Bosentan accord 125 mg film-coated tablet: detailed information

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Bosentan Accord 125 mg film-coated tablets (Bosentan Accord 125 mg film-coated tablet)

Composition:

Active substance: bosentan;

One film-coated tablet contains bosentan (as monohydrate) 125 mg;

Excipients: maize starch, pregelatinized starch (maize), sodium starch glycolate (type A), povidone K-90, magnesium stearate;

Film coating Opadry 03K520012 yellow, including: hypromellose 6cP (E 464); titanium dioxide (E 171); triacetin, talc (E553b), yellow iron oxide (E 172), red iron oxide (E 172), purified water.

Pharmaceutical form. Film-coated tablets.

Basic physicochemical properties: oval, biconvex, film-coated tablets, approximately 11.00 mm in length, 5.00 mm in width, light orange in color, with "IB2" embossed on one side and plain on the other side.

Pharmacotherapeutic group

Antihypertensive agents for the treatment of pulmonary arterial hypertension. Bosentan.

ATC code C02K X01.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Bosentan is a dual endothelin receptor antagonist, structurally related to endothelin receptors A and B (ETA and ETB). Bosentan reduces 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 and has the ability to induce fibrosis, cellular proliferation, hypertrophy, and myocardial remodeling, as well as exhibits anti-inflammatory activity. These effects are mediated by endothelin binding to ETA and ETB receptors located in the vascular endothelium and smooth muscle cells. ET-1 concentrations in tissues and plasma are elevated in certain cardiovascular diseases and connective tissue disorders, including pulmonary arterial hypertension (PAH), scleroderma, acute and chronic heart failure, myocardial ischemia, systemic hypertension, and atherosclerosis, suggesting a role for ET-1 in the pathogenesis and progression of these conditions. In PAH and heart failure, in the absence of endothelin receptor antagonism, elevated ET-1 levels strongly correlate with disease severity and prognosis.

Bosentan prevents ET-1 and other endothelin peptides from binding to ETA and ETB receptors, with slightly higher affinity for ETA receptors (Ki = 4.1–43 nM) than for ETB receptors (Ki = 38–730 nM). Bosentan specifically blocks endothelin receptors and does not bind to other receptors.

Efficacy

Animal models

In animals with pulmonary hypertension, chronic oral administration of bosentan reduced pulmonary vascular resistance and reversibly affected pulmonary hypertrophy and right ventricular hypertrophy. In an animal model of pulmonary fibrosis, bosentan reduced collagen deposition in the lungs.

Efficacy in adult patients with PAH

Two randomized, double-blind, multicenter, placebo-controlled studies were 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 or secondary pulmonary hypertension, predominantly scleroderma). After 4 weeks of bosentan treatment at a dose of 62.5 mg twice daily, the maintenance doses studied were 125 mg twice daily in study AC-052-351 and 125 mg twice daily or 250 mg twice daily in study AC-052-352.

Bosentan was added to the patients' existing therapy, which included combinations of anticoagulants, vasodilators (e.g., calcium channel blockers), diuretics, oxygen, and digoxin, but not epoprostenol. Control was maintained using placebo in addition to background therapy.

The primary endpoint in each study was the change in the 6-minute walk distance at week 12 (in the first study) and at week 16 (in the second study). In both studies, bosentan treatment resulted in a significant improvement in exercise capacity. Compared to baseline, placebo treatment led to an increase in walking distance of 76 m (p = 0.02; t-test) and 44 m (p = 0.0002; Mann-Whitney U test) from the primary endpoint of each study, respectively. Differences between the two bosentan dose groups (125 mg twice daily and 250 mg twice daily) were not statistically significant, although a trend toward improved exercise tolerance was observed in the group receiving 250 mg twice daily.

Improvement in exercise capacity (walking distance) was evident after 4 weeks of treatment, clearly evident after 8 weeks, and sustained throughout the 28-week double-blind treatment period in the selected patient group.

In a retrospective analysis of response based on changes in exercise time (by WHO functional class) and dyspnea in 95 patients randomized to receive bosentan 125 mg twice daily in placebo-controlled studies, it was found that at week 8, the condition of 66 patients improved, 22 remained stable, and 7 worsened. Of the 22 patients whose condition remained stable at week 8, 6 improved by weeks 12–16, and 4 worsened compared to baseline. Of the 7 patients whose condition worsened at week 8, 3 improved by weeks 12–16, and 4 worsened compared to baseline.

In patients with PAH, bosentan treatment was associated with an increased cardiac index and significant reductions in pulmonary artery pressure, pulmonary vascular resistance (PVR), and mean right atrial pressure.

Bosentan use was associated with a reduction in PAH symptoms. Measurements of dyspnea during walking demonstrated improvement in patients receiving bosentan. Treatment with the drug led to improvement in WHO functional class in 42.4% of patients (placebo: 30.4%). Overall change in WHO functional class during both studies was significantly better in the bosentan group compared to placebo. Treatment with bosentan was associated with a significant reduction in the rate of clinical worsening compared to placebo over 28 weeks.

In a randomized, double-blind, multicenter, placebo-controlled study (AC-052-364 [EARLY]), patients with PAH classified as WHO functional class II (mean baseline 6-minute walk distance: 435 m) received bosentan 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily or placebo for 6 months.

	PVR (dyn·sec/cm5)		6-minute walk distance (m)
	Placebo (n=88)	Bosentan (n=80)	Placebo (n=91)	Bosentan (n=86)
Baseline (BL); mean (standard deviation)	802 (365)	851 (535)	431 (92)	443 (83)
Change from baseline; mean (standard deviation)	128 (465)	-69 (475)	-8 (79)	11 (74)
Treatment effect	-22.6 %		19
95 % CI	-34, -10		-4,42
p-value	< 0.0001		0.0758
CI = confidence interval; PVR = pulmonary vascular resistance; SD = standard deviation

The study included patients who were either untreated for PAH or those who had been on long-term sildenafil at a stable dose. The co-primary endpoint was the percentage change from baseline in PVR and the change from baseline in 6-minute walk distance over 6 months compared to placebo.

Bosentan treatment was associated with a reduction in the rate of clinical worsening, defined as a composite of symptomatic progression, hospitalization for PAH, and death compared to placebo (relative risk reduction 77%, 95% CI 20–94%, p = 0.0114). The treatment effect was driven by improvement in the symptomatic progression component. One hospitalization related to worsening PAH was recorded in the bosentan group and three hospitalizations in the placebo group. Only one death occurred in each treatment group during the 6-month double-blind study, thus precluding conclusions about survival.

Long-term data were obtained from patients treated with bosentan during the controlled phase and/or those who were switched from placebo to bosentan in the uncontrolled open-label extension phase of the EARLY study. The mean duration of bosentan treatment was 3.6 ± 1.8 years (up to 6.1 years), with 73% of patients receiving the drug for at least 3 years and 62% for at least 4 years. Patients could receive additional PAH therapy as permitted by the open-label extension study. Most patients had idiopathic or hereditary PAH (61%). Overall, 78% of patients were classified as WHO functional class II. Kaplan-Meier survival estimates were 90% and 85% at 3 and 4 years, respectively, after initiation of bosentan treatment. Over the same period, PAH progression (defined as all-cause death, lung transplantation, atrial septostomy, or initiation of intravenous or subcutaneous prostacyclin therapy) was not observed in 88% and 79% of patients, respectively. The relative contributions of prior placebo treatment during the double-blind phase and other medications initiated during the open-label extension phase are unknown.

