Trakley® DT (Tracleer® DT)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceBoszentanBoszentan
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    • Dosage form: & nbspTAbsorbers are dispersible.
    Composition:

    1 tablet contains:

    active substance: bosentan monohydrate - 33.045 mg (in terms of bosentan - 32.00 mg);

    auxiliary matter: microcrystalline cellulose PH 102 - 116.265 mg, calcium hydrophosphate - 101,500 mg, cut karma vine of sodium vine - 11,600 mg, Silica colloidal dioxide - 2,900 mg, wine acid - 7,000 mg, Tutti flavoring-Frutti (identical to natural) - 9,000 mg, aspartame (E 951) - 3,700 mg, acesulfame potassium - 1,800 mg, magnesium stearate - 3,190 mg.

    Description:

    Ploskotsilindricheskie tablets from almost white to pale yellow, with a facet and two risks, passing to the side surface, on one side and engraving "32" on the other side.

    Pharmacotherapeutic group:vasodilator
    ATX: & nbsp

    C.02.K.X   Other antihypertensive drugs

    Pharmacodynamics:

    Bozanthan is a non-selective antagonist of endothelin receptors of the type ETA and ETat. Boszentan reduces both pulmonary and systemic vascular resistance, leading to an increase in cardiac output without increasing the heart rate (heart rate). Neurohormone endothelium-1 (ET-1) is one of the most powerful among the currently known vasoconstrictors, which also has the ability to stimulate fibrosis, cell proliferation, hypertrophy and remodeling, and also exhibits pro-inflammatory activity. These effects are induced by binding of endothelin-1 (ET-1) to ET receptorsA and ETatlocated in the endothelium and cells of the smooth muscles of the vessels. The concentration of ET-1 in tissues and plasma increases in certain cardiovascular diseases and connective tissue diseases, including pulmonary arterial hypertension (PAH), scleroderma, acute and chronic heart failure, myocardial ischaemia, systemic hypertension and atherosclerosis, which suggests participation of ET-1 in the pathogenesis of these diseases. With PAH and heart failure, in the absence of receptor antagonism to ET, elevated ET-1 concentrations strongly correlate with the severity and prognosis of these diseases.

    Boszentan competes with ET-1 and others ET peptides for binding to ETA and ETat, with a slightly higher affinity for the receptors ETA (Ki = 4.1-43 nmol), in comparison with the receptors ETB (Ki = 38-730 nmol).

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

    When studying PAH on animal models it was shown that prolonged administration of bosentan inward reduces pulmonary vascular resistance and promotes the reverse development of hypertrophy of the vessels of the lungs and the right ventricle. It was shown that with pulmonary fibrosis bosentan reduces the accumulation of collagen in the lungs.

    The results of invasive hemodynamic studies have shown that the treatment with bosentan leads to a significant increase in the 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 PAH (primary and secondary, predominantly associated with scleroderma) III-IV functional class (FC) of the World Health Organization classification (WHO) bosentan in combination with anticoagulants, vasodilators (calcium channel blockers), diuretics, oxygen and digoxin, but not epoprostenol, accompanied by a reduction in symptoms of PAH and a significant increase in exercise tolerance (for results of the test with 6-minute walking).These effects were observed after 4 weeks, clearly manifested after 8 weeks and persisted until 28 weeks in a subgroup of active treatment patients.

    A study of patients with PAH II FC showed a significant increase in time to the onset of clinical deterioration (combined point, including the progression of symptoms, hospitalization due to PAH and death).

    In patients with PAH III FC and heart defects in combination with violations of hemodynamic parameters according to the type of Eisenmenger syndrome, an increase in the average oxygen saturation value indicated that bosentan does not exacerbate hypoxemia, and that the mean value of pulmonary vascular resistance is significantly reduced in the bosentan group.

    The study of bosentan in patients with PAH III FK in combination with HIV infection showed an increase in physical activity tolerance compared to baseline data.

    In the two major placebo-controlled trials and their open extensions in all patients receiving bosentan, for a long time carried out an assessment of vital indicators.The average duration of bosentan intake was 1.9 ± 0.7 years (0.1 to 3.3 years), the clinical state of patients was monitored on average for 0.2 ± 0.6 years. The majority of patients confirmed the diagnosis of primary PAH (72%) and determined III FC (84%) according to WHO classification. The survival rate in the group as a whole (according to the Kaplan-Meyer method) after 1 year of treatment with bosentan was 93%, and after 2 years - 84%. In patients with systemic scleroderma, Kaplan-Mayer survival rates were lower.

    Studies conducted in children with PAH

    The study of the parameters of the pharmacokinetics of bosentan was carried out in children with PAH II-III FC at the age of 3 to 15 years for 12 weeks of therapy with the drug. Analysis of hemodynamic parameters indicates an increase in cardiac index (SI) by 0.5 l / min / m2, as well as a moderate decrease in mean pulmonary artery pressure (DLA) to 8 mm Hg. and pulmonary vascular resistance (LSS) - up to 389 dyne-s / cm5.

