Definition of double-blind research

Active substance:

Content

Pharmacological groups

Nosological classification (ICD-10)

Description of the dosage form

Tablets, film coated, 62.5 mg: round, biconvex, cylindrical, orange-white in color, with engraving “62.5” on one side.

Tablets, film coated, 125 mg: oval, biconvex, cylindrical, orange-white color, with an engraving “125” on one side.

pharmachologic effect

Pharmacodynamics

Bosentan is a non-selective endothelin receptor antagonist (AER) with affinity for endothelin receptors types A and B (ETA and ETB). Bosentan reduces both pulmonary and systemic vascular resistance, leading to an increase in cardiac output without an increase in heart rate.

Neurohormone endothelin-1 (ET-1) is one of the most powerful vasoconstrictors, has the ability to induce fibrosis, cell proliferation, hypertrophy and remodeling of the myocardium, and also shows proinflammatory activity.

These effects are caused by the binding of ET-1 to the ETA and ETB receptors located in the endothelium and vascular smooth muscle cells. The concentration of ET-1 in tissues and blood plasma increases with certain cardiovascular diseases and connective tissue pathology, in

Definition of double-blind research

Bosentan competes with ET-1 and other ET peptides for binding to ETA and ETB receptors with a slightly higher affinity for ETA receptors (Ki = 4.1–43 nmol) compared to ETB receptors (Ki = 38-730 nmol) . Bosentan specifically blocks ET receptors and does not bind to other receptors.

Efficacy in adult patients with PAH. The results of two clinical studies in adult patients with functional III – IV class PAH showed that when bosentan is added to standard therapy, which may include anticoagulants, vasodilators (for example, CCA), diuretics, oxygen therapy and digoxin, but does not include epoprostenol, reliably increased tolerance to physical exertion. The main end point in each of the studies was a change in the distance of the test with a 6-minute walk on the 12th week in the first study and on the 16th in the second. Improvement of exercise tolerance was observed after 4 weeks of therapy, was evident at the 8th week and persisted until the 28th week of double-blind treatment in a subgroup of a sample of patients. In patients receiving treatment with bosentan, a decrease in the severity of symptoms of PAH was observed. Also in patients of this subgroup, an improvement in the severity of dyspnea was noted during the test with walking. The first study showed that the use of bosentan is accompanied by an increase in cardiac index and is combined with a significant decrease in pressure in the pulmonary artery, pulmonary vascular resistance and average pressure in the right atrium. The results of the study of the use of bosentan in patients with PAH II FC (the average distance of the test with 6-minute walk – 435 m) for 6 months showed a decrease in the frequency of clinical deterioration in patients, as well as a reduction in the number of deaths and hospitalizations due to PAH. Due to the worsening of the course of PAH, in the group of patients receiving bosentan, 1 case of hospitalization was noted, while in the group of patients not receiving bosentan – 3 cases. When observed for 6 months, 1 case of death was registered in each group, which does not allow us to estimate the effect of bosentan on survival. In patients with PAH III FC and Eisenmenger syndrome associated with congenital heart disease, when bosentan was administered in doses of 62.5 mg 2 times a day and 125 mg 2 times a day after 16 weeks of therapy, there was no worsening of hypoxemia (oxygen saturation in plasma blood increased by 1%). The average vascular resistance in the pulmonary artery decreased significantly, improved exercise tolerance improved (the average distance of the test with 6-minute walk increased by 53 m).

In a study of bosentan in patients with PAH III FC associated with HIV infection, a significant increase in exercise tolerance was shown. Improved survival rates in the long term were observed in all patients receiving bosentan in two placebo-controlled studies, as well as in their extensions. The average duration of application of bosentan is (1.9 ± 0.7) years (from 0.1 years to 3.3 years), the observation was carried out for (2 ± 0.6) years. In the majority of patients, the diagnosis of primary PAH (72%) and PAH III FC (84%) was confirmed. The overall survival rate in the population as a whole after 93 years of bosentan use is 93%, and after 2 years it is 84% ​​(estimated by the Kaplan-Meier method). Survival in patients with primary PAH after 1 and 2 years was higher – 96 and 89%, respectively. According to a comparative study in 6 specialized centers (682 patients), the survival rate in patients with primary PAH receiving bosentan is comparable to the corresponding indicators of epoprostenol.