In a prospective, multicenter, randomized, double-blind, placebo-controlled study (AC-052-405 [BREATHE-5]), patients with WHO functional class III PAH and Eisenmenger’s syndrome associated with congenital heart disease received bosentan at a dose of 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily for the next 12 weeks. The primary objective was to demonstrate that bosentan would not worsen hypoxemia. After 16 weeks, mean blood oxygen saturation increased by 1% (95% CI –0.7 to 2.8%) in the bosentan group compared to placebo, indicating that bosentan did not worsen hypoxemia. Mean PVR was significantly reduced in the bosentan group (the predominant effect was 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 m (p = 0.0079), reflecting improved exercise capacity. Twenty-six patients continued on bosentan in the 24-week open-label extension phase (AC-052-409) of BREATHE-5 (mean treatment duration was 24.4 ± 2 weeks), and efficacy was generally maintained.

An open-label, uncontrolled, non-comparative study (AC-052-362 [BREATHE ON-4]) included 16 patients with WHO functional class III PAH associated with HIV infection. Patients received bosentan at a dose of 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily for the next 12 weeks. After 16 weeks of treatment, significant improvement in exercise capacity was observed: the mean increase in 6-minute walk distance was 91.4 m from a baseline mean of 332.6 m (p < 0.001). No conclusion can be drawn regarding the effect of bosentan on antiretroviral drug efficacy.

There is no study demonstrating a positive effect of bosentan on survival. However, long-term survival has been observed in all patients who received bosentan in two pivotal placebo-controlled studies (AC-052-351 and AC-052-352) and/or two uncontrolled open-label extension studies. The mean duration of bosentan exposure was 1.9 ± 0.7 years (minimum 0.1 year, maximum 3.3 years), with patients observed for a mean of 2 ± 0.6 years. Most patients had primary PAH (72%), classified as WHO functional class III (84%). In this overall population, Kaplan-Meier survival estimates were 93% and 84% (1 and 2 years after initiation of bosentan, respectively). Survival was lower in the subgroup of patients with secondary PAH associated with systemic sclerosis. The estimate may have been influenced by the initiation of epoprostenol therapy in 43 out of 235 patients.

Study in children with PAH

BREATHE-3 (AC-052-356)

Bosentan tablets were evaluated in an open-label, uncontrolled, non-placebo-controlled study in children aged 3 to 15 years with PAH. This study was primarily designed as a pharmacokinetic study (see section "Pharmacokinetics"). Patients had primary PAH or PAH associated with congenital heart disease and were classified as WHO functional class II or III prior to study initiation. Patients were divided into 3 groups based on body weight and received bosentan at a dose of approximately 2 mg/kg twice daily for 12 weeks. Half of the patients in each group were already receiving intravenous epoprostenol, and the epoprostenol dose remained unchanged throughout the study period.

The mean increase from baseline in cardiac index was 0.5 L/min/m², the mean decrease in mean pulmonary arterial pressure (PAP) was 8 mm Hg, and the mean reduction in PVR was 389 dyn·s·cm⁻⁵. Hemodynamic improvement from baseline was similar in patients who additionally received epoprostenol and in those who did not. Parameters of exercise tolerance testing at week 12 compared to baseline varied widely and were not significant.

FUTURE 1/2 (AC-052-365/AC-052-367)

FUTURE 1 was an uncontrolled, non-placebo-controlled study conducted with dispersible bosentan tablets at a maintenance dose of 4 mg/kg twice daily in patients aged 2 to 11 years. This study was primarily designed as a pharmacokinetic study (see section "Pharmacokinetics"). At study initiation, patients had idiopathic or familial PAH and were classified as WHO functional class II or III. In the FUTURE 1 study, the mean exposure duration was 13.1 weeks (range: 8.4–21.1). Patients were provided extended treatment with dispersible bosentan tablets at a dose of 4 mg/kg twice daily during the uncontrolled extension phase of the FUTURE 2 study, in which the mean treatment duration was 2.3 years (range: 0.2–5 years). Baseline data from the FUTURE 1 study indicated that patients were receiving epoprostenol. Patients had recently initiated specific PAH therapy during the study. Kaplan-Meier estimated PAH progression (death, lung transplantation, or hospitalization due to worsening PAH) over 2 years was 78.9%. Kaplan-Meier survival over 2 years was 91.2%.

FUTURE 3 (AC-052-373)

This was a randomized, non-placebo-controlled study using dispersible bosentan tablets at a dose of 32 mg. Sixty-four children with stable PAH aged 3 months to 11 years were randomized to 24 weeks of treatment with bosentan at a dose of 2 mg/kg twice daily or 2 mg/kg three times daily. The study was primarily designed as a pharmacokinetic study (see section "Pharmacokinetics"), so efficacy endpoints were only exploratory. PAH etiology, according to the Dana Point classification, included idiopathic and hereditary PAH and PAH associated with corrected heart surgery and ischemic heart disease related to systemic-to-pulmonary shunts, including Eisenmenger syndrome. Patients were classified as WHO functional class I, II, or III prior to initiation of treatment during the study. At study initiation, patients were receiving PAH therapy (most commonly PDE-5 inhibitor [sildenafil] alone [35.9%], bosentan alone [10.9%], or a combination of bosentan, iloprost, and sildenafil in 10.9% of patients) and continued PAH therapy during the study.

At study initiation, less than half of the included patients were receiving bosentan monotherapy without combination with other PAH therapies. 40.6% of patients received bosentan as monotherapy for 24 weeks of the study without experiencing PAH progression. Analysis of the overall cohort showed that most patients remained at least stable (i.e., without progression), based on non-pediatric-specific WHO functional class assessment (97% twice daily, 100% three times daily) and overall clinical well-being (94% twice daily, 93% once daily) throughout the treatment period. Kaplan-Meier estimate of PAH progression (death, lung transplantation, or hospitalization due to worsening PAH) over 24 weeks was 96.9% and 96.7% in the bosentan twice daily and three times daily groups, respectively. No evidence of clinical benefit was obtained for the 2 mg/kg three times daily dosing compared to 2 mg/kg twice daily.

Study in neonates with persistent pulmonary hypertension of the newborn (PPHN):

FUTURE 4 (AC-052-391)

A double-blind, placebo-controlled, randomized study was conducted in neonates, including preterm infants (gestational age 36–42 weeks) with PPHN. Patients with suboptimal response to inhaled nitric oxide (INO), despite at least 4 hours of continuous treatment, received bosentan dispersible tablets at a dose of 2 mg/kg twice daily or placebo via nasogastric tube in addition to standard INO therapy until complete weaning from INO or treatment failure (defined as need for extracorporeal membrane oxygenation [ECMO] or initiation of an alternative pulmonary vasodilator) and for more than 14 days.

The mean duration of treatment was 4.5 days (range: 0.5–10.0) in the bosentan group and 4.0 days (range: 2.5–6.5) in the placebo group.

Results did not indicate additional benefits of bosentan in this patient group.

The mean time to INO discontinuation was 3.7 days (95% CI 1.17; 6.95) in the bosentan group and 2.9 days (95% CI 1.26; 4.23) in the placebo group (p = 0.34).

The mean time to extubation was 10.8 days (95% CI 3.21; 12.21 days) with bosentan and 8.6 days (95% CI 3.71; 9.66 days) in the placebo group (p = 0.24).

