Traklir DT, 32 mg 56 pcs

Bosentan is a non-selective ETA and ETB type endothelin receptor antagonist. Bozentan reduces both pulmonary and systemic vascular resistance, resulting in increased cardiac output without an increase in HR.

The neurohormone endothelin-1 (ET-1) is one of the most potent vasoconstrictors that also has the ability to stimulate fibrosis, cell proliferation, hypertrophy and remodeling, and exhibits proinflammatory activity. These effects are induced when ET-1 binds to ETA and ETB receptors located in the endothelium and vascular smooth muscle cells. The concentration of ET-1 in tissues and blood plasma is increased in some cardiovascular diseases and connective tissue pathologies, including pulmonary arterial hypertension (LAH), scleroderma, acute and chronic heart failure, myocardial ischemia, arterial hypertension and atherosclerosis, which suggests the involvement of ET-1 in the pathogenesis and development of these diseases. In LAH and heart failure, in the absence of ET receptor antagonism, increased ET-1 concentration strictly correlates with the severity and prognosis of these diseases.

Bozentan competes with ET-1 and other ET peptides for binding to ETA and ETB receptors, with slightly higher affinity for ETA receptors (Ki=4.1-43 nmol), compared with ETB receptors (Ki=38-730 nmol).

Bozentan specifically blocks ET receptors and does not bind to other receptors.

In studies of LAH in animal models, it has been shown that long-term oral administration of bosentan reduces pulmonary vascular resistance and promotes the reversal of pulmonary and right ventricular vascular hypertrophy. In pulmonary fibrosis, bosentan has been shown to reduce collagen accumulation in the lungs.

The results of invasive hemodynamic studies have shown that treatment with bosentan leads to a significant increase in cardiac index as well as a significant decrease in pulmonary artery pressure, pulmonary vascular resistance and mean right atrial pressure.

. Long-term (during 12 and 16 weeks) treatment of adult patients with LAH (primary and secondary, mostly associated with scleroderma) of III-IV class according to WHO classification with bosentan in combination with anticoagulants, vasodilators (calcium channel blockers), diuretics, oxygen and digoxin, but not epoprostenol, was accompanied by a decrease in the severity of symptoms of LAH and a significant increase in exercise tolerance (according to the results of 6-minute walking test). These effects were noted after 4 weeks, clearly manifested after 8 weeks and persisted up to 28 weeks in the subgroup of patients with active treatment.

The study of patients with LAS II FC showed a significant increase in time to onset of clinical deterioration (a composite point including progression of disease symptoms, hospitalization due to LAS, and deaths).

In patients with LAH FC III and heart defects combined with hemodynamic abnormalities of the Eisenmenger syndrome type, an increase in mean blood oxygen saturation indicated that bosentan did not exacerbate hypoxemia and that mean pulmonary vascular resistance was significantly reduced in the bosentan group.

The study of bosentan in patients with LAH FC III combined with HIV infection showed an increase in exercise tolerance compared to baseline data.

The two primary placebo-controlled studies and their open-label extensions evaluated vital signs over time in all patients receiving bosentan. The mean duration of bosentan was 1.9±0.7 years (0.1 to 3.3 years), and patients’ clinical status was monitored for an average of 0.2±0.6 years. The diagnosis of primary LAH was confirmed in the majority of patients (72%) and the World Health Organization classification III FC (84%) was defined. Survival rate in the whole group (according to Kaplan-Meier method) after 1 year of Bozentan treatment was 93%, and after 2 years – 84%. In patients with systemic scleroderma the Kaplan-Meier survival rates were lower.

Studies conducted in children with LAS

The study of pharmacokinetic parameters of bozentan was conducted in children with LAS II-III FK at the age from 3 to 15 years during 12 weeks of therapy with the drug. Analysis of hemodynamic parameters indicated an increase in cardiac index (CI) of 0.5 L/min/m2, as well as a moderate decrease in mean pulmonary artery pressure (PAP) to 8 mm Hg and pulmonary vascular resistance (PV) to 389 dyn-c/cm5.

Bozentan, in dosage form dispersible tablets, was used at doses of 2 and 4 mg/kg body weight 2 times/day in 36 patients aged 2 to 11 years. The risk of disease progression (death, lung transplantation, or hospitalization due to worsening LAH), as assessed by the Kaplan-Meier method, was 78.9% after 2 years. The overall survival rate, as assessed by Kaplan-Meier, after 2 years was 91.2%.