In patients with systemic scleroderma, the Kaplan-Meier method of survival was lower.

Study of efficacy in children with PAH. Evaluation of pharmacokinetic parameters in children with PAH was carried out within 12 weeks of using bosentan.

Analysis of hemodynamic parameters indicates an increase in cardiac index by 0.5 l / min / m 2, as well as a decrease in pressure in the pulmonary artery by 8 mm Hg. Art. and pulmonary vascular resistance at 389 dyn · s · cm-5.

Systemic scleroderma with ulcerative lesions of the extremities. The results of two clinical studies in adult patients with systemic scleroderma and ulcerative lesions of the extremities (in the acute stage or in cases when the ulcerative lesion was observed during the last year) showed that the use of bosentan is accompanied by a significant decrease in the number of new ulcerative limb lesions compared with placebo in during the entire period of treatment.

In a study lasting 16 weeks in patients receiving bosentan, an average of 1.4 cases of new ulcerative lesions, and in those receiving placebo – 2.7 cases (p = 0.0042). In another study of 24 weeks duration, new ulcerative lesions of the extremities were noted in 1.9 and 2.7 cases, respectively (p = 0.0351). The effect of bosentan on the rate of healing of ulcerative lesions has not been established.

Pharmacokinetics

The pharmacokinetics of bosentan were studied in detail in studies involving healthy volunteers. The data on the study of pharmacokinetics in a limited number of patients with PAH indicate that the systemic exposure to bosentan in patients is 2 times higher than in healthy volunteers.

Pharmacokinetic parameters in healthy volunteers depend on the dose and time of administration. After intravenous injection of bosentan, its Vd and clearance decrease with increasing dose and increase with time. After oral administration, systemic exposure to bosentan is proportional at doses up to 500 mg. When ingesting a higher dose of bosentan, an increase in Cmax in the blood plasma and AUC in relation to the dose taken is disproportionate and is achieved at a slower rate.

Suction. The absolute bioavailability of bosentan in healthy volunteers after oral administration is about 50%, food intake does not affect bioavailability. Cmax in plasma is reached in 3-5 hours after taking the drug inside.

Distribution. Bosentan to a high degree (more than 98%) binds to plasma proteins, mainly albumin. Bosentan does not penetrate into red blood cells.

After a single injection / 250 mg dose of Vss is 18 liters.

Metabolism and excretion. After a single injection in a dose of 250 mg clearance is 8.2 l / h. T1 / 2 – 5.4 hours. With repeated use, the concentration of bosentan in the blood plasma decreases gradually and amounts to 50–65% of the concentration with a single use. Probably a decrease in the concentration of bosentan is due to the autoinduction of liver enzymes. The equilibrium state is reached within 3–5 days. Bosentan is excreted through the intestine with bile after the completion of metabolism in the liver with the participation of cytochrome P450 isoenzymes CYP2C9 and CYP3A4. Less than 3% of the ingested dose is excreted by the kidneys. During the metabolism of bosentan, 3 metabolites are formed, but only one of them has pharmacological activity. The pharmacologically active metabolite is preferentially excreted in the bile. In adult patients, the concentration of the active metabolite in the blood plasma is higher than in healthy volunteers. In patients with signs of cholestasis, the systemic effect of this metabolite may increase. Bosentan is an inducer of CYP2C9 and CYP3A4 isoenzymes, as well as, possibly, CYP2C19 isoenzyme and P-glycoprotein. In vitro, bosentan inhibits the activity of BSEP (Bile Salt Export Pump, a pump of bile acid salts) in cultures of hepatocytes. In vitro studies have shown that bosentan does not have a significant inhibitory effect on a number of CYP isoenzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, ZA4). Consequently, bosentan does not increase the concentration in blood plasma of drugs whose metabolism is mediated by these isoenzymes.

Pharmacokinetics in special groups of patients. Based on the studies of all parameters, it can be assumed that the pharmacokinetics of bosentan in adults and children over 2 years of age are not significantly affected by factors such as gender, body weight, race or age of the patient.