One patient in the bosentan group experienced treatment failure (need for ECMO as defined by protocol) based on increasing oxygenation index values over 8 hours after the first study drug dose. The condition of this patient recovered during the 60-day observation period.

Combination with epoprostenol

The combination of bosentan and epoprostenol was studied in two trials: AC-052-355 (BREATHE-2) and AC-052-356 (BREATHE-3). Study AC-052-355 was a multicenter, randomized, double-blind, parallel-group study comparing bosentan to placebo in patients with severe PAH receiving concomitant epoprostenol therapy. Study AC-052-356 was an open-label, non-placebo-controlled, uncontrolled study in which 10 out of 19 pediatric patients received combination therapy with bosentan and epoprostenol for 12 weeks. The safety profile of the combination did not differ from that expected for each component, and combination therapy was well tolerated in both children and adults. The clinical effect of this combination has not been demonstrated.

Systemic sclerosis with progressive digital ulceration (fingers and toes)

Two randomized, double-blind, multicenter, placebo-controlled studies were conducted in 122 (study AC-052-401 [RAPIDS-1]) and 190 (study AC-052-331 [RAPIDS-2]) adult patients with systemic sclerosis and digital ulceration (with history of active digital ulcers in the previous year).

In study AC-052-331, patients had at least one recently developed digital ulcer; 85% of patients had chronic digital ulceration at baseline. After 4 weeks of bosentan 62.5 mg twice daily, the maintenance dose of 125 mg twice daily was administered in both studies. The duration of double-blind treatment was 16 weeks in study AC-052-401 and 24 weeks in study AC-052-331.

Background therapy for systemic sclerosis and digital ulcers was permitted if it remained unchanged for at least 1 month prior to treatment initiation and throughout the double-blind study period.

The number of new ulcers from baseline (initial value) to end of study was the primary endpoint in both studies. Bosentan treatment resulted in a reduction in the number of new ulcers over the entire treatment period compared to placebo. In study AC-052-401, during 16 weeks of double-blind therapy, patients in the bosentan group had a mean of 1.4 new ulcers compared to 2.7 new ulcers in the placebo group. In study AC-052-331, during 24 weeks of double-blind study, the corresponding values were 1.9 compared to 2.7 new digital ulcers, respectively. In both studies, patients receiving bosentan were less likely to develop new ulcers during the study (they required more time to develop each subsequent new ulcer) than those receiving placebo. The effect of bosentan in reducing the number of new digital ulcers was more pronounced in patients with multiple ulcers.

In both cases, no effect of bosentan on the healing time of digital ulcers was observed.

Pharmacokinetics

Bosentan pharmacokinetics have been primarily studied in healthy volunteers. Limited data in patients indicate that the exposure to bosentan in adult PAH patients is approximately twice that in healthy adult volunteers.

In healthy volunteers, bosentan pharmacokinetics are dose- and time-dependent. Clearance and volume of distribution decrease with increasing intravenous dose and with increasing time.

After oral administration, systemic exposure is dose-proportional up to 500 mg. At higher oral doses, the increase in maximum concentration (Cmax) and area under the concentration-time curve (AUC) of bosentan relative to dose is disproportionate and occurs at a slower rate.

Absorption

In healthy volunteers, the absolute bioavailability of bosentan is approximately 50% and is independent of food intake. Cmax is reached within 3–5 hours.

Distribution

Bosentan binding to plasma proteins, primarily albumin, is 98%. Bosentan does not penetrate into erythrocytes.

The volume of distribution (approximately 18 L) is determined after intravenous administration of a 250 mg dose.

Metabolism and elimination

After a single intravenous dose of 250 mg, clearance is 8.2 L/h, and elimination half-life (t½) is 5.4 hours.

After multiple dosing, plasma concentrations of bosentan gradually decrease to 50–65% compared to those observed after a single dose. This reduction is likely due to autoinduction of hepatic metabolizing enzymes. Steady-state conditions are achieved within 3–5 days.

Bosentan is eliminated via bile, metabolized in the liver by CYP isoenzymes CYP2C9 and CYP3A4, and less than 3% of the orally administered dose is excreted in urine.

Bosentan forms three metabolites, only one of which is pharmacologically active. This metabolite is primarily excreted unchanged in bile. In adult patients, exposure to the active metabolite is higher than in healthy adult volunteers. In patients with signs of cholestasis, exposure to the active metabolite may be increased.

Bosentan is an inducer of CYP2C9 and CYP3A4, possibly also of CYP2C19 and P-glycoprotein. In vitro studies have shown that bosentan inhibits bile salt export in hepatocyte cultures.

Bosentan has been shown not to exert significant inhibitory effects on CYP isoenzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4). Therefore, it is unlikely that bosentan increases plasma concentrations of drugs metabolized by these isoenzymes.

Pharmacokinetics in special patient populations

Based on studies, bosentan pharmacokinetics are not expected to depend on gender, body weight, race, or age in the adult population.

Children

Pharmacokinetics in pediatric patients were studied in 4 clinical trials (BREATHE 3, FUTURE 1, FUTURE 3, and FUTURE 4). Pharmacokinetic data in children under 2 years of age are limited. In study AC-052-356 [BREATHE 3], the pharmacokinetics of single and multiple oral doses of bosentan were evaluated in children aged 3 to 15 years with PAH. An initial dose of 2 mg/kg twice daily was used. In this study, bosentan exposure subsequently decreased according to the known autoinduction properties of bosentan. Mean AUC values of bosentan in children receiving 31.25 mg, 62.5 mg, or 125 mg twice daily were 3,496 (49) ng·h/mL, 5,428 (79) ng·h/mL, and 6,124 (27) ng·h/mL, respectively, and were lower than the value of 8,149 (47) ng·h/mL observed in adult PAH patients receiving 125 mg twice daily. At steady state, systemic exposure in pediatric patients with body weights of 10–20 kg, 20–40 kg, and >40 kg was 43%, 67%, and 75%, respectively, compared to adult exposure.

In study AC-052-365 [FUTURE 1], dispersible tablets were administered to children with PAH aged 2 to 11 years. Dose proportionality was not established in steady-state plasma concentrations of bosentan, while AUC was similar for 2 mg/kg and 4 mg/kg doses (AUC ɽ: 3,577 ng·h × hour/mL and 3,371 ng·h × hour/mL at 2 mg/kg twice daily and 4 mg/kg twice daily, respectively). Mean bosentan exposure in children was approximately half the exposure in adult patients receiving the maintenance dose of 125 mg twice daily, but showed sufficient overlap with adult exposure.

In study AC-052-373 [FUTURE 3] using dispersible tablets, bosentan exposure in patients receiving 2 mg/kg twice daily was comparable to that observed in the FUTURE 1 study. In the overall patient group, administration of 2 mg/kg twice daily resulted in a daily exposure of 8,535 ng·h/mL; AUC was 4,268 ng·h/mL (CV 61%). In patients aged 3 months to 2 years, daily exposure was 7,879 ng·h/mL, AUC was 3,939 ng·h/mL (CV 72%). In patients aged 3 months to 1 year, AUC was 5,914 ng·h/mL (CV 85%), and in patients aged 1 to 2 years, AUC was 3,507 ng·h/mL (CV 70%). In patients aged 2 years, daily exposure was 8,820 ng·h/mL, AUC was 4,410 ng·h/mL (CV 58%). Bosentan dosing at 2 mg/kg three times daily did not increase exposure; daily exposure was 7,275 ng·h/mL (CV 83%).