. In a study involving 64 children aged 3 months to 11 years with stable LAH who received bosentan at a dose of 2 mg/kg body weight 2 or 3 times/day for 24 weeks, we found that the clinical condition of most patients remained stable according to FC (97% with 2 times/day, 100% with 3 times/day) and the researchers’ overall clinical assessment (94% with 2 times/day, 93% with 3 times/day). The uncomplicated course of LAH, as assessed by the Kaplan-Meier method (death, lung transplantation, or hospitalization due to worsening LAH), was noted in 96.9% and 96.7% of patients taking the drug 2 and 3 times/day, respectively.

There was no clinically significant benefit of using the drug at a dose of 2 mg/kg body weight 3 times/day compared to taking it 2 times/day.

Studies conducted in neonates with persistent neonatal pulmonary hypertension (PNPH)

In a double-blind, placebo-controlled, randomized study in infants born prematurely or normally (gestational age was 36-42 weeks) with PLHN and a suboptimal response to nitric oxide inhalation (iNO) duration of at least 4 h as an additional agent through the nasogastric tube was administered in the dosage form of dispersible tablets at a dose of 2 mg/kg body weight 2 times/day (n=13) or placebo (n=8) at the time of maximum NO concentration in plasma. Bozentan was used until iNO was completely withdrawn or until the effect of the ongoing treatment disappeared (need for extracorporeal membrane oxygenation [ECMO] or an alternative means of pulmonary vascular nasodilation). The maximum duration of treatment was 14 days.

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

The results obtained in this population do not indicate additional benefits of bosentan:

The mean duration of iNO with concomitant bosentan use was 3.7 days and 2.9 days with placebo (p=0.34);

The mean duration of IVC stay was 10.8 days with concomitant use of bosentan and 8.6 days with placebo (p=0.24);

-one patient who received bosentan had no treatment effect (need for ECMO, as required by protocol), as diagnosed by an increase in the oxygenation index 8 hours after the first dose of the drug. The patient’s condition improved over 60 days of follow-up.

Combined use with epoprostenol

The combined use of bosentan and epoprostenol was studied in two studies: Ten of 19 pediatric patients received bosentan and epoprostenol concomitantly for 12 weeks. The safety profile of the combined treatment did not differ from the safety profile when the drugs were used separately, the tolerability of the combined treatment in children and adult patients was good. No clinical benefits of the indicated combination treatment were observed.

Systemic scleroderma with ulcerative lesions of the extremities

. Results of two clinical studies in adult patients with systemic scleroderma and limb ulceration (either as an acute episode or if ulceration has been present for the past year) showed that there was a significant reduction in new limb ulceration over the duration of bosentan versus placebo.

Patients who received bosentan or placebo for 16 weeks had an average of 1.4 and 2.7 new ulcerous lesions, respectively (p=0.0042). In a study lasting 24 weeks, the number of new limb ulcer lesions in a patient averaged 1.9 and 2.7, respectively (p=0.0351). No effect of bosentan on the healing rate of ulcerative lesions was established.

Pharmacokinetics

Pharmacokinetic parameters in healthy volunteers depend on the dose and time of administration of bosentan. After oral administration, systemic exposure to bosentan is proportional at doses up to 500 mg. When bosentan is ingested at higher doses, plasma Cmax and AUC increase less in proportion to dose. Limited pharmacokinetic data suggest that exposure to bosentan in adult patients with LAS is approximately 2 times greater than in healthy volunteers.

Intake

After oral administration, Cmax in plasma is reached after 3-5 h. Absolute bioavailability of Bozentan in healthy volunteers after oral administration is approximately 50% and does not depend on food intake.

Distribution

Bosentan is highly (over 98%) bound to plasma proteins, mainly to albumin. Bozentan does not penetrate red blood cells. After a single intravenous injection at a dose of 250 mg, Vd is 18 liters.

Metabolism and excretion

After a single IV infusion of bozentan at a dose of 250 mg to its lirense is 8.2 L/h. T1/2 is 5.4 hr.

With multiple administration the plasma concentration of bosentan decreases gradually and is 50-65% of the concentration with single administration. The equilibrium state is reached within 3-5 days.