Children over 2 years old. Pharmacokinetic parameters with a single and repeated use of bosentan in the dosage form of a film-coated tablet were studied in children with PAH, the dose of the drug was selected based on the body weight of the patients (AC-052-356 – BREATHE-3). The effect of bosentan decreased with time according to the characteristic curve of bosentan, due to the ability of bosentan to autoinduction. The average values ​​of AUC (CV%) in children receiving bosentan 2 times a day in doses of 31.25; 62.5 and 125 mg were 3.496 ng · h / ml (49%), 5.428 ng · h / ml (79%) and 6.124 (27%) ng · h / ml, respectively, and were lower than the values ​​of 8.149 ng · h / ml (47%) in adult patients with PAH who received 125 mg of bosentan. In the equilibrium state, systemic exposure in children weighing 10–20, 20–40, and more than 40 kg was 43, 67, and 75% of the corresponding indicators in adults.

Liver dysfunction. In patients with mild hepatic impairment (5–6 points on the Child-Pugh scale), there were no significant changes in the pharmacokinetics of bosentan. Compared with healthy volunteers, in patients with mild hepatic impairment, the AUC values ​​of bosentan in equilibrium are higher by 9%, and the active metabolite Ro 48-5033 – by 33%. In patients with moderately impaired liver function (7–9 points on the Child-Pugh scale) and PAH associated with portal hypertension, the AUC of bosentan in equilibrium was 4.7 times, and the active metabolite Ro 48-5033 – in 12.4 times higher than in patients with PAH with preserved renal function.

Definition of double-blind research

The pharmacokinetics of bosentan in patients with severely impaired liver function (10 points or higher on the Child-Pugh scale) has not been studied. It is recommended to avoid the use of the drug Tracleer ® in patients with moderate and severe abnormal liver function (7 points or more on the Child-Pugh scale).

Impaired renal function. In patients with severely impaired renal function (Cl creatinine 15–30 ml / min), the concentration of bosentan in the blood plasma is reduced by about 10%. The concentration of metabolites of bosentan in plasma increases by about 2 times compared with patients with preserved renal function. Patients with impaired renal function do not require dose adjustment. The use of bosentan in patients undergoing hemodialysis has not been studied. Given the physico-chemical properties of bosentan and its high degree of binding to plasma proteins, no significant withdrawal of bosentan from the vascular bed during hemodialysis is expected.

Indications of the drug Tracleer ®

treatment of pulmonary arterial hypertension II – IV FC (according to the WHO classification) with the aim of improving exercise tolerance and clinical symptoms in adults and children over 3 years old, in

– primary (idiopathic and hereditary) pulmonary arterial hypertension;

– secondary pulmonary arterial hypertension on the background of scleroderma in the absence of significant interstitial lung lesions;

– pulmonary arterial hypertension associated with congenital heart defects and, in particular, with impaired hemodynamic parameters by the type of Eisenmenger syndrome;

decrease in the number of new digital ulcers in adults with systemic scleroderma and progressive ulcerative lesions of the extremities.

Contraindications

hypersensitivity to bosentan or any of the components of the drug;

abnormal liver function of moderate and severe severity (7 or more points on the Child-Pugh scale);

the initial increase in liver transaminase activity (ACT and / or ALT) is more than 3 times from VGN;

severe hypotension (SAD less than 85 mm Hg. Art.);

simultaneous use with cyclosporine;

use in women of reproductive age who do not use reliable methods of contraception;

age up to 3 years (solid dosage form).

With care: severe hypotension (SAD less than 85 mm Hg. Art.); chronic obstructive pulmonary disease (COPD); slight abnormal liver function (less than 7 points on the Child-Pugh scale); with PAH I FC (insufficient clinical data on the efficacy and safety of use). The effects of Tracleer ® on the healing of existing digital ulcers have not been established.

Use during pregnancy and lactation

In preclinical studies, the reproductive toxicity of bosentan (teratogenic and fetotoxic effects) has been established. Clinical studies on the use of the drug in women during pregnancy were not performed. The possible risk of using Tracleer ® during pregnancy has not been studied. The use of the drug Traklir ® during pregnancy is contraindicated.