Data from BREATHE 3, FUTURE 1, and FUTURE 3 studies indicate that bosentan exposure reaches a plateau at lower doses in children than in adults, and administration of doses higher than 2 mg/kg twice daily (4 mg/kg twice daily or 2 mg/kg three times daily) does not lead to increased bosentan exposure in children.

In study AC-052-391 [FUTURE 4] conducted in neonates, bosentan concentration slowly and continuously increased during the first dosing interval, resulting in low exposure (AUC in whole blood: 164 ng·h/mL). At steady state, AUC was 6,165 ng·h/mL (CV 133%), which is similar to exposure observed in adult PAH patients receiving 125 mg twice daily, considering a blood/plasma distribution ratio of 0.6.

The consequences of these findings regarding hepatotoxicity are unknown. Gender and concomitant intravenous epoprostenol administration did not significantly affect bosentan pharmacokinetics.

Hepatic impairment

In patients with mild hepatic impairment (Child-Pugh class A), no significant changes in pharmacokinetics were observed. Steady-state AUC of bosentan was 9% higher, and AUC of the active metabolite (Ro 48-5033) was 33% higher than in healthy adult volunteers.

The effect of moderate hepatic impairment (Child-Pugh class B) on the pharmacokinetics of bosentan and its primary metabolite (Ro 48-5033) was studied in a trial including 5 patients with PAH associated with portal hypertension and hepatic impairment (Child-Pugh class B) and 3 patients with other causes and normal liver function. In pediatric patients with liver impairment (Child-Pugh class B), mean (95% CI) steady-state AUC of bosentan was 360 (212–613) ng·h/mL, i.e., 4.7 times higher than in 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). Although the number of included patients was limited and with high variability, these data indicate a marked increase in exposure to bosentan and its primary metabolite Ro 48-5033 in patients with moderate hepatic impairment (Child-Pugh class B).

Pharmacokinetics of bosentan have not been studied in patients with hepatic impairment (Child-Pugh class C). Bosentan is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh class B or C).

Renal impairment

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 in these patients increased approximately 2-fold compared to normal renal function. Dose adjustment is not required in patients with renal impairment. There is no clinical experience in patients on dialysis.

Considering the physicochemical properties and high plasma protein binding, bosentan is not expected to be significantly removed from circulation by dialysis.

Preclinical safety data

A two-year carcinogenicity study in animals showed an increased incidence of combined hepatocellular adenoma and carcinoma in males at plasma concentrations approximately 2–4 times higher than the plasma concentration achieved at the therapeutic dose in humans. Oral administration of bosentan to animals for 2 years resulted in a slight increase in combined follicular cell adenoma and carcinoma of the thyroid in males at plasma concentrations approximately 9–14 times higher than those achieved at the therapeutic dose in humans. Bosentan was negative in genotoxicity tests. In animal studies, a mild thyroid hormonal imbalance induced by bosentan was observed. However, no evidence of bosentan's effect on thyroid function (thyroxine, TSH) in humans has been obtained.

The effect of bosentan on mitochondrial function is unknown.

In animal studies, teratogenicity of bosentan was observed at plasma concentrations higher than 1.5 times the plasma concentration achieved at the therapeutic dose in humans. Teratogenic effects, including craniofacial and great vessel malformations, were dose-dependent. Similar patterns of developmental malformations were observed with other ET receptor antagonists, demonstrating a class effect in animals in which specific genes have been artificially blocked (knocked out) to study their functions to simulate human diseases.

Women of childbearing potential must use appropriate contraceptive measures.

Testicular tubular atrophy and fertility impairment were associated with chronic administration of endothelin receptor antagonists in animals.

In fertility studies in male and female animals, no effect on sperm count, motility, and viability or on mating performance or fertility was observed at exposures 21 and 43 times higher, respectively, than the expected therapeutic level in humans. There was also no adverse effect on embryonic development prior to implantation or on implanted embryos.

A slight increase in the incidence of testicular tubular atrophy was observed in animals receiving oral bosentan at doses up to 125 mg/kg/day (approximately 4 times the maximum recommended human dose [MRHD] and the lowest tested dose) for 2 years, but not at doses higher than 1500 mg/kg/day (approximately 50 times the MRHD) for 6 months. In a juvenile toxicity study in animals treated from day 4 after birth to maturity, a decrease in absolute testicular and epididymal weight and a decrease in epididymal sperm count after weaning were observed. The maximum non-toxic dose was 21 times (on day 21 after birth) and 2.3 times (on day 69 after birth) higher than the therapeutic exposure in humans, respectively.

However, no effect on overall development, growth, sensory, cognitive, and reproductive functions was observed with therapeutic use in humans on day 21 after birth in 7 cases (males) and 19 cases in females. In older age (day 69 after birth), no effect of bosentan was observed with increased therapeutic exposure during use in children with PAH: 1.3 times (in males) and 2.6 times (in females).

Clinical Characteristics

Indications

Treatment of pulmonary arterial hypertension to improve exercise tolerance and clinical symptoms in patients classified as WHO functional class III.

Efficacy has been demonstrated in the following conditions:

Primary (idiopathic and hereditary) pulmonary arterial hypertension;
Secondary pulmonary arterial hypertension associated with scleroderma without significant interstitial lung disease;
Pulmonary arterial hypertension associated with congenital systemic-to-pulmonary shunts and Eisenmenger syndrome.

Some improvement has also been demonstrated in patients with pulmonary arterial hypertension classified as WHO functional class II.

Reduction in the number of new digital ulcers in adults with systemic sclerosis and progressive ulcerative lesions of extremities (fingers and toes).

Contraindications

Hypersensitivity to bosentan or to any of the excipients of the medicinal product.

Moderate to severe hepatic impairment (Child-Pugh class B or C).

Elevated baseline liver aminotransferase activity (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) more than 3 times the upper limit of normal.

Concomitant use of cyclosporine A.

Pregnancy.

Women of childbearing potential who are not using reliable contraceptive methods.

Interaction with other medicinal products and other forms of interaction

Interaction studies have been conducted only in adults.

Bosentan is an inducer of the cytochrome P450 (CYP) isoenzymes CYP2C9 and CYP3A4.

In vitro laboratory data also indicate induction of CYP2C19. Therefore, plasma concentrations of substances metabolized by these isoenzymes may be reduced when co-administered with bosentan. Potential changes in the efficacy of drugs metabolized by these isoenzymes should be considered. Dose adjustments of these medicinal products may be required at the initiation, dose change, or discontinuation of concomitant bosentan therapy.

Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these isoenzymes may increase bosentan plasma concentrations (see ketoconazole). The effect of CYP2C9 inhibitors on bosentan concentration has not been studied; therefore, such combinations should be used with caution.

Fluconazole and other inhibitors such as CYP2C9 and CYP3A4. Concomitant use with fluconazole, which primarily inhibits CYP2C9 and to a lesser extent CYP3A4, may lead to a significant increase in bosentan plasma concentration. Therefore, this combination is not recommended. For the same reason, concomitant use of potent CYP3A4 inhibitors (such as ketoconazole, itraconazole, or ritonavir) and CYP2C9 inhibitors (such as voriconazole) with bosentan is not recommended.