Bozentan is metabolized in the liver with the participation of cytochrome P450 isoenzymes CYP2C9 and CYP3A4. Bozentan is excreted through the intestine with the bile, less than 3% of the oral dose is excreted by the kidneys.

Bozentan metabolism produces 3 metabolites, one of which has pharmacological activity. The pharmacologically active metabolite is primarily excreted with bile. In adult patients, plasma concentrations of the active metabolite are higher than in healthy volunteers. In patients with signs of cholestasis the systemic effect of this metabolite may increase.

Bozentan is an inducer of CYP2C9 and CYP3A4 isoenzymes, and possibly of CYP2C19 isoenzyme and P-glycoprotein. In vitro bosentan inhibits the activity of BSEP (bile acid salt excretion pump).

In in vitro studies showed that bosentan has no significant inhibitory effect on a number of CYP isoenzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4). Therefore, bozentan does not increase the plasma concentration of drugs whose metabolism is mediated by these isoenzymes.

A comparison of dosage forms

In a cross-match study we studied pharmacokinetic parameters in 16 healthy adult volunteers who were taking bosentan in the dosage form of film-coated tablets with a dose of 62.5 mg or in the dosage form of dispersible tablets with a dose of 64 mg (2 tablets of 32 mg). After taking dispersible tablets plasma concentrations of bosentan were lower than those after taking film-coated tablets (ratio of geometric mean values of AUC0-∞ 0.87). The type of dosage form had no significant effect on the Tmax and T1/2 of bosentan.

Pharmacokinetics in Special Patients

Based on the results of studies, it is assumed that the pharmacokinetics of bosentan in adult patients is not significantly affected by factors such as sex, body weight, race or age.

Children

The pharmacokinetics of bosentan has also been studied in children. However, the pharmacokinetic characteristics of bosentan in children under 2 years of age have not been fully determined due to limited data in this patient population.

The results of a study of pharmacokinetics in 19 children with LAS between the ages of 3 and 15 years with single and multiple oral administration of bosentan in the dosage form of film-coated tablets at a dose of 2 mg/kg body weight 2 times/day indicate that exposure to bosentan decreases with time in complete agreement with the autoinduction properties of bosentan. The mean AUC (CV%) values of bosentan in children receiving bosentan at doses of 31.25 mg, 62.5 mg, or 125 mg 2 times/day were 3.496 (49%), 5.228 (79%), and 6.124 (27%) ng×h/mL, respectively, and were below the mean of this figure (8.149 (47%) ng×h/mL) in adult patients with LAH who received bosentan at the 125 mg 2 times/day dose. At equilibrium, systemic exposure in children with body weights of 10-20 kg, 20-40 kg, and over 40 kg was 43%, 67%, and 75%, respectively, of those in adults.

A study of dispensable tablets in 36 patients with LAS aged 2 to 11 years found no proportional dependence of pharmacokinetic parameters on the dose amount, since in the equilibrium state the plasma concentration and AUC values were close when bosentan was taken orally at a dose of 2 mg/kg and 4 mg/kg body weight 2 times/day respectively (AUCtt: 3.577 and 3.371 ng×h/ml). Total systemic exposure to bosentan at a dose of 125 mg 2 times/day in children was approximately 2-fold lower than in adult patients, and in most cases exposure rates in children and adults were the same.

Overall, in the group of children (n=31) who received bosentan at a dose of 2 mg/kg body weight 2 times/day, its mean daily exposure was 8.535 ng×h/mL and its AUCtt was 4.268 ng×h/mL (CV: 61%). In children aged 3 months to 2 years, the mean daily exposure was 7.879 ng×h/mL, and the AUCtt was 3.939 ng×h/mL (CV: 72%). In children 3 months to 1 year (n=2), the AUCtt was 5.914 ng×h/mL (CV: 85%), and in patients 1 to 2 years (n=7) the AUCtt was 3.507 ng×h/mL (CV: 70%). In patients older than 2 years (n=22), the mean daily exposure to bosentan was 8,820 ng×h/mL, and the AUCtt was 4,410 ng×h/mL (CV: 58%). Administration of bosentan at a dose of 2 mg/kg 3 times/day did not increase plasma concentrations of bosentan, and the mean daily exposure was 7.275 ng×h/ml (CV: 83%, n=27).