Use in women of reproductive age. Before starting treatment with Traklir ® in women of reproductive age, it is necessary to confirm the absence of pregnancy, doctors are obliged to give recommendations for the prevention of pregnancy, and patients should begin using reliable methods of contraception. Patients and doctors who prescribe treatment should take into account that, due to the pharmacokinetic interaction, Tracleer ® can reduce the effectiveness of hormonal contraceptive agents. For this reason, women of reproductive age are not recommended to use the method of hormonal contraception (drugs used orally, in the form of injections, transdermal therapeutic systems (TTC) or implants), as the only one; they need to use an additional or alternative method of reliable contraception. If there are doubts about the method of contraception used, for an individual selection of a reliable method of contraception the patient should consult a gynecologist. Considering the decrease in the effectiveness of hormonal contraception and the possible negative impact of pregnancy on the course of PAH, it is recommended to conduct a pregnancy test on a monthly basis during therapy with Tracleer ®, which will allow us to diagnose early pregnancy.

It is not established whether bosentan is excreted in breast milk. Breastfeeding is not recommended during the period of treatment with Traklir ®.

Side effects

In 20 placebo-controlled studies conducted for various indications, 2486 patients received bosentan in doses ranging from 100 to 2000 mg and 1,838 patients received placebo. The duration of treatment averaged 45 weeks.

The most common (in 1% or more receiving bosentan and 0.5% receiving placebo), noted headache (11.5 vs. 9.8%), lower extremity edema and / or fluid retention (13.2 vs. 10.9% ), increased activity of hepatic transaminases AST and / or ALT (10.9 versus 4.6%) and anemia / decrease in hemoglobin (9.9 versus 4.9%).

The use of bosentan is associated with a dose-dependent increase in liver transaminase activity and a decrease in hemoglobin.

Adverse reactions in 20 placebo-controlled studies of bosentan, depending on the incidence, were grouped as follows: very often (>1/10); often (>1/100, 1/1000, 1/10000, 1 – anemia or decrease in hemoglobin, when blood transfusion is necessary; infrequently – thrombocytopenia; neutropenia, leukopenia.

On the part of the immune system: often – hypersensitivity reactions (including dermatitis, pruritus, rash) 2; rarely, anaphylactic reactions and / or angioedema.

From the nervous system: very often – headache 3; often – faint 4.

From the side of the cardiovascular system: often – a feeling of heartbeat 4, flushing of the skin of the face, decrease in blood pressure 4.

On the part of the digestive system: often – nausea, vomiting, abdominal pain, diarrhea.

On the part of the hepatobiliary system: often – gastroesophageal reflux disease, diarrhea; infrequently, an increase in liver transaminase activity associated with hepatitis and / or jaundice; rarely – liver cirrhosis, liver failure.

On the part of the skin and subcutaneous tissue: often – redness of the skin.

General disorders and disorders at the injection site: very often – peripheral edema, fluid retention 5.

1 Frequency cannot be estimated from available data.

2 Hypersensitivity reactions were observed in 9.9% of patients who received bosentan, and in 9.1% – placebo.

3 Headache was noted by 11.5% of patients who received bosentan, and 9.8% were given a placebo.

4 These reactions may be due to the underlying disease.

5 The appearance of peripheral edema and fluid retention was noted by 13.2% of patients who received bosentan and 10.9% received placebo.

In the post-marketing period, there are reports of rare cases of cirrhosis of unknown etiology with long-term use of the drug Tracleer ® in patients with severe concomitant diseases, while using multiple medications.

Also noted are rare cases of liver failure. These cases increase the importance of strict adherence to monthly monitoring of liver function during the entire period of treatment with Traklir ®.

Uncontrolled studies in children with PAH (AC-052-356 – BREATH-3). The safety profile of bosentan in children (BREATH-3: n = 19, bosentan 2 mg / kg 2 times a day for 12 weeks) did not differ from the corresponding safety profile in adult patients with PAH in the reference studies. The most frequent in children was a flush to the skin of the face (21%), a headache and an increase in liver transaminase activity (16% for each adverse reaction).