Cyclosporine A. Concomitant use of bosentan and cyclosporine A (a calcineurin inhibitor) is contraindicated. When used in combination, the initial concentration of bosentan was approximately 30 times higher than with bosentan monotherapy. At steady state, bosentan plasma concentration was 3–4 times higher than with bosentan alone. The mechanism of this interaction is most likely due to inhibition of bosentan uptake transporter protein in hepatocytes caused by cyclosporine. Cyclosporine A plasma concentration (a CYP3A4 substrate) decreased by approximately 50%. This was most likely due to bosentan-induced CYP3A4 induction.

Tacrolimus, sirolimus. There are no data on the concomitant use of tacrolimus or sirolimus with bosentan. Concomitant use of tacrolimus or sirolimus with bosentan may increase bosentan plasma concentration, similar to the interaction observed with cyclosporine A. Concomitant use of bosentan may lead to decreased plasma concentrations of tacrolimus and sirolimus; therefore, this combination is not recommended. Close monitoring of patients requiring combination therapy with bosentan and tacrolimus or sirolimus is necessary, with attention to blood concentrations of these drugs.

Glibenclamide. Concomitant use with bosentan 125 mg twice daily for 5 days reduces plasma concentration of glibenclamide (a CYP3A4 substrate) by 40%, with potential for significant reduction in hypoglycemic effect. Bosentan plasma concentration was also reduced by 29%. In addition, increased incidence of elevated aminotransferases was observed in patients receiving concomitant therapy. Both glibenclamide and bosentan inhibit bile acid metabolism, which may explain the elevated aminotransferases. This combination should not be used. There are no data on the interaction of bosentan with other sulfonylureas.

Rifampicin. Concomitant use of bosentan 125 mg twice daily with rifampicin, a potent inducer of CYP2C9 and CYP3A4, in 9 healthy volunteers for 7 days resulted in a 58% reduction in bosentan plasma concentration. This reduction may reach up to 90% in individual cases. As a result, the expected therapeutic effect of bosentan is significantly reduced when co-administered with rifampicin. Concomitant use of bosentan and rifampicin is not recommended. There are insufficient data on other CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, and St. John’s wort), but their concomitant use is expected to reduce systemic exposure to bosentan. Clinically significant reduction in efficacy cannot be excluded.

Lopinavir + ritonavir (and other protease inhibitors). Concomitant use of bosentan 125 mg twice daily with lopinavir + ritonavir 400 mg + 100 mg twice daily for 9.5 days in healthy volunteers led to a 48-fold increase in bosentan plasma concentration compared to bosentan alone. On day 9, bosentan plasma concentration was approximately 5 times higher than with bosentan monotherapy. This interaction is most likely due to ritonavir-mediated inhibition of hepatic uptake transporter protein and CYP3A4, thereby reducing bosentan elimination. Monitoring of bosentan tolerability is required when co-administered with lopinavir + ritonavir or other protease inhibitors.

After 9.5 days of concomitant use with bosentan, plasma exposure of lopinavir and ritonavir decreased slightly (by approximately 14% and 17%, respectively), not reaching clinical significance. However, full induction by bosentan may not have been achieved; therefore, further reduction in protease inhibitor concentrations cannot be excluded. Appropriate monitoring of HIV therapy is required. Similar effects may be expected with other protease inhibitors.

Other antiretroviral agents. Due to lack of data, no specific recommendations can be made regarding other antiretroviral agents. Because of the pronounced hepatotoxicity of nevirapine, which may increase liver toxicity associated with bosentan, this combination is not recommended.

Hormonal contraceptives. Concomitant use of bosentan 125 mg twice daily for 7 days with a single dose of an oral contraceptive containing 1 mg norethisterone and 35 µg ethinylestradiol resulted in a 14% and 31% reduction in AUC of norethisterone and ethinylestradiol, respectively. However, in individual patients, the reduction in protection was up to 56% and 66%, respectively. Therefore, use of hormonal contraceptives alone, regardless of route of administration (oral, injectable, transdermal, or implanted), is not considered a reliable method of contraception.

Warfarin. Concomitant use of warfarin with bosentan 500 mg twice daily for 6 days reduced plasma concentrations of S-warfarin (CYP2C9 substrate) and R-warfarin (CYP3A4 substrate) by 29% and 38%, respectively. Clinical experience with concomitant use of bosentan and warfarin in patients with PAH has not shown clinically significant changes in international normalized ratio (INR) or warfarin dose (baseline compared to end of clinical studies). Additionally, the frequency of warfarin dose adjustments during the studies due to changes in INR or adverse effects was similar in patients receiving bosentan and placebo. When using warfarin or similar oral anticoagulants, dose adjustment at the initiation of bosentan therapy is not required, but INR monitoring should be performed, especially at the beginning of bosentan treatment and during titration.

Simvastatin. Concomitant use with bosentan 125 mg twice daily for 5 days reduces plasma concentration of simvastatin (a CYP3A4 substrate) and its active metabolite beta-hydroxy acid by 34% and 46%, respectively. Bosentan plasma concentration is not affected by concomitant use with simvastatin. Monitoring of cholesterol levels and further dose adjustments should be considered.

Ketoconazole. Concomitant use of bosentan 62.5 mg twice daily with ketoconazole, a potent CYP3A4 inhibitor, increases bosentan plasma concentration by approximately 2-fold. Dose adjustment of bosentan is not required, and similar increases in bosentan plasma concentration are expected with other strong CYP3A4 inhibitors (itraconazole, ritonavir). However, when combined with a CYP3A4 inhibitor, patients with poor CYP2C9 metabolism are at risk of higher increases in bosentan plasma concentration, potentially leading to dangerous adverse reactions.

Epoprostenol. Limited data from a study (AC-052-356 [BREATHE-3]) in which 10 children received a combination of bosentan and epoprostenol suggest that after single and multiple doses, Cmax and AUC from time of dosing to the last quantifiable concentration of bosentan were similar in patients with or without continuous epoprostenol infusion.

Sildenafil. Concomitant use of bosentan 125 mg twice daily (steady state) with sildenafil 80 mg three times daily (steady state) for 6 days in healthy volunteers resulted in a 63% reduction in AUC from time of dosing to the last quantifiable concentration of sildenafil and a 50% increase in AUC of bosentan. Therefore, this combination should be used with caution.

Tadalafil. Bosentan (125 mg twice daily) reduced systemic exposure to tadalafil (40 mg once daily) by 42% and Cmax by 27% after multiple doses of concomitant administration. Tadalafil did not affect the exposure (AUC and Cmax) of bosentan or its metabolites.

Digoxin. Concomitant use of bosentan 500 mg twice daily with digoxin for 7 days reduced AUC, Cmax, and Cmin by 12%, 9%, and 23%, respectively. The mechanism of this interaction may be induction of P-glycoprotein. This interaction is not considered clinically significant.

Pediatric patients

Interaction studies have been conducted only in adult patients.

Special Warnings and Precautions

The efficacy of bosentan has not been established in patients with severe PAH. Transition to therapy recommended for severe disease stage (e.g., epoprostenol) should be considered if the patient's clinical condition worsens (see section "Dosage and Administration").

The benefit-risk ratio of bosentan use has not been established in patients with WHO functional class I PAH.

Bosentan therapy should only be initiated when the patient's baseline systolic arterial blood pressure is above 85 mm Hg.

