Bosentan zentiva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BOSENTAN ZENTIVA

Composition:

Active substance: bosentan;

One film-coated tablet contains bosentan (as monohydrate) 62.5 mg or 125 mg;

Excipients: pregelatinized corn starch 1500, povidone K-30, sodium starch glycolate type A, magnesium stearate, purified water;

Film coating: Oparay orange 03K93638 containing hypromellose, titanium dioxide (E 171), triacetin, yellow iron oxide (E 172), red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

for 62.5 mg tablets: orange-white, round, film-coated tablets, debossed with "B" on one side and "62.5" on the other;

for 125 mg tablets: orange-white, oval, film-coated tablets, debossed with "B" on one side and "125" on the other.

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 close to both endothelin A and B (ETA and ETB) receptors. Bosentan reduces both pulmonary and systemic vascular resistance, leading to an increase in 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, cell proliferation, hypertrophy, myocardial remodeling, and also exhibits anti-inflammatory activity. 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 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 improved 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 involving 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 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 patients' existing therapy, which included anticoagulants, vasodilators (e.g., calcium channel blockers), diuretics, oxygen, and digoxin, but not epoprostenol. Control was achieved using placebo plus 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 week 16 (in the second study). In both studies, bosentan treatment led to a significant improvement in exercise capacity. With placebo, the walk distance increased from baseline by 76 m (p = 0.02; t-test) and 44 m (p = 0.0002; Mann-Whitney U test) at the primary endpoint of each study, respectively. Differences between the two groups (125 mg twice daily vs. 250 mg twice daily) were not statistically significant, but a trend toward improved exercise tolerance was observed in the group receiving 250 mg twice daily.

Improvement in exercise tolerance (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 walking time (by WHO functional classification) and dyspnea in 95 patients randomized to receive bosentan 125 mg twice daily in placebo-controlled studies, it was found that at week 8, 66 patients improved, 22 remained stable, and 7 worsened. Of the 22 patients who were stable at week 8, 6 improved and 4 worsened by weeks 12–16 compared to baseline. Of the 7 patients who worsened at week 8, 3 improved and 4 worsened by weeks 12–16 compared to baseline.

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

Bosentan treatment was associated with reduced PAH symptoms. Dyspnea measurements during walking demonstrated improvement in patients receiving bosentan. Treatment 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 bosentan-treated patients compared to placebo. Bosentan treatment significantly slowed 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 WHO functional class II PAH (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.

Patients included were either untreated for PAH or those on stable sildenafil therapy at a constant dose. The co-primary endpoints were percent change from baseline in PVR and change from baseline in 6-minute walk distance over 6 months compared to placebo.

Bosentan treatment was associated with a reduced rate of clinical worsening, defined as a composite of symptomatic progression, hospitalization due to PAH, or death, compared to placebo (77% relative risk reduction, 95% CI 20–94%, p = 0.0114). The treatment effect was driven by improvement in the symptomatic progression component. One hospitalization due to worsening PAH occurred in the bosentan group and three in the placebo group. One death occurred in each treatment group during the 6-month double-blind phase, so no conclusion on survival could be drawn.

Long-term data were obtained from patients treated with bosentan in the controlled phase and/or those switched from placebo to bosentan in the open-label extension phase of the EARLY study. Mean duration of bosentan exposure was 3.6 ± 1.8 years (up to 6.1 years), with 73% of patients on treatment for at least 3 years and 62% for at least 4 years. Most patients had idiopathic or hereditary PAH (61%). Overall, 78% of patients were in WHO functional class II. Kaplan-Meier survival estimates were 90% and 85% at 3 and 4 years, respectively, after treatment initiation. PAH progression-free rates (defined as all-cause death, lung transplantation, atrial septostomy, or initiation of intravenous or subcutaneous prostacyclin therapy) were 88% and 79% at 3 and 4 years, respectively. The contributions of prior placebo treatment during the double-blind phase and other medications initiated during the open-label extension 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 complex due to congenital heart defect received bosentan 62.5 mg twice daily for 4 weeks, then 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 does not worsen hypoxemia. Mean PVR was significantly reduced in the bosentan group (a greater effect was observed in the subgroup 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 bosentan in a 24-week open-label extension phase (AC-052-409) of BREATHE-5 (mean treatment duration: 24.4 ± 2 weeks), with maintained efficacy.

