Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340, Beerse, Belgium
Pharmacotherapeutic group: other antihypertensives
ATC code: C02KX01
Bosentan is a dual endothelin receptor antagonist (ERA) with affinity for both endothelin A and B (ETA and ETB) receptors. Bosentan decreases both pulmonary and systemic vascular resistance resulting in increased cardiac output without increasing heart rate.
The neurohormone endothelin-1 (ET-1) is one of the most potent vasoconstrictors known and can also promote fibrosis, cell proliferation, cardiac hypertrophy and remodelling, and is pro-inflammatory. These effects are mediated by endothelin binding to ETA and ETB receptors located in the endothelium and vascular smooth muscle cells. ET-1 concentrations in tissues and plasma are increased in several cardiovascular disorders and connective tissue diseases, including PAH, scleroderma, acute and chronic heart failure, myocardial ischaemia, systemic hypertension and atherosclerosis, suggesting a pathogenic role of ET-1 in these diseases. In PAH and heart failure, in the absence of endothelin receptor antagonism, elevated ET-1 concentrations are strongly correlated with the severity and prognosis of these diseases.
Bosentan competes with the binding of ET-1 and other ET peptides to both ET A and ETB receptors, with a slightly higher affinity for ETA receptors (Ki = 4.1–43 nanomolar) than for ETB receptors (Ki = 38–730 nanomolar). Bosentan specifically antagonises ET receptors and does not bind to other 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 in the lungs.
Two randomised, double-blind, multi-centre, placebo-controlled studies have been conducted in 32 (study AC-052-351) and 213 (study AC-052-352 [BREATHE-1]) adult patients with WHO functional class III–IV PAH (primary pulmonary hypertension or pulmonary hypertension secondary mainly to scleroderma). After 4 weeks of bosentan 62.5 mg twice daily, the maintenance doses studied in these studies were 125 mg twice daily in AC-052-351, and 125 mg twice daily and 250 mg twice daily in AC-052-352. Bosentan was added to patients' current therapy, which could include a combination of anticoagulants, vasodilators (e.g. calcium channel blockers), diuretics, oxygen and digoxin, but not epoprostenol. Control was placebo plus current therapy.
The primary endpoint for each study was change in 6-minute walk distance at 12 weeks for the first study and 16 weeks for the second study. In both studies, treatment with bosentan resulted in significant increases in exercise capacity. The placebo-corrected increases in walk distance compared with baseline were 76 metres (p=0.02; t-test) and 44 metres (p=0.0002; Mann-Whitney U test) at the primary endpoint of each study, respectively. The differences between the two groups, 125 mg twice daily and 250 mg twice daily, were not statistically significant but there was a trend towards improved exercise capacity in the group treated with 250 mg twice daily.
The improvement in walk distance was apparent after 4 weeks of treatment, was clearly evident after 8 weeks of treatment and was maintained for up to 28 weeks of double-blind treatment in a subset of the patient population.
In a retrospective responder analysis based on change in walking distance, WHO functional class and dyspnoea of the 95 patients randomised to bosentan 125 mg twice daily in the placebo-controlled studies, it was found that at week 8, 66 patients had improved, 22 were stable and 7 had deteriorated. Of the 22 patients stable at week 8, 6 improved at week 12/16 and 4 deteriorated compared with baseline. Of the 7 patients who deteriorated at week 8, 3 improved at week 12/16 and 4 deteriorated compared with baseline. Invasive haemodynamic parameters were assessed in the first study only. Treatment with bosentan led to a significant increase in cardiac index associated with a significant reduction in pulmonary artery pressure, pulmonary vascular resistance and mean right atrial pressure.
A reduction in symptoms of PAH was observed with bosentan treatment. Dyspnoea measurement during walk tests showed an improvement in bosentan-treated patients. In the AC-052-352 study, 92% of the 213 patients were classified at baseline as WHO functional class III and 8% as class IV. Treatment with bosentan led to a WHO functional class improvement in 42.4% of patients (placebo 30.4%). The overall change in WHO functional class during both studies was significantly better among bosentan-treated patients as compared with placebo-treated patients. Treatment with bosentan was associated with a significant reduction in the rate of clinical worsening compared with placebo at 28 weeks (10.7% vs 37.1%, respectively; p=0.0015).
