) 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… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Bosentan is a specific and competitive antagonist at endothelin receptor types ET A and ET B . Bosentan has a slightly higher affinity for ET A receptors than for ET B 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 ET A and ET B 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.

12.3Pharmacokinetics General After oral administration, maximum plasma concentrations of bosentan are attained within 3–5 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%–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 50–65% 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. 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 (AUC ss ) 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 TRACLEER 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 15–30 mL/min), plasma concentrations of bosentan were essentially unchanged and plasma concentrations of the three metabolites were increased about 2-fol… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES

14.1Pulmonary Arterial Hypertension WHO Functional Class III-IV 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 twice daily and 250 mg twice daily) of TRACLEER with placebo. The smaller study (Study 351) compared 125 mg twice daily with placebo.

Patients had severe (WHO functional Class III–IV) PAH: idiopathic or heritable PAH (72%) or PAH associated with scleroderma or other connective tissue diseases (21%), or to autoimmune diseases (7%). There were no patients with PAH associated with 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 twice daily for 4 weeks and then at 125 mg twice daily or 250 mg twice daily 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 Ability Results of the 6-minute walk distance at 3 months (Study 351) or 4 months (BREATHE-1) are shown in Table 4. Table 4: Effects of TRACLEER on 6-Minute Walk Distance BREATHE-1 Study 351 TRACLEER 125 mg twice daily (n=74) TRACLEER 250 mg twice daily (n=70) Placebo (n=69) TRACLEER 125 mg twice daily (n=21) Placebo (n=11) Distance in meters: mean ± standard deviation.

Changes are to week 16 for BREATHE-1 and to week 12 for Study 351. Baseline 326 ± 73 333 ± 75 344 ± 76 360 ± 86 355 ± 82 End point 353 ± 115 379 ± 101 336 ± 129 431 ± 66 350 ± 147 Change from baseline 27 ± 75 46 ± 62 -8 ± 96 70 ± 56 -6 ± 121 Placebo – subtracted 35 p=0.01; by Wilcoxon; 54 p=0.0001; by Wilcoxon; 76 p=0.02; by Student's t-test. In both trials, treatment with TRACLEER resulted in a significant increase in exercise ability.

The improvement in walk distance was apparent after 1 month of treatment (with 62.5 mg twice daily) and fully developed by about 2 months of treatment (Figure 5). It was maintained for up to 7 months of double-blind treatment. Walking distance was somewhat greater with 250 mg twice daily, but the potential for increased hepatotoxicity causes this dose not to be recommended [see Dosage and Administration (2.2) ] .

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. Figure 5. Mean Change in 6-min Walk Distance (BREATHE-1) Change from baseline in 6-minute walking distance from start of therapy to week 16 in the placebo and combined TRACLEER (125 mg twice daily and 250 mg twice daily) groups.

Values are expressed as mean ± standard error of the mean. Figure 5 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 5).

The relationship between hemodynamic effects and improvements in 6-minute walk distance is unknown. Table 5: Change from Baseline to Week 12: Hemodynamic Parameters TRACLEER 125 mg twice daily Placebo Values shown are means ± SD CI (L/min/m 2 ) n=20 n=10 Baseline 2.35±0.73 2.48±1.03 Absolute Change 0.50±0.46 -0.52±0.48 Treatment Effect 1.02 p≤0.001; Mean PAP (mmHg) n=20 n=10 Baseline 53.7±13.4 55.7±10.5 Absolute Change -1.6±5.… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis 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 twice daily, on a mg/m 2 basis). In the same study, doses greater than 2000 mg/kg/day (about 32 times the MRHD) were associated with an increased incidence of colon adenomas in both males and females.

In rats, dietary administration of bosentan for two years was associated with an increased incidence of brain astrocytomas in males at doses as low as 500 mg/kg/day (about 16 times the MRHD). In a comprehensive battery of in vitro tests (the microbial mutagenesis assay, the unscheduled DNA synthesis assay, the V-79 mammalian cell mutagenesis assay, and human lymphocyte assay) and an in vivo mouse micronucleus assay, there was no evidence for any mutagenic or clastogenic activity of bosentan. Impairment of Fertility/Testicular Function The development of testicular tubular atrophy and impaired fertility has been linked with the chronic administration of certain endothelin receptor antagonists in rodents.

Treatment with bosentan at oral doses of up to 1500 mg/kg/day (50 times the MRHD on a mg/m 2 basis) or intravenous doses up to 40 mg/kg/day had no effects on sperm count, sperm motility, mating performance or fertility in male and female rats. An increased incidence of testicular tubular atrophy was observed in rats given bosentan orally at doses as low as 125 mg/kg/ day (about 4 times the MRHD and the lowest doses tested) for two years but not at doses as high as 1500 mg/kg/day (about 50 times the MRHD) for 6 months.

Effects on sperm count and motility were evaluated only in the much shorter duration fertility studies in which males had been exposed to the drug for 4–6 weeks. An increased incidence of tubular atrophy was not observed in mice treated for 2 years at doses up to 4500 mg/kg/day (about 75 times the MRHD) or in dogs treated up to 12 months at doses up to 500 mg/kg/day (about 50 times the MRHD).