An open-label, non-comparative extension study (AC-052-362 [BREATHE ON-4]) included 16 patients with WHO functional class III PAH associated with HIV infection. Patients received bosentan 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: 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 bosentan’s effect on antiretroviral drug efficacy.

No study has demonstrated a positive effect of bosentan on survival. However, prolonged survival has been observed in all patients receiving bosentan in two pivotal placebo-controlled studies (AC-052-351 and AC-052-352) and/or two uncontrolled open-label extension studies. Mean duration of bosentan exposure was 1.9 ± 0.7 years (range: 0.1–3.3 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%). Kaplan-Meier survival estimates in this overall population were 93% and 84% at 1 and 2 years after bosentan initiation, respectively. Survival was lower in the subgroup with secondary PAH associated with systemic sclerosis. This may have been influenced by epoprostenol therapy.

Studies in children with PAH

BREATHE-3 (AC-052-356)

Bosentan in film-coated tablets was evaluated in an open-label, uncontrolled, non-placebo-controlled study in children aged 3 to 15 years with PAH. The study was primarily designed as a pharmacokinetic study (see section "Pharmacokinetics"). Patients had primary PAH or PAH associated with congenital heart disease and were in WHO functional class II or III before study initiation. Patients were divided into 3 groups by body weight and received bosentan at 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.

Mean increase from baseline in cardiac index was 0.5 L/min/m², mean decrease in mean pulmonary artery pressure was 8 mmHg, and mean decrease in PVR was 389 dyn·s·cm⁻⁵. Hemodynamic improvement from baseline was similar in patients receiving epoprostenol and those not receiving it. Changes in exercise tolerance parameters 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 with orally dispersible bosentan tablets at a maintenance dose of 4 mg/kg twice daily in patients aged 2 to 11 years. The study was primarily designed as a pharmacokinetic study (see section "Pharmacokinetics"). At study initiation, patients had idiopathic or familial PAH and were in WHO functional class II or III. In FUTURE 1, mean exposure duration was 13.1 weeks (range: 8.4–21.1). Patients continued long-term bosentan treatment in the form of dispersible tablets at 4 mg/kg twice daily during the uncontrolled extension phase FUTURE 2, where mean treatment duration was 2.3 years (range: 0.2–5 years). Baseline data from FUTURE 1 included patients receiving epoprostenol. Patients had recently initiated specific PAH therapy during the study. Kaplan-Meier PAH progression-free rate (death, lung transplantation, or hospitalization due to worsening PAH) at 2 years was 78.9%. Two-year Kaplan-Meier survival rate was 91.2%.

FUTURE 3 (AC-052-373)

In this randomized, non-placebo-controlled study with orally dispersible bosentan tablets at a dose of 32 mg, 64 children with stable PAH aged 3 months to 11 years were randomized to 24 weeks of bosentan treatment at 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 cardiac surgery and ischemic heart disease with systemic-pulmonary shunts, including Eisenmenger syndrome. Patients were in WHO functional class I, II, or III before study initiation. At study start, patients were receiving PAH therapy (most commonly PDE-5 inhibitor [sildenafil] alone [35.9%], bosentan alone [10.9%], or 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 enrolled patients were receiving bosentan monotherapy without combination with other PAH drugs. 40.6% of patients remained on bosentan monotherapy for 24 weeks without PAH worsening. Analysis of the overall cohort showed that most patients remained at least stable (i.e., without worsening), based on non-pediatric-specific WHO functional class assessment (97% twice daily, 100% three times daily) and overall clinical condition (94% twice daily, 93% three times daily) throughout the treatment period. Kaplan-Meier PAH progression-free rate (death, lung transplantation, or hospitalization due to worsening PAH) at 24 weeks was 96.9% and 96.7% in the twice-daily and three-times-daily bosentan groups, respectively. No evidence of clinical benefit was found for the 2 mg/kg three times daily dose 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 orally dispersible bosentan tablets at 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 up to 14 days.