In a randomised, double-blind, multi-centre, placebo-controlled study (AC-052-364 [EARLY]), 185 PAH patients in WHO functional class II (mean baseline 6-minute walk distance of 435 metres) received bosentan 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily (n=93), or placebo (n=92) for 6 months. Enrolled patients were PAH-treatment-naïve (n=156) or on a stable dose of sildenafil (n=29). The co-primary endpoints were percentage change from baseline in pulmonary vascular resistance (PVR) and change from baseline in 6-minute walk distance to Month 6 versus placebo. The table below illustrates the pre-specified protocol analyses.
| PVR (dyn.sec/cm5) | 6-Minute Walk Distance (m) | |||
|---|---|---|---|---|
| Placebo (n=88) | Bosentan (n=80) | Placebo (n=91) | Bosentan (n=86) | |
| Baseline (BL); mean (SD) | 802 (365) | 851 (535) | 431 (92) | 443 (83) |
| Change from BL; mean (SD) | 128 (465) | −69 (475) | −8 (79) | 11 (74) |
| Treatment effects | −22.6% | 19 | ||
| 95% CL | −34, −10 | −4, 42 | ||
| P-value | <0.0001 | 0.0758 | ||
CL = confidence limit; PVR = pulmonary vascular resistance; SD = standard deviation.
Treatment with bosentan was associated with a reduction in the rate of clinical worsening, defined as a composite of symptomatic progression, hospitalisation for PAH and death, compared with placebo (proportional risk reduction 77%, 95% confidence interval [CI] 20–94%, p=0.0114). The treatment effect was driven by improvement in the component symptomatic progression. There was one hospitalisation related to PAH worsening in the bosentan group and three hospitalisations in the placebo group. Only one death occurred in each treatment group during the 6-month double-blind study period, therefore no conclusion can be drawn on survival.
Long-term data were generated from all 173 patients who were treated with bosentan in the controlled phase and/or were switched from placebo to bosentan in the open-label extension phase of the EARLY study. The mean duration of exposure to bosentan treatment was 3.6 ± 1.8 years (up to 6.1 years), with 73% of patients treated for at least 3 years and 62% for at least 4 years. Patients could receive additional PAH treatment as required in the open-label extension. The majority of patients were diagnosed with idiopathic or heritable PAH (61%). Overall, 78% of patients remained in WHO functional class II. Kaplan-Meier estimates of survival were 90% and 85% at 3 and 4 years after the start of treatment, respectively. At the same timepoints, 88% and 79% of patients remained free from PAH worsening (defined as all-cause death, lung transplantation, atrial septostomy or start of intravenous or subcutaneous prostanoid treatment). The relative contributions of previous placebo treatment in the double-blind phase and of other medications started during the open-label extension period are unknown.
In a prospective, multi-centre, randomised, double-blind, placebo-controlled study (AC-052-405 [BREATHE-5]), patients with PAH WHO functional class III and Eisenmenger physiology associated with congenital heart disease received bosentan 62.5 mg twice daily for 4 weeks, then 125 mg twice daily for a further 12 weeks (n=37, of whom 31 had a predominantly right to left, bidirectional shunt). The primary objective was to show that bosentan did not worsen hypoxaemia. After 16 weeks, the mean oxygen saturation was increased in the bosentan group by 1.0% (95% CI –0.7%–2.8%) as compared to the placebo group (n=17), showing that bosentan did not worsen hypoxaemia. The mean pulmonary vascular resistance was significantly reduced in the bosentan group (with a predominant effect observed in the subgroup of patients with bidirectional intracardiac shunt). After 16 weeks, the mean placebo-corrected increase in 6-minute walk distance was 53 metres (p=0.0079), reflecting improvement in exercise capacity. Twenty-six patients continued to receive bosentan in the 24-week open-label extension phase (AC-052-409) of the BREATHE-5 study (mean duration of treatment = 24.4 ± 2.0 weeks) and, in general, efficacy was maintained.
An open-label, non-comparative study (AC-052-362 [BREATHE-4]) was performed in 16 patients with WHO functional class III PAH associated with HIV infection. Patients were treated with bosentan 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily for a further 12 weeks. After 16 weeks' treatment, there were significant improvements from baseline in exercise capacity: the mean increase in 6-minute walk distance was 91.4 metres from 332.6 metres on average at baseline (p < 0.001). No formal conclusion can be drawn regarding the effects of bosentan on antiretroviral drug efficacy (see also section 4.4).