Changes in laboratory parameters

Changes in liver transaminase activity. In the clinical program, a dose-dependent increase in liver transaminase activity was observed during the 26 weeks of treatment, developed gradually, as a rule, asymptomatic. In the post-marketing period, there were reports of rare cases of development in patients with cirrhosis and liver failure. The mechanism of occurrence of the above adverse reactions is unclear. The activity of hepatic transaminases may spontaneously decrease with continued treatment without changing the dose of Traklir ® or after its reduction, nevertheless, discontinuation of treatment or a short break in therapy may still be required.

In 20 studies conducted, liver transaminases increased 3 times or more in 11.2% of patients receiving bosentan, and 2.4% – placebo. An increase of 8 and more times higher VGN was observed in 3.6% of patients receiving bosentan, and in 0.4% – placebo. It was noted that the increased activity of hepatic transaminases is associated with an increase in plasma bilirubin concentration (2 or more times as high VGN) in patients with no obstruction of the biliary tract in 0.2% of cases (5 patients) receiving bosentan, and in 0.3 % of cases (6 patients) – placebo.

Hemoglobin. A decrease in hemoglobin below 1 g / l from baseline values ​​was observed in 8% of patients receiving bosentan, and in 3.9% – placebo.

Interaction

Bozentan is metabolized with the participation of cytochrome CYP and its isoenzymes CYP2C9 and CYP3A4. Inhibition of the isoenzyme CYP3A4 increases the plasma concentration of bosentan (see ketoconazole). The effect of inhibition of the isoenzyme CYP2C9 on the concentration of bosentan in the blood plasma was not studied. When combined use caution should be exercised. Simultaneous use with fluconazole, which mainly has an inhibitory effect on the CYP2C9 isoenzyme and only a minor effect on the CYP3A4 isoenzyme, may be accompanied by an increase in plasma plasma bosentan. This combination is not recommended. For the same reason, simultaneous use of Traklir ® and potent inhibitors of CYP3A4 isoenzyme (for example ketoconazole, itraconazole or ritonavir) and inhibitor of CYP2C9 isoenzyme (for example, voriconazole) is not recommended.

Bosentan is an inducer of CYP2C9 and CYP3A4 isoenzymes. According to an in vitro study, the role of inducer of CYP2C19 isoenzyme is also assumed. Therefore, with simultaneous use of the drug Traklir ® and drugs, the metabolism of which is mediated by these isoenzymes, their concentration in the blood plasma decreases. It is necessary to consider the possibility of reducing the effectiveness of drugs, the metabolism of which is carried out with the participation of these same isoenzymes. It may be necessary to adjust the dose of the simultaneously used drugs after starting the administration of the drug Traklir ®, changing its dose or cancellation.

Cyclosporine: the simultaneous use of the drug Traklir ® and cyclosporine (calcineurin inhibitor) is contraindicated. With this combination of drugs, the minimum initial concentration of bosentan in the blood plasma increases by 30 times compared with the use of bosentan in monotherapy. Css of bosentan in plasma increases by 3-4 times compared with the concentration of bosentan in monotherapy. A possible mechanism of this interaction is the inhibition by cyclosporin of the transport protein responsible for the entry of bosentan into hepatocytes. The concentration of cyclosporine in the blood plasma is reduced by almost 50%.

Tacrolimus, sirolimus: simultaneous use with Traklir ® in clinical studies has not been studied, however, it is assumed that the concentration of bosentan in the blood plasma may increase by analogy with cyclosporine. Plasma concentrations of tacrolimus and sirolimus may decrease with combined use with Traklir ®. In connection with this, Tracleer ® should not be used simultaneously with tacrolimus or sirolimus. If it is necessary to use this combination, it is necessary to monitor the patient’s condition and the concentration of tacrolimus and sirolimus in the blood plasma.

Glibenclamide: with simultaneous use of the drug Traklir ® at a dose of 125 mg 2 times a day for 5 days, the concentration of glibenclamide (CYP3A4 isoenzyme substrate) in plasma decreases by 40%, which can be accompanied by a significant decrease in the hypoglycemic effect of glibenclamide. The concentration of bosentan in the blood plasma is also reduced by 29%. In addition, patients receiving concomitant treatment, increases the risk of increased activity of hepatic transaminases. Both active substances, glibenclamide and bosentan, have an inhibitory effect on the pump of transport of bile salts, due to which it is possible to explain the increased activity of hepatic transaminases. In connection with this, Tracleer ® should not be used simultaneously with glibenclamide. There is no evidence of a possible drug interaction with other sulfonylurea derivatives.