Mean treatment duration 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 benefit of bosentan in this patient group.

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).

Mean time to mechanical ventilation weaning was 10.8 days (95% CI 3.21; 12.21) with bosentan and 8.6 days (95% CI 3.71; 9.66) in the placebo group (p = 0.24).

One patient in the bosentan group experienced treatment failure (need for ECMO per protocol definition) due to increasing oxygenation index values over 8 hours after the first study drug dose. The patient recovered during the 60-day follow-up 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 of 19 pediatric patients received combination therapy with bosentan and epoprostenol for 12 weeks. The safety profile of the combination was consistent with that expected from each component, and combination therapy was well tolerated in both children and adults. The clinical effect of this combination was not 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 past year).

In study AC-052-331, patients had at least one recently developed digital ulcer; 85% had persistent digital ulceration at baseline. After 4 weeks of bosentan 62.5 mg twice daily, the maintenance dose of 125 mg twice daily was studied in both trials. The double-blind treatment duration 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 allowed if unchanged for at least 1 month before treatment initiation and throughout the double-blind study period.

The number of new ulcers from baseline to study end was the primary endpoint in both studies. Bosentan treatment reduced the number of new ulcers throughout the treatment period compared to placebo. In study AC-052-401, over 16 weeks of double-blind therapy, patients in the bosentan group had a mean of 1.4 new ulcers compared to 2.7 in the placebo group. In study AC-052-331, over 24 weeks of double-blind therapy, the corresponding values were 1.9 vs. 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 suggest that bosentan exposure 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 over time.

After oral administration, systemic exposure is dose-proportional up to 500 mg. At higher oral doses, increases in maximum concentration (Cmax) and area under the concentration-time curve (AUC) are non-proportional and occur more slowly relative to dose.

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 is highly bound (98%) to plasma proteins, primarily albumin. Bosentan does not penetrate into erythrocytes.

The volume of distribution (approximately 18 L) was 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 and metabolized in the liver by CYP isoenzymes CYP2C9 and CYP3A4. Less than 3% of an orally administered dose is excreted unchanged 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 not been shown to have 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 sex, body weight, race, or age in the adult population.

Children

Pharmacokinetics in pediatric patients were studied in four 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], pharmacokinetics of single and multiple oral doses of bosentan were evaluated in children aged 3 to 15 years with PAH. The initial dose was 2 mg/kg twice daily. In this study, bosentan exposure subsequently decreased, consistent with its known autoinduction properties. Mean AUC values in children receiving 31.25 mg, 62.5 mg, 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 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% of that in adults, respectively.

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, but AUC was similar for 2 mg/kg and 4 mg/kg doses (AUC ɽ: 3,577 ng·h × h/mL and 3,371 ng·h × h/mL at 2 mg/kg twice daily and 4 mg/kg twice daily, respectively). Mean bosentan exposure in children was approximately half that in adult patients receiving the 125 mg twice daily maintenance dose but showed sufficient overlap with adult exposure.

In study AC-052-373 [FUTURE 3] with dispersible tablets, bosentan exposure in patients receiving 2 mg/kg twice daily was comparable to that in FUTURE 1. In the overall patient group, 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 those aged 1 to 2 years, 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 indicate that bosentan exposure reaches a plateau at lower doses in children than in adults, and doses above 2 mg/kg twice daily (4 mg/kg twice daily or 2 mg/kg three times daily) do not increase bosentan exposure in children.