The findings confirm that plasma concentrations of bosentan reach a plateau in children when administered at lower doses compared to adults. In addition, taking the drug in doses higher than 2 mg/kg 2 times/day (4 mg/kg 2 times/day or 2 mg/kg 3 times/day) does not result in increased exposure to bosentan in children.

In a study conducted in neonates, bosentan concentrations increased slowly and continued to increase after the end of the first drug administration, demonstrating low exposure (AUC0-12 in whole blood 164 ng×h/mL, n=11). At equilibrium, the AUCtt was 6.165 ng×h/mL (CV: 133%, n=7), which is comparable to the exposure value in adult patients with LAH when taking bosentan at a dose of 125 mg twice daily, given a whole blood to plasma distribution ratio of 0.6.

The significance of the findings with respect to hepatotoxicity of the drug has not been determined. The pharmacokinetics of Bozentan are not significantly affected by gender and concomitant use of epoprostenol.

Hepatic impairment

In patients with mild hepatic impairment (class A according to Child-Pugh classification), no significant changes in pharmacokinetics of the drug were noted. In these patients the equilibrium AUC of bosentan was 9% higher and its active metabolite, Ro 48-5033, was 33% higher compared to that of healthy volunteers.

The effect of moderate hepatic impairment (Child-Pugh Class B) on the pharmacokinetic parameters of bosentan and its major metabolite, Ro 48-5033, was studied in 5 patients with LAH due to portal hypertension and moderate hepatic impairment and in 3 patients with LAH due to other causes and normal liver function. In patients with class B hepatic insufficiency, the mean equilibrium AUC of bosentan was 360 (212-613) ng×h/mL, which was 4.7 times higher, and the mean AUC of the active metabolite Ro 48-5033 was 106 (584-192) ng×h/mL, i.e., 12.4 times higher than in patients with normal liver function (bosentan: mean AUC: 76.1 [9.07-638] ng×h/mL; Ro 48-5033: mean AUC: 8.57 [1.28-57.2] ng×h/mL). Despite the small number of patients and the high variability in the data obtained, these results indicate a significant increase in systemic exposure to bosentan and its major metabolite Ro 48-5033 in patients with moderate hepatic impairment (Child-Pugh class B).

The pharmacokinetics of bosentan in patients with severe hepatic impairment (Child-Pugh class C) has not been studied. Traclyr® DT is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh class B or C).

In patients with severe renal impairment (CKR 15-30 ml/min), plasma concentrations of bosentan are decreased by approximately 10%. Plasma concentrations of bosentan metabolites are increased approximately 2-fold compared to patients with normal renal function. No dose adjustment is required in patients with renal impairment. The use of bozentan against the background of hemodialysis has not been studied. Given the physicochemical properties of bozentan and its high degree of binding to plasma proteins, significant excretion of bozentan from the vascular bed during hemodialysis is not expected.

Indications

Active ingredient

Composition

Active ingredient: bosentan monohydrate;

Excipients: microcrystalline cellulose PH102 – 116.265 mg, calcium hydrophosphate – 101.5 mg, croscarmellose sodium – 11.6 mg, colloidal silica – 2.9 mg, tartaric acid – 7 mg, Tutti Frutti flavoring (natural identical) – 9 mg, aspartame (E951) – 3.7 mg, acesulfame potassium – 1.8 mg, magnesium stearate – 3.19 mg.

How to take, the dosage

Interaction

Bozentan is metabolized with the participation of CYP2C9 and CYP3A4 isoenzymes. Concomitant use with CYP3A4 isoenzyme inhibitors (e.g. ketoconazole) increases the plasma concentration of bosentan. The effect of CYP2C9 isoenzyme inhibition on the plasma concentration of bosentan has not been studied; caution is required with such combinations. Concomitant use with fluconazole, which mainly inhibits CYP2C9 isoenzyme and slightly – CYP3A4 isoenzyme, may be accompanied by increased plasma concentration of bozentan; this combination is not recommended. For the same reason it is not recommended to use bozentan with potent CYP3A4 isoenzyme inhibitors (such as ketoconazole, itraconazole or ritonavir) and CYP2C9 isoenzyme inhibitors (such as voriconazole) in combination.

Bozentan is an inducer of the CYP2C9 and CYP3A4 isoenzymes, and in vitro studies suggest CYP2C19 as well. Therefore, with concomitant use of bozentan and drugs whose metabolism is mediated by these isoenzymes, their plasma concentrations are reduced. The possibility of decreased efficacy of drugs whose metabolism is mediated by these same isoenzymes should be taken into account. It may be necessary to adjust the dose of concomitantly used drugs after starting bozentan, changing the dose or cancelling it.