There are no studies to demonstrate beneficial effects of Tracleer treatment on survival. However, long-term vital status was recorded for all 235 patients who were treated with bosentan in the two pivotal placebo-controlled studies (AC-052-351 and AC-052-352) and/or their two uncontrolled, open-label extensions. The mean duration of exposure to bosentan was 1.9 years ± 0.7 years (min: 0.1 years; max: 3.3 years) and patients were observed for a mean of 2.0 ± 0.6 years. The majority of patients were diagnosed as primary pulmonary hypertension (72%) and were in WHO functional class III (84%). In this total population, Kaplan-Meier estimates of survival were 93% and 84% 1 and 2 years after the start of treatment with bosentan, respectively. Survival estimates were lower in the subgroup of patients with PAH secondary to systemic sclerosis. The estimates may have been influenced by the initiation of epoprostenol treatment in 43/235 patients.
Bosentan film-coated tablets were evaluated in an open-label uncontrolled study in 19 paediatric patients with PAH aged 3 to 15 years. This study was primarily designed as a pharmacokinetic study (see section 5.2). Patients had primary pulmonary hypertension (10 patients) or PAH related to congenital heart diseases (9 patients) and were in WHO functional class II (n=15, 79%) or class III (n=4, 21%) at baseline. Patients were divided into three body-weight groups and dosed with bosentan at approximately 2 mg/kg twice daily for 12 weeks. Half of the patients in each group were already being treated with intravenous epoprostenol and the dose of epoprostenol remained constant for the duration of the study.
Haemodynamics were measured in 17 patients. The mean increase from baseline in cardiac index was 0.5 L/min/m², the mean decrease in mean pulmonary arterial pressure was 8 mmHg, and the mean decrease in PVR was 389 dyn·sec·cm-5. These haemodynamic improvements from baseline were similar with or without co-administration of epoprostenol. Changes in exercise test parameters at week 12 from baseline were highly variable and none were significant.
FUTURE 1 was an open-label, uncontrolled study that was conducted with the dispersible tablet formulation of bosentan administered at a maintenance dose of 4 mg/kg twice daily to 36 patients from 2 to 11 years of age. It was primarily designed as a pharmacokinetic study (see section 5.2). At baseline, patients had idiopathic (31 patients [86%]) or familial (5 patients [14%]) PAH, and were in WHO functional class II (n=23, 64%) or class III (n=13, 36%). In the FUTURE 1 study, the median exposure to study treatment was 13.1 weeks (range: 8.4 to 21.1). 33 of these patients were provided with continued treatment with bosentan dispersible tablets at a dose of 4 mg/kg twice daily in the FUTURE 2 uncontrolled extension phase for a median overall treatment duration of 2.3 years (range: 0.2 to 5.0 years). At baseline in FUTURE 1, 9 patients were taking epoprostenol. 9 patients were newly initiated on PAH-specific medication during the study. The Kaplan-Meier event-free estimate for worsening of PAH (death, lung transplantation, or hospitalisation for PAH worsening) at 2 years was 78.9%. The Kaplan-Meier estimate of overall survival at 2 years was 91.2%.
In this open-label randomised study with the bosentan 32 mg dispersible tablet formulation, 64 children with stable PAH from 3 months to 11 years of age were randomised to 24 weeks' bosentan treatment 2 mg/kg twice daily (n=33) or 2 mg/kg three times daily (n=31). 43 (67.2%) were ≥2 years to 11 years old, 15 (23.4%) were between 1 and 2 years old, and 6 (9.4%) were between 3 months and 1 year old. The study was primarily designed as a pharmacokinetic study (see section 5.2), and efficacy endpoints were only exploratory. The aetiology of PAH, according to Dana Point classification , included idiopathic PAH (46%), heritable PAH (3%), associated PAH after corrective cardiac surgery (38%), and PAH related to congenital heart disease associated with systemic-to- pulmonary shunts , including Eisenmenger syndrome (13%). Patients were in WHO functional class I (n=19, 29 ), class II (n=27, 42) or class III (n=18, 28%) at start of study treatment. At study entry, patients were treated with PAH medications (most frequently phosphodiesterase type-5 inhibitor [sildenafil] alone [35.9%], bosentan alone [10.9%], and a combination of bosentan, iloprost, and sildenafil [10.9%]) and continued their PAH treatment during the study.