In study AC-052-391 [FUTURE 4] in neonates, bosentan concentration increased slowly and continuously 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%), similar to exposure observed in adult PAH patients receiving 125 mg twice daily, considering a blood/plasma distribution ratio of 0.6.

The implications of these findings for hepatotoxicity are unknown. Sex 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 bosentan and its primary metabolite (Ro 48-5033) pharmacokinetics 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, 4.7 times higher than in patients with normal liver function (mean [95% CI] AUC 76.1 [9.07–638] ng·h/mL). Mean (95% CI) AUC of the active metabolite (Ro 48-5033) was 106 (58.4–192) ng·h/mL, 12.4 times higher than in patients with normal liver function (mean [95% CI] AUC 8.57 [1.28–57.2] ng·h/mL). Although the number of patients was limited and highly variable, these data indicate a marked increase in bosentan and its primary metabolite Ro 48-5033 exposure in patients with moderate hepatic impairment (Child-Pugh class B).

Pharmacokinetics of bosentan have not been studied in patients with severe 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 bosentan concentration decreased by approximately 10%. Plasma concentrations of bosentan metabolites increased approximately twofold compared to normal renal function. Dose adjustment is not required in patients with renal impairment. Clinical experience is lacking in patients on dialysis.

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

Non-clinical safety data

A 2-year carcinogenicity study in animals showed increased incidence of combined hepatocellular adenoma and carcinoma in males at plasma concentrations approximately 2–4 times higher than those 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. Animal studies showed mild thyroid hormone imbalance due to bosentan, but 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.

Teratogenicity of bosentan was observed in animal studies at plasma concentrations higher than 1.5 times those achieved at the therapeutic dose in humans. Teratogenic effects, including craniofacial and major vessel malformations, were dose-dependent. Similar patterns of developmental malformations were observed with other endothelin receptor antagonists, demonstrating a class effect in animals with genetically knocked-out ET receptors 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 effects on sperm count, motility, or viability, or on mating performance or fertility, were observed at exposures 21 and 43 times higher, respectively, than the expected therapeutic level in humans. No adverse effects were observed on embryonic development prior to or after implantation.

Slight increases in testicular tubular atrophy were 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 above 1500 mg/kg/day (approximately 50 times MRHD) for 6 months. In a juvenile toxicity study where animals were treated from day 4 postpartum to maturity, reduced absolute testicular and epididymal weights and reduced epididymal sperm count after weaning were observed. The maximum non-toxic dose was 21 times (on day 21 postpartum) and 2.3 times (on day 69 postpartum) higher than the therapeutic exposure in humans, respectively.

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

A certain 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 the 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).

Baseline elevation of liver transaminase 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 methods of contraception.

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.

Laboratory data also indicate induction of CYP2C19. Therefore, plasma concentrations of substances metabolized by these isoenzymes may be reduced when co-administered with bosentan. The possibility of altered efficacy of medicinal products 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 of 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 by cyclosporine. The plasma concentration of cyclosporine A (a CYP3A4 substrate) decreased by approximately 50%. This was most likely due to induction of CYP3A4 by bosentan.

Tacrolimus, sirolimus. There are no data on the concomitant use of tacrolimus or sirolimus with bosentan. Co-administration of tacrolimus or sirolimus with bosentan may increase bosentan plasma concentration, similar to the interaction with cyclosporine A. Concomitant use of bosentan may lead to decreased plasma concentrations of tacrolimus and sirolimus, and therefore is not recommended. Careful monitoring of patients requiring combination therapy with bosentan and tacrolimus or sirolimus is necessary due to the potential impact on blood concentrations of these drugs.

Glibenclamide. Concomitant administration with bosentan at a dose of 125 mg twice daily for 5 days reduced plasma concentrations of glibenclamide (a CYP3A4 substrate) by 40%, with a potential for significant reduction in its 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 elevation in aminotransferases. This combination should not be used. Data on the interaction of bosentan with other sulfonylureas are lacking.

Rifampicin. Concomitant administration 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. A clinically significant reduction in efficacy cannot be excluded.