A positive effect of bosentan on the healing of existing digital ulcers has not been established.

Liver Function

Bosentan-associated elevations in liver aminotransferases (AST and/or ALT) are dose-dependent. Changes in liver enzyme levels usually occur within the first 26 weeks of treatment, but may also occur later (see section "Adverse Reactions"). This increase in liver enzymes may be partly related to competitive inhibition of bile acid export from hepatocytes; however, other mechanisms not fully elucidated are likely involved in the development of liver dysfunction. Accumulation of bosentan in hepatocytes leading to cytolytic damage with potentially severe liver injury, or an immunological mechanism, cannot be ruled out. The risk of liver dysfunction may also be increased when bosentan is used concomitantly with medicinal products that are inhibitors of the bile acid export pump, such as rifampicin, glyburide, and cyclosporine A (see sections "Contraindications" and "Interaction with Other Medicinal Products and Other Forms of Interaction"); however, data in this regard are limited.

Levels of hepatic aminotransferases should be determined prior to initiating treatment and subsequently once a month throughout the entire duration of drug use. Additionally, levels of hepatic aminotransferases should be determined 2 weeks after any dose increase.

Recommendations in case of elevated ALT/AST levels

ALT/AST level Treatment and monitoring recommendations

> 3 and ≤ 5 × ULN The result should be confirmed by a repeat test for liver enzymes. If confirmed, an individual decision should be made whether to continue treatment (possibly at a lower dose) or discontinue the drug (see section "Dosage and administration"). Monitoring of aminotransferase levels should continue at least every 2 weeks. If aminotransferase levels return to pre-treatment values, consideration may be given to continuing or resuming treatment with the drug according to the conditions described below.

> 5 and ≤ 8 × ULN The result should be confirmed by a repeat test for liver enzymes; if confirmed, the drug should be discontinued and aminotransferase levels should be monitored at least every 2 weeks. If aminotransferase levels return to pre-treatment values, consideration may be given to resuming treatment with the drug according to the conditions described below.

> 8 × ULN Treatment with the drug must be discontinued without considering the possibility of reinitiating treatment.

If clinical symptoms associated with liver injury occur, namely: nausea, vomiting, fever, abdominal pain, jaundice, abnormal somnolence or increased fatigue, flu-like symptoms (arthralgia, myalgia, fever), treatment with the drug must be discontinued without considering the possibility of reinitiating treatment.

Resumption of treatment with the drug

Resumption of treatment with the drug should only be considered if the anticipated benefit outweighs the potential risk and if hepatic aminotransferase levels have returned to pre-treatment values. Consultation with a hepatologist is recommended. Resumption of treatment should follow the instructions provided in the section "Dosage and administration". Aminotransferase levels should be monitored 3 days after resuming treatment with the drug, then again after the next 2 weeks, and subsequently according to the recommendations outlined above.

ULN = upper limit of normal

Hemoglobin concentration

A dose-dependent effect of bosentan on decreasing hemoglobin concentration in whole blood has been observed. In placebo-controlled studies with bosentan, the decline in hemoglobin levels was not progressive and stabilized after the first 4–12 weeks of therapy. Monitoring of this parameter is recommended monthly before initiating therapy for the first 4 months, and thereafter every 3 months. If clinically significant reduction in hemoglobin occurs, further patient evaluation should be performed to determine the cause and need for appropriate treatment. During the post-marketing period, cases of anemia requiring red blood cell transfusion have been reported.

Women of childbearing potential

Given that bosentan may reduce the efficacy of hormonal contraceptives, the risk of worsening pulmonary arterial hypertension (PAH) during pregnancy, and the teratogenic effects observed in animals:

Bosentan treatment should not be initiated in women of childbearing potential unless they use reliable contraceptive methods and have a negative pregnancy test prior to starting treatment;
Hormonal contraceptives should not be used as the sole method of contraception during bosentan treatment;
Monthly pregnancy testing is recommended during treatment to allow early detection of pregnancy.

Pulmonary veno-occlusive disease

Cases of pulmonary edema have been reported in patients with pulmonary veno-occlusive disease receiving vasodilators (mainly prostacyclins) concomitantly. The possibility of associated obliterative lung disease should be considered if signs of pulmonary edema occur during bosentan treatment in patients with PAH. Rare cases of pulmonary edema have been reported in patients previously treated with bosentan who had suspected pulmonary veno-occlusive disease.

PAH in patients with concomitant left ventricular dysfunction

No specific studies have been conducted in patients with PAH and concomitant left ventricular dysfunction. However, 1611 patients (804 receiving bosentan and 807 placebo) with severe chronic heart failure (CHF) were treated for an average of 1.5 years in a placebo-controlled study (study AC-052-301/302 [INCLUSIONS 1 and 2]). This study showed an increased number of hospitalizations due to CHF during the first 4–8 weeks of bosentan treatment, possibly due to fluid retention. In this study, fluid retention was associated with initial weight gain, decreased hemoglobin concentration, and increased incidence of leg edema. At the end of the study, no differences were observed in overall hospitalization due to heart failure or mortality between bosentan-treated and placebo groups. Patients should be monitored for signs of fluid retention (e.g., weight gain), especially if they also have severe systolic dysfunction. If such signs occur, diuretic therapy should be initiated or the dose of existing diuretics increased. Diuretic treatment should be considered before starting bosentan therapy in patients with signs of fluid retention.

PAH associated with HIV infection

There is limited clinical experience with bosentan use in patients with PAH associated with HIV infection who are receiving antiretroviral agents. Interaction studies between bosentan and lopinavir+ritonavir in healthy volunteers showed increased plasma concentrations of bosentan, with peak levels during the first 4 days of treatment. Careful monitoring of bosentan tolerability is required when prescribing bosentan to patients receiving ritonavir-boosted protease inhibitors, particularly during the initial phase, due to the risk of arterial hypotension, and liver function tests should be performed. An increased long-term risk of hepatotoxicity and hematological adverse reactions cannot be excluded when bosentan is used in combination with antiretroviral agents. Monitoring of HIV-infected patients is necessary, as interactions between antiretroviral drugs and bosentan may induce CYP450 enzymes, potentially affecting the efficacy of antiretroviral therapy.

Secondary PAH related to chronic obstructive pulmonary disease (COPD)

The safety and tolerability of bosentan were evaluated in an exploratory, uncontrolled 12-week study in patients with secondary PAH due to severe COPD (stage III according to GOLD classification). Increased minute ventilation and decreased oxygen saturation were observed. The most common adverse effect was dyspnea, which resolved after discontinuation of bosentan therapy.

Use with other medicinal products

Concomitant use of bosentan with cyclosporine A is contraindicated. Concomitant use of bosentan with glyburide, fluconazole, and rifampicin is not recommended (see section «Interaction with other medicinal products and other forms of interaction»).

Concomitant use of bosentan with a CYP3A4 inhibitor and a CYP2C9 inhibitor should be avoided.

Use during pregnancy or breastfeeding

Pregnancy

Animal studies indicate reproductive toxicity (teratogenic, embryotoxic—see section «Pharmacokinetics. Preclinical safety data»). There are no reliable data on the use of bosentan in pregnant women. The potential risk to humans has not been established. Bosentan is contraindicated during pregnancy (see section «Contraindications»).