The concomitant use of bosentan and cyclosporine (calcineurin inhibitor) is contraindicated. With this combination of drugs, the minimum initial plasma concentration of bosentan is increased by a factor of 30 compared to the use of bosentan with monotherapy. Css of bosentan in plasma increases by 3-4 times compared to bosentan concentration during monotherapy. A possible mechanism for this interaction is the inhibition by cyclosporine of the transport protein responsible for the entry of bosentan into hepatocytes. Concentration of cyclosporine in blood plasma decreases by almost 50%.

The simultaneous use of tacrolimus and sirolimus with bosentan has not been studied in clinical trials, but it has been suggested that plasma concentrations of bosentan may increase in a manner similar to that of cyclosporine. Plasma concentrations of tacrolimus and sirolimus may decrease when co-administered with bozentan. Therefore, bozentan should not be used concomitantly with tacrolimus or sirolimus. If it is necessary to use this combination, monitoring of the patient’s condition and plasma concentrations of tacrolimus and sirolimus is mandatory.

In concomitant use of bozentan in dose of 125 mg 2 times per day for 5 days the plasma concentration of glibenclamide (CYP3A4 isoenzyme substrate) is decreased by 40% that can be accompanied by significant decreasing of hypoglycemic effect of glibenclamide. Plasma concentration of bosentan also decreases by 29%. In addition, in patients receiving concomitant treatment, the risk of increased activity of hepatic transaminases increases. Both active substances, glibenclamide and bozentan, have an inhibitory effect on the bile acid salt transport pump, which may explain the increased activity of hepatic transaminases. In this regard, bozentan should not be used simultaneously with glibenclamide. There are no data on possible drug interactions with other sulfonylurea derivatives.

When used concomitantly for 7 days in a dose of 125 mg 2 times / day and the oral contraceptive for single administration – combined medicine containing norethisterone 1 mg and ethinylestradiol 35 µg, a decrease of AUC for its components by 14% and 31% respectively was noted. In some patients, the exposure reductions of norethisterone and ethinylestradiol reached 56% and 66%, respectively. Thus, hormonal contraception cannot be considered sufficiently effective, regardless of the route of administration of the drug – oral, injected, transdermal or in the form of implants.

Concomitant use in healthy volunteers with bozentan at a dose of 500 mg 2 times per day for 6 days decreased plasma concentrations of S-warfarin (CYP2C9 isoenzyme substrate) and R-warfarin (CYP3A4 isoenzyme substrate) by 29% and 38% respectively. The experience of concomitant use of bosentan and warfarin in patients with LAH was not accompanied by clinically significant changes in MHO and warfarin dose (at the end of the study compared to baseline values). In addition, the frequency of warfarin dose adjustments during the study due to MHO changes or adverse effects did not differ in patients receiving bosentan or placebo. No dose adjustment of warfarin or other oral anticoagulants is required at the start of therapy with bozentan, but mandatory MHO monitoring is recommended, especially at the beginning of bozentan use and during the dose escalation stages.

With concomitant use of bozentan in dose of 125 mg 2 times per day for 5 days the concentration of simvastatin (CYP3A4 isoenzyme substrate) and its active form beta-hydroxy acid in plasma decreases on 34 % and 46 % accordingly. Concomitant use of simvastatin does not affect the plasma concentration of bosentan. When concomitant use of simvastatin and bozentan it is recommended to control plasma cholesterol concentration with subsequent correction of simvastatin dose.

Special Instructions

Bozentan should be used with caution in severe arterial hypotension (systolic BP less than 85 mm Hg), COPD, mild liver function impairment (less than 7 points on the Child-Pugh scale); in Pulmonary Arterial Hypertension I FC (insufficient clinical data on efficacy and safety of use).

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

The increase in ACT, ALT activity associated with taking bosentan is dose-dependent. Changes in liver transaminase activity usually occur during the first 26 weeks of therapy, but may occur at later times. The risk of liver function impairment may also increase with concomitant use of medicines that inhibit the bile acid salt transport pump, such as rifampicin, glibenclamide and cyclosporine, although there is limited evidence to support this.