Lopinavir + ritonavir (and other protease inhibitors). Concomitant administration of bosentan 125 mg twice daily with lopinavir + ritonavir 400 mg + 100 mg twice daily for 9.5 days in healthy volunteers resulted in 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 the 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 administration with bosentan, plasma exposure to lopinavir and ritonavir decreased slightly but not clinically significantly (by approximately 14% and 17%, respectively). However, full induction by bosentan may not have been achieved, so 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 the liver toxicity of bosentan, this combination is not recommended.

Hormonal contraceptives. Concomitant administration 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 56% and 66%, respectively. Therefore, the use of hormonal contraceptives alone, regardless of the route of administration (oral, injectable, transdermal, or implanted), is not considered a reliable method of contraception.

Warfarin. Concomitant administration 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). Furthermore, 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 and similar oral anticoagulants, dose adjustment is not required at the initiation of bosentan therapy; however, INR monitoring should be performed, especially at the start of bosentan treatment and during titration.

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

Ketoconazole. Concomitant administration 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 field studies have not demonstrated clinically relevant adverse effects from such an increase. A similar increase in bosentan plasma concentration is expected when used with other strong CYP3A4 inhibitors (itraconazole, ritonavir). However, when combined with a CYP3A4 inhibitor, patients with poor CYP2C9 metabolism are at risk of a greater increase 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, indicate that after administration of single and multiple doses, Cmax and AUC ratios from time of dosing to the last quantifiable concentration of bosentan were similar in patients with or without continuous epoprostenol infusion.

Sildenafil. Concomitant administration 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 from time of dosing to the last quantifiable concentration 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 administration 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 clinically significant.

Pediatric population

Interaction studies have been conducted only in adult patients.

Special precautions for use.

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.

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

Treatment with Bosentan Zentiva should only be initiated when the patient's overall systolic blood pressure is above 85 mm Hg.

The effect of bosentan on healing of existing digital ulcers has not been established.

Liver function

Bosentan-associated elevation of liver aminotransferases (i.e., AST and/or ALT) is 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 partly be related to competitive inhibition of bile salt 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 potential severe liver injury, or an immunological mechanism, cannot be excluded. The risk of liver dysfunction may also be increased when bosentan is used concomitantly with medicinal products that are inhibitors of the bile salt export pump (e.g., rifampicin, glyburide, and cyclosporine A) (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"), although data on this are limited.

Liver aminotransferase levels must be measured before starting treatment and thereafter monthly throughout the duration of treatment. Additionally, liver aminotransferase levels should be measured 2 weeks after any dose increase of the drug.

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 repeat testing of 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 according to the conditions described below.

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

8 × ULN Treatment with the drug must be discontinued without considering the possibility of reinitiation.

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

Reinitiation of treatment with the drug

Reinitiation of treatment should only be considered if the expected benefit outweighs the potential risk and if liver aminotransferase levels have returned to pre-treatment values. Hepatologist consultation is recommended. Reinitiation of treatment should follow instructions provided in the section "Dosage and administration". Aminotransferase levels should be monitored 3 days after reinitiation of treatment, then every 2 weeks thereafter, and subsequently according to the recommendations outlined above.

Hemoglobin concentration

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

Women of childbearing potential

Considering that bosentan may reduce the effectiveness of hormonal contraceptives, the risk of worsening PAH during pregnancy, and the teratogenic effects observed in animals:

• Treatment with bosentan should not be initiated in women of childbearing potential unless they are using reliable contraceptive methods and have a negative pregnancy test before starting treatment;
• Hormonal contraceptives cannot be used as the sole method of contraception during bosentan treatment;
• Monthly pregnancy testing is recommended during treatment to enable 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). The possibility of associated obliterative 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 were suspected of having 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 [ENTRANCE 1 and 2]). This study demonstrated an increased number of hospitalizations due to CHF during the first 4–8 weeks of bosentan treatment, which may have been 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 patients receiving bosentan and those receiving placebo. Patients should be monitored for signs of fluid retention (e.g., weight gain), especially if they also have severe systolic dysfunction. If such signs are detected, treatment with diuretics should be initiated or the dose of existing diuretics increased. Diuretic therapy should be considered before starting bosentan treatment 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 therapy. 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. When prescribing bosentan to patients receiving ritonavir-boosted protease inhibitors, careful monitoring of bosentan tolerability is required, especially at the beginning of the initiation phase, considering the risk of arterial hypotension, and liver function should be checked. A prolonged increased risk of hepatotoxicity and hematological adverse reactions with bosentan in combination with antiretroviral drugs cannot be excluded. Monitoring of HIV-infected patients is necessary, as interactions between antiretroviral drugs and bosentan may result in bosentan induction of CYP450, 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). An increase in minute ventilation and a decrease in 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). There are no reliable data on bosentan use in pregnant women. The potential risk to humans has not been established. Bosentan is contraindicated during pregnancy.

Use in women of childbearing potential

Before initiating treatment with Bosentan Zentiva in women of childbearing potential, pregnancy must be excluded, appropriate advice on reliable contraceptive methods provided, and reliable contraception initiated. Patients prescribed the drug should be informed that due to possible pharmacokinetic interactions, bosentan may lead to ineffectiveness of hormonal contraceptives. Therefore, women of childbearing potential should not use hormonal contraceptives (including oral, injectable, implantable, or transdermal forms) 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, gynecological consultation 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 treatment to ensure early detection of pregnancy.

Breastfeeding period

There is no information on the excretion of bosentan into breast milk; therefore, breastfeeding is not recommended during treatment with the drug.

Fertility

Animal studies have demonstrated testicular effects. In a study evaluating the effect of bosentan on testicular function in male patients with PAH, reduced sperm concentration compared to baseline values of at least 42% was observed in 8 out of 24 patients after 3 or 6 months of bosentan treatment. Based on these findings and preclinical data, a negative effect of bosentan on spermatogenesis in men cannot be excluded. A long-term effect on fertility in male children after bosentan treatment cannot be excluded.

Ability to influence reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Dosage

Pulmonary Arterial Hypertension (PAH)

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

Adults

In adult patients, treatment with bosentan should be initiated at a dose of 62.5 mg twice daily for 4 weeks, followed by an increase to the maintenance dose of 125 mg twice daily. The same recommendations apply when resuming bosentan treatment after interruption.

Actions in Case of Clinical Worsening of PAH

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

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

Discontinuation of Treatment

Experience with abrupt discontinuation of bosentan in PAH patients 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 during the discontinuation period is recommended.

Bosentan discontinuation should be performed gradually, particularly when introducing alternative therapy.

Systemic Sclerosis with Progressive Digital Ulceration (fingers and toes)

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

Adults

Bosentan therapy should be initiated at a dose of 62.5 mg twice daily for 4 weeks, followed by an increase to the maintenance dose of 125 mg twice daily. The same recommendations apply when re-initiating bosentan after treatment interruption.

Controlled clinical experience with this indication 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.

Method of Administration

Tablets should be taken orally in the morning and evening, independent of food intake, with water.

Children

Pulmonary Arterial Hypertension

Pharmacokinetic data in pediatric patients indicate that plasma concentrations of bosentan 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 an increase in 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 initial and maintenance dose is 2 mg/kg administered in the morning and evening.

In newborns with persistent pulmonary hypertension of the newborn, no benefit of bosentan has been demonstrated 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 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 at doses up to 2000 mg daily for 2 months in patients with conditions other than pulmonary hypertension. The most commonly reported adverse reaction was mild to moderate headache.

Severe overdose may lead to pronounced arterial hypotension, requiring active cardiovascular support. During the post-marketing period, 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 management of blood pressure. Bosentan is not removed by dialysis.