At study start, less than half of the patients included (45.3% [29/64]) had bosentan treatment alone not combined with other PAH medication. 40.6% (26/64) remained on bosentan monotherapy during the 24 weeks of study treatment without experiencing PAH worsening. The analysis on the global population included (64 patients) showed that the majority had remained at least stable (i.e. without deterioration) based on non-paediatric-specific WHO functional class assessment (97% twice daily, 100% three times daily) and physician’s global clinical impression (94% twice daily, 93% three times daily) during the treatment period. The Kaplan-Meier event-free estimate for worsening of PAH (death, lung transplantation, or hospitalisation for PAH worsening) at 24 weeks was 96.9% and 96.7% in the twice daily and three times daily groups, respectively.
There was no evidence of any clinical benefit with 2 mg/kg three times daily as compared to 2 mg/kg twice daily dosing.
This was a double-blind, placebo-controlled, randomised study in pre-term or term neonates (gestational age 36–42 weeks) with PPHN. Patients with suboptimal response to inhaled nitric oxide (iNO) despite at least 4 hours of continuous treatment were treated with bosentan dispersible tablets at 2 mg/kg twice daily (N=13) or placebo (N=8) via nasogastric tube as add-on therapy on top of iNO until complete weaning of iNO or until treatment failure (defined as need for extra-corporeal membrane oxygenation [ECMO] or initiation of alternative pulmonary vasodilator), and for a maximum of 14 days.
The median exposure to study treatment was 4.5 (range: 0.5–10.0) days in the bosentan group and 4.0 (range: 2.5–6.5) days in the placebo group.
The results did not indicate an additional benefit of bosentan in this population:
The combination of bosentan and epoprostenol has been investigated in two studies: AC-052-355 (BREATHE-2) and AC-052-356 (BREATHE-3). AC-052-355 was a multi-centre, randomised, double-blind, parallel-group study of bosentan versus placebo in 33 patients with severe PAH who were receiving concomitant epoprostenol therapy. AC-052-356 was an open-label, uncontrolled study; 10 of the 19 paediatric patients were on concomitant bosentan and epoprostenol therapy during the 12-week study. The safety profile of the combination was not different from the one expected with each component and the combination therapy was well tolerated in children and adults. The clinical benefit of the combination has not been demonstrated.
Two randomised, double-blind, multi-centre, placebo-controlled studies have been conducted in 122 (study AC-052-401 [RAPIDS-1]) and 190 (study AC-052-331 [RAPIDS-2]) adult patients with systemic sclerosis and digital ulcer disease (either ongoing digital ulcers or a history of digital ulcers within the previous year). In study AC-052-331, patients had to have at least one digital ulcer of recent onset, and across the two studies 85% of patients had ongoing digital ulcer disease at baseline. After 4 weeks of bosentan 62.5 mg twice daily, the maintenance dose studied in both these studies was 125 mg twice daily. The duration of double-blind therapy was 16 weeks in study AC-052-401, and 24 weeks in study AC-052-331.
Background treatments for systemic sclerosis and digital ulcers were permitted if they remained constant for at least 1 month prior to the start of treatment and during the double-blind study period.
The number of new digital ulcers from baseline to study endpoint was a primary endpoint in both studies. Treatment with bosentan resulted in fewer new digital ulcers for the duration of therapy, compared with placebo. In study AC-052-401, during 16 weeks of double-blind therapy, patients in the bosentan group developed a mean of 1.4 new digital ulcers vs 2.7 new digital ulcers in the placebo group (p=0.0042). In study AC-052-331, during 24 weeks of double-blind therapy, the corresponding figures were 1.9 vs 2.7 new digital ulcers, respectively (p=0.0351). In both studies, patients on bosentan were less likely to develop multiple new digital ulcers during the study and took longer to develop each successive new digital ulcer than did those on placebo. The effect of bosentan on reduction of the number of new digital ulcers was more pronounced in patients with multiple digital ulcers.
No effect of bosentan on time to healing of digital ulcers was observed in either study.
The pharmacokinetics of bosentan have mainly been documented in healthy subjects. Limited data in patients show that the exposure to bosentan in adult PAH 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.
In healthy subjects, the absolute bioavailability of bosentan is approximately 50% and is not affected by food. The maximum plasma concentrations are attained within 3–5 hours.
Bosentan is highly bound (>98%) to plasma proteins, mainly albumin. Bosentan does not penetrate into erythrocytes.
A volume of distribution (Vss) of about 18 litres was determined after an intravenous dose of 250 mg.
After a single intravenous dose of 250 mg, the clearance was 8.2 L/h. The terminal elimination half- life (t½) is 5.4 hours.
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 metabolising liver enzymes. Steady-state conditions are reached within 3–5 days.