Hormonal contraceptives: with the simultaneous use of Traklir ® at a dose of 125 mg 2 times a day and an oral contraceptive for a single dose – a combined preparation containing 1 mg of norethisterone and 35 mcg of ethinyl estradiol for 7 days – a decrease in AUC for its components by 14 and 31% respectively. In individual patients, the reduction in the exposure of norethisterone and ethinyl estradiol reached 56 and 66%, respectively. Thus, hormonal contraception can not be considered sufficiently effective, regardless of the route of administration of the drug – inside, injection, transdermal, or in the form of implants.

Warfarin: when used simultaneously in healthy volunteers with Traklir ® at a dose of 500 mg, the concentration of S-warfarin (CYP2C9 isoenzyme substrate) and R-warfarin (CYP3A4 isoenzyme substrate) plasma levels decrease by 29 and 38 for 6 days % respectively. The experience of the simultaneous use of the drug Traklir ® and warfarin in patients with PAH was not accompanied by significant clinically changes in the MHO and the dose of warfarin (at the end of the study compared with baseline values). In addition, the frequency of dose adjustment of warfarin during the study due to changes in MHO or due to side effects did not differ in patients receiving bosentan or placebo. No dose adjustment of warfarin or other oral anticoagulants is required at the beginning of therapy with Traklir ®. However, a mandatory control of MHO is recommended, especially at the beginning of the application of Traklir ® and at the stages of increasing the dose.

Simvastatin: with simultaneous use of the drug Traklir ® at a dose of 125 mg 2 times a day, the concentration of simvastatin (the substrate of the isoenzyme CYP3A4) and its active β-hydroxy acid in plasma decreases by 34 and 46%, respectively, for 5 days. Simultaneous use of simvastatin does not affect the concentration of bosentan in the blood plasma. When simvastatin and Traklir ® are used together, it is recommended that plasma cholesterol concentration be monitored, followed by a dose adjustment of simvastatin.

Ketoconazole: the simultaneous use of the drug Tracleer ® at a dose of 62.5 mg 2 times a day and ketoconazole, a powerful inhibitor of the CYP3A4 isoenzyme, is accompanied by a twofold increase in plasma concentration of bosentan for 6 days. Dose adjustment of the drug Tracleer ® is not carried out.

An increase in plasma concentration of bosentan is also expected with simultaneous use of itraconazole and ritonavir, despite the lack of confirmation in in vivo studies. However, with a combination of bosentan and a CYP3A4 inhibitor in patients with a reduced metabolism of the CYP2C9 isoenzyme, there is a risk of a significant increase in the concentration of bosentan, which may increase the frequency and severity of side effects of the drug.

Rifampicin: when Traklir ® was used in healthy volunteers for 7 days at a dose of 125 mg 2 times a day and rifampicin, which is an inducer of CYP2C9 and CYP3A4 isoenzymes, plasma plasma bosentan decreased by 58% and in individual patients 90%. As a result, a significant reduction in the effect of Tracliera ® is possible when used together with rifampicin. Data on joint use with other inducers of CYP3A4 isoenzyme, such as carbamazepine, phenobarbital, phenytoin, as well as drugs, which include St. John’s wort, is not enough, however with a high degree of probability, when used together, Traclir cannot be excluded. ®.

Epoprostenol: The limited results of the study (AC-052-356 – BREATH-3), during which 10 children received Tracleer ® in combination with epoprostenol, indicate that after a single and repeated administration of these drugs Cmax bosentan in plasma and AUC were about the same in patients receiving and not receiving an infusion of epoprostenol.

Sildenafil: with simultaneous use of the drug Traklir ® at a dose of 125 mg 2 times a day (equilibrium) and sildenafil at a dose of 80 mg 3 times a day for 6 days in healthy volunteers there was a decrease in AUC of sildenafil by 63% and an increase in AUC of bosentan – 50%. Changes in the concentrations of substances in the plasma do not have clinical significance, the dose adjustment of drugs is not required.