Adverse reactions

In studies conducted across various therapeutic indications, a total of 2,486 patients received bosentan at daily doses ranging from 100 mg to 2000 mg, and 1,838 patients received placebo. The average duration of treatment was 45 weeks. Adverse reactions occurred in at least 1% of patients treated with bosentan and at a frequency at least 0.5% higher 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 decreases in hemoglobin concentration.

Adverse reactions observed in clinical studies and during post-marketing experience with 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 (> 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Within each frequency grouping, 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	anaemia, decreased haemoglobin levels (see section "Special precautions and warnings")
	frequency not known	anaemia or decreased haemoglobin levels requiring erythrocyte transfusion1
	uncommon	thrombocytopenia1, neutropenia, leukopenia1
Immune system disorders	common	hypersensitivity reactions (including dermatitis, pruritus and rash)2
	uncommon	anaphylaxis and/or angioedema1
Nervous system disorders	very common	headache3
	common	syncope1,4
Cardiac disorders	common	palpitations1,4
Eye disorders	frequency not known	blurred vision
Vascular disorders	common	flushing, arterial hypotension1,4
Respiratory, thoracic and mediastinal disorders	common	nasal congestion1
Gastrointestinal disorders	common	gastroesophageal reflux disease, diarrhoea
Hepatobiliary disorders	very common	liver function test abnormalities (see section "Special precautions and warnings")
	uncommon	elevated aminotransferase levels associated with hepatitis (including possible exacerbation of underlying hepatitis) and/or jaundice1 (see section "Special precautions and warnings")
	rare	liver cirrhosis, liver failure1
Skin and subcutaneous tissue disorders	common	erythema
General disorders and administration site conditions	very common	oedema, fluid retention5

1 Data obtained after discontinuation of the drug; frequencies are 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 in 11.5% of patients receiving bosentan and in 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 after long-term bosentan therapy have been reported in patients with multiple comorbidities and concomitant medication use. Rare cases of hepatic 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

Safety results from the first uncontrolled pediatric study using film-coated tablets (BREATHE-3: 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 the main adult studies in patients with PAH. During the BREATHE-3 study, the most frequently reported adverse reactions were flushing (21%), headache, and liver function abnormalities (biochemical parameter) (each 16%).

A combined analysis of uncontrolled pediatric studies conducted in patients with PAH using bosentan 32 mg, crushed tablet (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 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).

Safety results in this combined analysis of uncontrolled pediatric studies were similar to those observed in the main adult studies in patients with PAH, except for infections, which were more frequent 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 frequently reported 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 under 2 years of age, including 6 patients aged 3 months to 1 year. Adverse reactions of liver abnormalities and anemia (decreased hemoglobin) were observed in 9% and 5% of patients, respectively.

In a randomized, placebo-controlled study conducted in neonates with persistent pulmonary hypertension of the newborn (FUTURE-4), a total of 13 neonates 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 frequently reported 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 usually occurred within the first 26 weeks of treatment, typically developed gradually, and were mostly asymptomatic. Rare cases of liver cirrhosis and hepatic failure have been reported after discontinuation of the drug.

The mechanism of this adverse effect is not known. These increases may resolve spontaneously while continuing treatment with maintenance doses of bosentan or after dose reduction, but interruption or discontinuation of the drug may be required.

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) receiving bosentan and in 0.3% (6 patients) receiving 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 neonates with PPHN receiving bosentan at a dose of 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, but 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 within the reference range below the lower limit of normal was observed in 6 out of 13 neonates with PPHN during treatment.

Reporting of adverse reactions

Reporting of adverse reactions after drug registration is important. It allows continuous 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 through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions.

No special storage conditions required.

Keep out of reach of children.

Packaging. 14 tablets in a blister pack. 4 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Pharmasience International Limited.

Manufacturer's address and location of business operations.

Address of business operations: 81-83 Griva Digeni Avenue, 1st Floor, Yakovidis Tower, NICOSIA, 1090, Cyprus.