Bosentan is eliminated by biliary excretion following metabolism in the liver by the cytochrome P450 isoenzymes, CYP2C9 and CYP3A4. Less than 3% of an administered oral dose is recovered in urine.
Bosentan forms three metabolites and only one of these is pharmacologically active. This metabolite is mainly excreted unchanged via the bile. In adult patients, the exposure to the active metabolite is greater than in healthy subjects. In patients with evidence of the presence of cholestasis, the exposure to the active metabolite may be increased.
Bosentan is an inducer of CYP2C9 and CYP3A4 and possibly also of CYP2C19 and the P-glycoprotein. In vitro, bosentan inhibits the bile salt export pump in hepatocyte cultures.
In vitro data demonstrated that bosentan had no relevant inhibitory effect on the CYP isoenzymes tested (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4). Consequently, bosentan is not expected to increase the plasma concentrations of medicinal products metabolised by these isoenzymes.
Based on the investigated range of each variable, 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.
Pharmacokinetics were studied in paediatric patients in 4 clinical studies (BREATHE-3, FUTURE 1, FUTURE-3 and FUTURE-4; see section 5.1). Due to limited data in children below 2 years of age, pharmacokinetics remain not well characterised in this age category.
Study AC-052-356 (BREATHE-3) evaluated the pharmacokinetics of single and multiple oral doses of the film-coated tablet formulation of bosentan in 19 children aged from 3 to 15 years with PAH who were dosed on the basis of body weight with 2 mg/kg twice daily. In this study, 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 paediatric patients treated with 31.25, 62.5 or 125 mg twice daily were 3,496 (49), 5,428 (79), and 6,124 (27) ng·h/mL, respectively, and were lower than the value of 8,149 (47) ng·h/mL observed in adult patients with PAH receiving 125 mg twice daily. At steady state, the systemic exposures in paediatric patients weighing 10–20 kg, 20–40 kg and >40 kg were 43%, 67% and 75%, respectively, of the adult systemic exposure.
In study AC-052-365 (FUTURE 1), dispersible tablets were administered in 36 PAH children aged from 2 to 11 years. No dose proportionality was observed, as steady-state bosentan plasma concentrations and AUCs were similar at oral doses of 2 and 4 mg/kg (AUCτ: 3,577 ng·h/mL and 3,371 ng·h/mL for 2 mg/kg twice daily and 4 mg/kg twice daily, respectively). The average exposure to bosentan in these paediatric patients was about half the exposure in adult patients at the 125 mg twice daily maintenance dose but showed a large overlap with the exposures in adults.
In study AC-052-373 (FUTURE 3), using dispersible tablets, the exposure to bosentan in the patients treated with 2 mg/kg twice daily was comparable to that in the FUTURE 1 study. In the overall population (n=31), 2 mg/kg twice daily resulted in a daily exposure of 8,535 ng·h/mL; AUCτ was 4,268 ng·h/mL (CV: 61%). In patients between 3 months and 2 years the daily exposure was 7,879 ng·h/mL; AUCτ was 3,939 ng·h/mL (CV: 72%). In patients between 3 months and 1 year (n=2) AUCτ was 5,914 ng·h/mL (CV: 85%), and in patients between 1 and 2 years (n=7) AUCτ was 3,507 ng·h/mL (CV: 70%). In the patients above 2 years (n=22) the daily exposure was 8,820 ng·h/mL; AUCτ was 4,410 ng·h/mL (CV: 58%). Dosing bosentan 2 mg/kg three times daily did not increase exposure; daily exposure was 7,275 ng·h/mL (CV: 83%, n=27).
Based on the findings in studies BREATHE-3, FUTURE 1, and FUTURE-3, it appears that the exposure to bosentan reaches a plateau at lower doses in paediatric patients than in adults, and that doses higher than 2 mg/kg twice daily (4 mg/kg twice daily or 2 mg/kg three times daily) will not result in greater exposure to bosentan in paediatric patients.
In study AC-052-391 (FUTURE 4) conducted in neonates, bosentan concentrations increased slowly and continuously over the first dosing interval, resulting in low exposure (AUC0-12 in whole blood: 164 ng·h/mL, n=11). At steady state, AUCτ was 6,165 ng·h/mL (CV: 133%, n=7), which is similar to the exposure observed in adult PAH patients receiving 125 mg twice daily and taking into account a blood/plasma distribution ratio of 0.6.
The consequences of these findings regarding hepatotoxicity are unknown. Gender and concomitant use of intravenous epoprostenol had no significant effect on the pharmacokinetics of bosentan.