Use in women of childbearing potential

Before initiating bosentan therapy in women of childbearing potential, pregnancy must be excluded, appropriate advice on reliable contraception provided, and reliable contraception initiated. Prescribers and patients must be aware that due to possible pharmacokinetic interactions, bosentan may reduce the efficacy of hormonal contraceptives (see section «Interaction with other medicinal products and other forms of interaction»). Therefore, women of childbearing potential should not use hormonal contraceptives (including oral, injectable, implantable, or transdermal) as the sole method of contraception and should use an additional or alternative reliable contraceptive method. In case of any doubts regarding individual contraceptive use for each patient, consultation with a gynecologist is recommended. Due to the potential ineffectiveness of hormonal contraception during bosentan treatment and the risk of significant worsening of PAH during pregnancy, monthly pregnancy testing is recommended during bosentan therapy to ensure early detection of pregnancy.

Breastfeeding period

Data from one case report indicate the presence of bosentan in human milk at low concentrations. Information on the effects of bosentan on breastfed infants is insufficient. A risk to the breastfed infant cannot be excluded. Breastfeeding is not recommended during bosentan treatment.

Fertility

Animal studies have demonstrated testicular effects. In a study assessing the impact of bosentan on testicular function in male patients with PAH, reduced sperm concentration of at least 50% compared to baseline was observed in 6 out of 24 patients (25%) after 6 months of bosentan treatment. Based on these findings and preclinical data, it cannot be excluded that bosentan may have a negative effect on spermatogenesis in men. A long-term effect on fertility in male children cannot be excluded following bosentan treatment.

Ability to affect reaction speed when driving or operating machinery

No specific studies have been conducted to assess the direct effect of bosentan on the ability to drive or operate machinery. However, bosentan may cause arterial hypotension with symptoms such as dizziness or fainting, which may affect the ability to drive or operate machinery.

Method of Administration and Dosage

Method of Administration

Take tablets orally in the morning and evening, independently of food intake, with water.

Dosage

Pulmonary Arterial Hypertension (PAH)

Treatment must be initiated and monitored only by a physician experienced in the management of PAH.

Adults

For adult patients, treatment with bosentan should be initiated at a dose of 62.5 mg (use bosentan tablets of appropriate strength) twice daily for 4 weeks, followed by an increase to the maintenance dose of 125 mg twice daily. These same recommendations may be applied when resuming bosentan treatment after an interruption.

Actions in Case of Clinical Worsening of PAH

In case of clinical worsening (e.g., a decrease of at least 10% in the 6-minute walk test compared to previous results), despite bosentan treatment for at least 8 weeks (with the target dose maintained for at least 4 weeks), alternative treatment options should be considered. However, some patients who do not show a response after 8 weeks of bosentan treatment may respond positively after an additional 4–8 weeks of therapy.

In case of late clinical worsening despite bosentan treatment (after several months of therapy), treatment should be re-evaluated. Some patients may not respond adequately to the 125 mg dose of bosentan twice daily but may experience slight improvement in exercise capacity when the dose is increased to 250 mg twice daily. A careful benefit/risk assessment of such use should be performed, considering that higher doses may increase the risk of hepatotoxicity.

Discontinuation of Treatment

Experience with abrupt discontinuation of bosentan in patients with PAH is limited. No signs of acute rebound effect have been observed. However, to avoid potential harmful clinical worsening due to a possible rebound effect, the dose should be tapered gradually (reduce the dose by half over 3–7 days). Enhanced monitoring is recommended during the discontinuation period.

Bosentan discontinuation should be performed gradually when introducing alternative therapy.

Systemic Sclerosis with Progressive Ulcerative Limb Lesions (Fingers and Toes)

Treatment must be initiated and monitored only by a physician experienced in the management of systemic sclerosis.

Adults

Bosentan treatment should be initiated at a dose of 62.5 mg (use bosentan tablets of appropriate strength) twice daily for 4 weeks, followed by an increase to the maintenance dose of 125 mg twice daily. These same recommendations may be applied when re-initiating bosentan after a treatment interruption.

Controlled clinical experience with these symptoms is limited to 6 months.

The patient’s response to treatment and the need for continued therapy should be continuously evaluated, and a careful benefit/risk assessment of bosentan use should be performed, considering the impact of dosing on hepatotoxicity.

Special Patient Populations

Patients with Hepatic Impairment

Bosentan is contraindicated in patients with moderate to severe hepatic dysfunction. Dose adjustment is not required in patients with mild hepatic impairment (Child-Pugh class A).

Patients with Renal Impairment

Dose adjustment is not required in patients with renal impairment.

Dose adjustment is not required in patients undergoing dialysis.

Elderly Patients

Dose adjustment is not required in patients aged 65 years and older.

Children

Pulmonary Arterial Hypertension

Pharmacokinetic data in pediatric patients indicate that bosentan plasma concentrations in children aged 1–15 years with pulmonary arterial hypertension were on average lower than in adult patients and did not increase with bosentan doses exceeding 2 mg/kg body weight or with increasing dosing frequency from twice to three times daily (see section "Pharmacokinetics"). It is considered that increasing the dose or dosing frequency will not provide additional clinical benefit.

Based on pharmacokinetic data in children aged 1 year and older, the recommended starting and maintenance dose is 2 mg/kg twice daily (morning and evening).

In neonates with persistent pulmonary hypertension of the newborn, no benefit of bosentan has been observed when added to standard therapy. No dosage recommendations can be provided (see sections "Pharmacodynamics" and "Pharmacokinetics").

Systemic Sclerosis with Active Digital Ulceration

Safety and efficacy data for bosentan use in patients under 18 years of age are lacking. Pharmacokinetic data for bosentan in young children are not available.

Overdose

Bosentan has been administered as a single dose of up to 2400 mg to healthy volunteers and up to 2000 mg daily for 2 months to patients with conditions other than pulmonary hypertension. The most common adverse reaction was mild to moderate headache.

Severe overdose may lead to pronounced arterial hypotension, requiring active cardiovascular support. During post-marketing surveillance, an overdose of 10,000 mg of bosentan was reported in a male adolescent. Symptoms included nausea, vomiting, dizziness, increased sweating, and blurred vision. The patient fully recovered within 24 hours with supportive care for blood pressure. Bosentan is not removed by dialysis.

Adverse Reactions

In studies conducted across various therapeutic indications, a total of 2486 patients received bosentan at daily doses ranging from 100 mg to 2000 mg, and 1838 patients received placebo. The average duration of treatment was 45 weeks. Adverse reactions occurred in at least 1% of patients receiving bosentan and at least 0.5% more frequently than in the placebo group. The most common adverse reactions were headache (11.5%), edema/fluid retention (13.2%), liver function test abnormalities (10.9%), and anemia/hemoglobin decrease (9.9%).

Bosentan treatment was associated with dose-dependent increases in liver aminotransferases and reductions in hemoglobin concentration.

Adverse reactions observed in clinical studies and following discontinuation of bosentan are listed below according to the following classification of frequency: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1000 to < 1/100); rare (> 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from the available data).

Within each frequency category, adverse reactions are listed in order of decreasing severity. There are no clinically significant differences in adverse reactions between the overall data set and the approved indications.