Hepatic transaminase activity (ACT and ALT) should be monitored before initiation of therapy with bosentan, and then once a month during treatment.

If AST/ALT activity is 3-5 times higher, repeat measurement of AST/ALT activity; if ACT and ALT activity is confirmed, the daily dose of bozentan should be reduced or discontinued; hepatic transaminase activity should be monitored every 2 weeks. If liver transaminases have returned to pre-treatment levels, the feasibility of continuing or resuming bozentan as described below shall be assessed.

If AST/ALT activity is 5-8 times higher, reassessment of AST/ALT activity should be performed; if ACT and ALT activity are confirmed, bozentan should be discontinued; liver transaminase activity should be monitored every 2 weeks. If liver transaminases have returned to pre-therapy levels, the possibility of resuming bozentan as described below shall be assessed.

If AST/ALT activity is 8 times higher, therapy should be discontinued and resumption of bozentan should be ruled out.

In case of associated clinical symptoms of liver damage, i.e., if nausea, vomiting, elevated body temperature, abdominal pain, jaundice, increased fatigue and apathy, with flu-like symptoms (arthralgia, myalgia, fever), therapy with bozentan should be discontinued and resumption is not recommended.

The therapy with bosentan may be resumed only if the expected therapeutic effect of therapy exceeds the potential risk of adverse reactions, and if the liver transaminase activity does not exceed the values recorded before initiating treatment with bosentan. Liver transaminase activity should be monitored 3 days after resumption of therapy, then repeat the monitoring, and then return to the regular monitoring regimen.

In placebo-controlled studies, the decrease in hemoglobin associated with the use of bosentan is not progressive; hemoglobin stabilizes after the first 4-12 weeks of therapy. It is recommended to control this index before the therapy, after 1 and 3 months of therapy and 1 time in 3 months thereafter. If clinically significant decrease of hemoglobin is observed, further patients’ examination should be carried out in order to determine the reasons and necessity of appropriate therapy.

The data obtained in the study of the effect of bosentan on spermatogenesis do not allow to exclude the possibility of the effect of endothelin receptor antagonists on spermatogenesis in men, and the lack of systemic effect with long-term use does not contradict the results of toxicological studies of bosentan.

The possibility of concomitant veno-occlusive disease should be considered if signs of pulmonary edema appear in patients with pulmonary arterial hypertension while taking bosentan.

If clinically pronounced fluid retention is noted during treatment, whether accompanied by an increase in body weight or not, an examination should be performed to clarify the cause of fluid retention (use of bosentan or heart failure), and to assess the need for continuation of treatment with bosentan or its withdrawal.

In patients with pulmonary arterial hypertension as a result of severe COPD the use of bozentan is accompanied by an increase in minute ventilation rate and a decrease in oxygen saturation; of the side effects most frequently noted is dyspnea, the severity of which decreased with cancellation of bozentan.

In diabetic patients concomitant use of bozentan and glibenclamide is not recommended due to the risk of increased liver transaminase activity. For the treatment of diabetes in patients receiving bozentan, other hypoglycemic agents for oral administration or insulin injections should be used.

Impact on driving and operating machinery

Bozentan may cause dizziness, so patients should exercise caution when driving vehicles and other potentially dangerous activities during treatment.

Contraindications

Side effects

Blood system: frequent – anemia, decreased hemoglobin; frequency unknown – anemia or decreased hemoglobin when hemotransfusion is necessary; infrequent – thrombocytopenia, neutropenia, leukopenia

Immune system: frequent – hypersensitivity reactions, including dermatitis, skin itching and rash (9.9% vs. 9.1%, compared with placebo); anaphylactic and/or angioedema.

Nervous system disorders: very common: headache (11.5% vs. 9.8%, compared to placebo).

Cardiovascular system: often – fainting, palpitations, decreased BP (may be associated with an underlying disease), flushes to the skin of the face.

The digestive system: often – gastroesophageal reflux disease; infrequent – increased liver transaminase activity associated with hepatitis and/or jaundice; rarely – liver cirrhosis, liver function failure. In the post-marketing period there are reports of rare cases of liver cirrhosis of unclear etiology during long-term use of bozentan in patients with severe comorbidities, simultaneously using multiple medications; in rare cases – failure of liver function.

Skin and subcutaneous tissues: often – redness of the skin.

General disorders and disorders at the injection site: very often – peripheral edema, fluid retention.