Digoxin, nimodipin, losartan: simultaneous use of the drug Traklir ® at a dose of 500 mg 2 times a day for 7 days is accompanied by a decrease in AUC, Cmax and Cmin of digoxin in the blood plasma by 12, 9 and 23%, respectively. The mechanism of this interaction is probably related to the effect on the glycoprotein R. The clinical significance of this interaction is negligible.

The simultaneous use of nimodipine or losartan does not affect the exposure of bosentan.

Lopinavir / ritonavir (and other protease inhibitors of increased activity): with the simultaneous use of the drug Traklir ® at a dose of 125 mg 2 times a day and a combination of lopinavir / ritonavir 400 + 100 mg 2 times a day for 9.5 days in healthy volunteers, the initial Cmin plasma bosentan was about 48 times higher than the concentration when using only bosentan. Css bosentan in the blood plasma on day 9 was 5 times higher than when taking only bosentan. Inhibition of the CYP3A4 isoenzyme by ritonavir and the transport protein responsible for the transport of bosentan to hepatocytes, thereby reducing the clearance of bosentan, and this mechanism can probably be explained in this way. In patients receiving both Traklir ® and drugs containing a combination of lopinavir / ritonavir or other protease inhibitors of increased activity, control of the tolerability of Traklir ® is necessary. When combined with the drug Traklir ® for 9.5 days, the concentrations of lopinavir and ritonavir are reduced to a clinically insignificant level (approximately 14 and 17%, respectively). It is necessary to monitor the effectiveness of HIV therapy. It is assumed that other protease inhibitors of increased activity in combination with ritonavir may have the same effect.

Other protease inhibitors of increased activity: due to the lack of data, specific recommendations on the use of bosentan with other drugs of this group cannot be given. Due to the pronounced toxic effect on the liver of nevirapine, which can also enhance the adverse effects of bosentan on the liver, the combined use of this combination is not recommended.

Dosage and administration

Inside, in the morning and in the evening, irrespective of meal time, without chewing and washing down with water.

Treatment of PAH II – IV FC (according to the WHO classification) in order to improve the physical stress tolerance of clinical symptoms

Use in adults

For adults, the initial dose is 62.5 mg 2 times a day for 4 weeks, then the dose is increased to maintenance – 125 mg 2 times a day.

In some patients with ineffective use of the drug Tracleer ® when taking a dose of 125 mg 2 times a day, there may be a slight increase in exercise tolerance with an increase in dose to 250 mg 2 times a day. It is necessary to carefully evaluate the benefit / risk ratio, given the negative dose-dependent effect of the drug on the liver.

Termination of therapy. There is limited experience in observing patients after a sudden cessation of therapy with Traklir ®. There is no information about clinically significant worsening of the course of PAH as a result of abrupt withdrawal of the drug. However, in order to reduce the risk of clinical deterioration of patients and prevent withdrawal, it is recommended to reduce the dose of the drug gradually (reducing it by half within 3–7 days), while at the same time initiating alternative therapy.

Decrease in the number of new digital ulcers in adults with systemic scleroderma and progressive ulcerative lesions of the extremities. The initial dose of the drug Tracleer ® is 62.5 mg 2 times / day for 4 weeks, then the dose is increased to supporting 125 mg 2 times a day. The clinical condition of patients should be monitored regularly, carefully evaluating the benefit / risk ratios for further therapy with Tracleer ® and taking into account the possibility of a negative effect of the drug on liver function. Data on the efficacy and safety of the drug in children under 18 are not available.

Special patient groups

Liver dysfunction. Patients with mild liver dysfunction (5–6 points on the Child-Pugh scale) do not require dose adjustment. The use of the drug Tracleer ® in patients with moderate severity and severe abnormal liver function should be avoided (7 points and higher on the Child-Pugh scale).

Impaired renal function. Patients with impaired renal function do not require dose adjustment. Patients on hemodialysis do not require dose adjustment.

Use in elderly patients. Patients over 65 years of age do not require dose adjustment.

Use in children over 3 years old and in patients with low body mass

Pulmonary arterial hypertension. For children older than 3 years, as well as for patients with low body weight (less than 40 kg), Traklir ® is administered in doses, based on the calculation of the body weight of the child / patient.

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