In patients with mildly impaired liver function (Child-Pugh class A) no relevant changes in the pharmacokinetics have been observed. The steady-state AUC of bosentan was 9% higher and the AUC of the active metabolite, Ro 48-5033, was 33% higher in patients with mild hepatic impairment than in healthy volunteers.
The impact of moderately impaired liver function (Child-Pugh class B) on the pharmacokinetics of bosentan and its primary metabolite Ro 48-5033 was investigated in a study including 5 patients with pulmonary hypertension associated with portal hypertension and Child-Pugh class B hepatic impairment, and 3 patients with PAH from other causes and normal liver function. In the patients with Child-Pugh class B liver impairment, the mean (95% CI) steady-state AUC of bosentan was 360 (212–613) ng⋅h/mL, i.e. 4.7 times higher, and the mean (95% CI) AUC of the active metabolite Ro 48-5033 was 106 (58.4–192) ng⋅h/mL, i.e. 12.4 times higher than in the patients with normal liver function (bosentan: mean [95% CI] AUC: 76.1 [9.07–638] ng⋅h/mL; Ro 48-5033: mean [95% CI] AUC 8.57 [1.28–57.2] ng⋅h/ml). Though the number of patients included was limited and with high variability, these data indicate a marked increase in the exposure to bosentan and its primary metabolite Ro 48-5033 in patients with moderate liver function impairment (Child-Pugh class B).
The pharmacokinetics of bosentan have not been studied in patients with Child-Pugh class C hepatic impairment. Tracleer is contraindicated in patients with moderate to severe hepatic impairment, i.e. Child-Pugh class B or C (see section 4.3).
In patients with severe renal impairment (creatinine clearance 15–30 mL/min), plasma concentrations of bosentan decreased by approximately 10%. Plasma concentrations of bosentan metabolites increased about 2-fold in these patients as compared with subjects with normal renal function. No dose adjustment is required in patients with renal impairment. There is no specific clinical experience in patients undergoing dialysis. Based on physicochemical properties and the high degree of protein binding, bosentan is not expected to be removed from the circulation by dialysis to any significant extent (see section 4.2).
A 2-year carcinogenicity study in mice showed an increased combined incidence of hepatocellular adenomas and carcinomas in males, but not in females, at plasma concentrations about 2 to 4 times the plasma concentrations achieved at the therapeutic dose in humans. 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 males, but not in females, at plasma concentrations about 9 to 14 times the plasma concentrations achieved at the therapeutic dose in humans. Bosentan was negative in tests for genotoxicity. There was evidence of a mild thyroid hormonal imbalance induced by bosentan in rats. However, there was no evidence of bosentan affecting thyroid function (thyroxine, TSH) in humans.
The effect of bosentan on mitochondrial function is unknown.
Bosentan has been shown to be teratogenic in rats at plasma levels higher than 1.5 times the plasma concentrations achieved at the therapeutic dose in humans. Teratogenic effects, including malformations of the head and face and of the major vessels, were dose dependent. The similarities of the pattern of malformations observed with other ET receptor antagonists and in ET knock-out mice indicate a class effect. Appropriate precautions must be taken for women of childbearing potential (see sections 4.3, 4.4 and 4.6).
Development of testicular tubular atrophy and impaired fertility has been linked with chronic administration of endothelin receptor antagonists in rodents.
In fertility studies in male and female rats, no effects on sperm count, motility and viability, or on mating performance or fertility were observed at exposures that were 21 and 43 times the expected therapeutic level in humans, respectively; nor was there any adverse effect on the development of the pre-implantation embryo or on implantation.
Slightly 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 maximum recommended human dose [MRHD] and the lowest doses tested) for two years but not at doses as high as 1,500 mg/kg/day (about 50 times the MRHD) for 6 months. In a juvenile rat toxicity study, where rats were treated from Day 4 post partum up to adulthood, decreased absolute weights of testes and epididymides, and reduced number of sperm in epididymides were observed after weaning. The NOAEL was 21 times (at Day 21 post partum) and 2.3 times (Day 69 post partum) the human therapeutic exposure, respectively.
However, no effects on general development, growth, sensory, cognitive function and reproductive performance were detected at 7 (males) and 19 (females) times the human therapeutic exposure at Day 21 post partum. At adult age (Day 69 post partum), no effects of bosentan were detected at 1.3 (males) and 2.6 (females) times the therapeutic exposure in children with PAH.
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