System-organ class	Frequency	Adverse reactions
Blood and lymphatic system disorders	common	anemia, decreased hemoglobin levels (see section "Special precautions")
	frequency unknown	anemia or decreased hemoglobin levels requiring erythrocyte transfusion¹
	uncommon	thrombocytopenia¹, neutropenia, leukopenia¹
Immune system disorders	common	hypersensitivity reactions (including dermatitis, pruritus, and rash)²
Immune system disorders	rare	anaphylaxis and/or angioedema¹
Nervous system disorders	very common	headache³
Nervous system disorders	common	syncope^1,4
Eye disorders	frequency unknown	blurred vision¹
Cardiac disorders	common	palpitations^1,4
Vascular disorders	common	hyperemia, arterial hypotension^1,4
Respiratory, thoracic and mediastinal disorders	common	nasal congestion¹
Gastrointestinal disorders	common	gastroesophageal reflux disease, diarrhea
Hepatobiliary disorders	very common	abnormal liver function tests (see section "Special precautions")
	uncommon	elevated aminotransferase levels associated with hepatitis (including possible exacerbation of underlying hepatitis) and/or jaundice¹ (see section "Special precautions")
	rare	liver cirrhosis, liver failure¹
Skin and subcutaneous tissue disorders	common	erythema
General disorders and administration site conditions	very common	edema, fluid retention⁵

1 Data obtained after discontinuation of the drug; frequency is based on statistical modeling of data from placebo-controlled clinical trials.

2 Hypersensitivity reactions were reported in 9.9% of patients receiving bosentan and in 9.1% of patients receiving placebo.

3 Headache was reported by 11.5% of patients receiving bosentan and by 9.8% of patients receiving placebo.

4 These types of reactions may also be related to the underlying disease.

5 Edema or fluid retention was reported in 13.2% of patients receiving bosentan and in 10.9% of patients receiving placebo.

During the post-marketing surveillance period, isolated cases of unexplained liver cirrhosis have been reported after long-term bosentan therapy in patients with multiple comorbidities and concomitant medication use. Rare cases of liver failure have also been reported. Therefore, strict adherence to the monthly schedule for monitoring liver function during bosentan treatment is required.

Pediatric population

Uncontrolled clinical studies in pediatric patients

Results of the safety study in the first uncontrolled pediatric trial using film-coated tablets (BREATHE-3: 19 children, age 10 years [range 3–15 years], no placebo control, bosentan 2 mg/kg twice daily, treatment duration 12 weeks) were similar to those observed in main adult studies in patients with PAH. During the BREATHE-3 study, the most frequent adverse reactions were flushing (21%), headache, and liver function abnormalities (biochemical parameter) (each 16%).

A combined analysis of uncontrolled pediatric studies using bosentan 32 mg dispersible tablets (FUTURE-1/2, FUTURE-3/extension) included a total of 100 children receiving bosentan at doses of 2 mg/kg twice daily, 2 mg/kg three times daily, or 4 mg/kg twice daily. At study initiation, 6 patients were aged from 3 months to 1 year, 15 children were aged 1 to 2 years, and 79 were aged 2 to 12 years. The mean duration of treatment was 71.8 weeks (0.4–258 weeks).

The safety profile observed in this combined analysis of uncontrolled pediatric studies was similar to that observed in main adult studies in patients with PAH, except for infections, which were more common in children than in adults (69.0% vs. 41.3%). This difference in infection frequency may be partly due to the longer mean treatment duration in children (median 71.8 weeks) compared to adults (mean 17.4 weeks). The most common adverse reactions were upper respiratory tract infections (25%), pulmonary (arterial) hypertension (20%), rhinopharyngitis (17%), pyrexia (15%), vomiting (13%), bronchitis (10%), abdominal pain (10%), and diarrhea (10%). No significant differences in adverse event rates were observed between patients older and younger than 2 years; however, this conclusion is based on only 21 children aged up to 2 years, including 6 patients aged from 3 months to 1 year. Adverse reactions of liver abnormalities and anemia (decreased hemoglobin) were reported in 9% and 5% of patients, respectively.

In a randomized, placebo-controlled study conducted in patients with persistent pulmonary hypertension of the newborn (FUTURE-4), a total of 13 newborns received dispersible bosentan at a dose of 2 mg/kg twice daily (8 patients received placebo). The mean duration of treatment with bosentan and placebo was 4.5 days (range 0.5–10.0 days) and 4.0 days (range 2.5–6.5 days), respectively. The most common adverse reactions with bosentan and placebo were anemia (decreased hemoglobin) (7 and 2 patients), generalized edema (3 and 0 patients), and vomiting (2 and 0 patients), respectively.

Laboratory abnormalities

Liver function test abnormalities

In the clinical program, dose-dependent increases in liver transaminases typically occurred within the first 26 weeks of treatment, usually developed gradually, and were mostly asymptomatic. Rare cases of liver cirrhosis and liver failure have been reported after discontinuation of the drug.

The mechanism of this adverse effect is unknown. These increases may resolve spontaneously during continued maintenance therapy with bosentan or after dose reduction, but discontinuation or interruption of treatment may be necessary (see section "Dosage and Administration").

In 20 integrated placebo-controlled studies, elevations in liver transaminases > 3 times ULN (upper limit of normal) were observed in 11.2% of patients treated with bosentan, compared to 2.4% of patients receiving placebo. Elevations up to 8 times ULN were observed in 3.6% of patients receiving bosentan and in 0.4% of patients receiving placebo. Elevations in liver transaminases were associated with increased bilirubin (> 2 times ULN) without signs of biliary obstruction in 0.2% (5 patients) of those taking bosentan and in 0.3% (6 patients) of those taking placebo.

In a pooled analysis of 100 patients with PAH from uncontrolled pediatric studies FUTURE-1/2 and FUTURE-3/extension, elevations in liver transaminases > 3 times ULN were observed in 2% of patients.

In the FUTURE-4 study, which included 13 newborns with PPHN receiving bosentan 2 mg/kg twice daily for less than 10 days (range: 0.5–10.0 days), there were no cases of liver aminotransferase > 3 times ULN during treatment; however, one case of hepatitis was reported 3 days after discontinuation of bosentan.

Hemoglobin

In placebo-controlled studies in adults, decreases in hemoglobin concentration below 10 g/dL from baseline values were reported in 8.0% of patients receiving bosentan and in 3.9% of patients receiving placebo.

In a pooled analysis of 100 children with PAH from uncontrolled pediatric studies FUTURE-1/2 and FUTURE-3/extension, 10.0% of patients experienced a decrease in hemoglobin concentration from baseline to levels below 10 g/dL.

In the FUTURE-4 study, a decrease in hemoglobin levels below the lower limit of normal within the reference range was observed during treatment in 6 out of 13 newborns with PPHN.

Reporting of adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at:

https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions

Alu-Alu blister: no special storage conditions required.

PVC/PE/PVDC-Alu blister: store at temperatures not exceeding 30 °C.

Keep out of the reach of children.

Packaging

14 film-coated tablets per blister, 4 blisters per pack.

Prescription status. Prescription only.

Manufacturer

Accord Healthcare Polska Sp. z o.o. / Accord Healthcare Polska Sp. z o.o.

Manufacturer's address and location of operations

ul. Lutomierska 50, Pabianice, 95-200, Poland

Marketing Authorization Holder

Accord Healthcare B.V. / Accord Healthcare B.V.

Inquiries regarding product quality, safety concerns, improper use, or complaints are accepted 24/7 (24 hours a day, 7 days a week) via phone: +380993100335 or by email: [email protected]

Marketing Authorization Holder's address

Winthontlaan 200, 3526 KV Utrecht, the Netherlands