    Boszentan, in a dosage form, dispersible tablets, was used at a dose of 2 and 4 mg / kg body weight 2 times a day in 36 patients aged 2 to 11 years. The risk of worsening of the course of the disease (death,lung transplantation or hospitalization due to deterioration of PAH), which was assessed by the Kaplan-Mayer method, after 2 years was 78.9%. The overall survival rate, according to the Kaplan-Meier evaluation, after 2 years was 91.2%.

    In a study involving 64 children aged 3 months to 11 years with stable PAH who received bosentan in a dose of 2 mg / kg body weight 2 or 3 times a day for 24 weeks, it was found that the clinical status of the majority of patients remained stable according to the functional class (97% - with the drug 2 times a day, 100% - 3 times a day) and the results of the general clinical evaluation of the researchers (94% - when taking the drug 2 times a day, 93% - 3 times a day). Uncomplicated course of PAH according to the Kaplan-Mayer method (death, lung transplantation or hospitalization due to worsening of PAH) was noted in 96.9% and 96.7% of patients taking the drug 2 and 3 times a day, respectively.

    Clinically significant benefits of using the drug at a dose of 2 mg / kg body weight 3 times a day compared with its reception 2 times a day is not established.

    Studies conducted in neonates with persistent pulmonary hypertension of newborns (PLGH)

    In a double-blind, placebo-controlled randomized trial in children born prematurely or at normal times (gestational age was 36-42 weeks) with PLHG and with a suboptimal response to inhalation of nitric oxide (iNO), lasting not less than 4 hours, as an additional agent through the nasogastric tube was injected bosentan in a dosage form, dispersible tablets at a dose of 2 mg / kg body weight 2 times a day (N= 13) or placebo (N= 8) at the moment of maximum concentration iNO in the blood plasma. Boszentan applied until complete cancellation iNO or to the disappearance of the effect of the treatment (the need for extracorporeal membrane oxygenation [ECMO] or the use of an alternative vasodilatation device of the lung vessels). The maximum duration of treatment was 14 days.

    The average 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 using bosentan:

    - Average duration of use iNO while simultaneous use of bosentan was 3.7 days and 2.9 days - placebo (p = 0.34).

    - The average length of stay on the ventilator was 10.8 days with simultaneous use of bosentan and 8.6 days - placebo (p = 0.24).

    - One patient receiving bosentan, the effect of treatment was absent (the need for ECMO, according to protocol requirements), which was diagnosed on the basis of an increase in the oxygenation index 8 hours after the administration of the first dose of the drug. The patient's condition improved within 60 days of follow-up.

    Joint use with epoprostenol

    The combined use of bosentan and epoprostenol was studied in two studies: 10 out of 19 pediatric patients received concomitantly bosentan and epoprostenol for 12 weeks. The safety profile of the combined treatment did not differ from the safety profile when the drugs were used separately, tolerability of the combined treatment in children and adult patients was good. The clinical advantages of this combined treatment were not observed.

    Systemic scleroderma with ulcerative lesions of the limbs

    The results of two clinical studies in adult patients with systemic scleroderma and ulcerative lesions of the extremities (at the stage of exacerbation or in cases where the ulcerative lesion was noted during the last year)that during the entire period of bosentan administration a significant decrease in the number of new ulcerative lesions of the limbs is observed in comparison with placebo.

    In patients who received bosentan or placebo for 16 weeks, an average of 1.4 and 2.7 new ulcerative lesions, respectively (p = 0.0042). In a 24-week study, the number of new ulcerative limb lesions in the patient was, on average, 1.9 and 2.7, respectively (p = 0.0351). The effect of bosentan on the healing rate of ulcerative lesions has not been established.

    Pharmacokinetics:

    Pharmacokinetic parameters in healthy volunteers depend on the dose and time of taking bosentan. After oral administration, the systemic exposure of bosentan is proportional in doses up to 500 mg. When ingesting higher doses of bosentan, the maximum concentration in the blood plasma (CmOh) and AUC (the area under the "concentration-time" curve) increase in proportion to the dose. Limited pharmacokinetic data indicate that the exposure of bosentan in adult patients with PAH is approximately 2 times higher than in healthy volunteers.

    Suction

    Absolute bioavailability of bosentan after ingestion is about 50% and does not depend on the time of ingestion. FROMmOh in blood plasma is achieved 3-5 hours after taking the drug inside.

    Distribution

    Bozentan in high degree (more than 98%) binds to blood plasma proteins, mainly with albumin. Boszentan does not penetrate into the red blood cells. After a single intravenous injection at a dose of 250 mg, the volume of distribution is about 18 liters.

    Metabolism and excretion

    After a single intravenous administration of bosentan at a dose of 250 mg, its clearance is 8.2 l / h, the half-life (T1/2) - 5.4 hours With repeated use, the concentration of bosentan in the blood plasma is reduced gradually to 50-65% of the concentration values ​​for a single application. The state of stable equilibrium is reached within 3-5 days.

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

    Bozanthan forms 3 metabolites, one of which has pharmacological activity. The pharmacologically active metabolite is excreted mainly unchanged with bile. In adults, the concentration of 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.

    Boszentan is an isoenzyme inducer CYP2C9 and CYP3A4, and also possibly isoenzyme CYP2C19 and P-glycoprotein. In vitro bosentan suppresses activity BSEP (pump removal of bile salts).

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

    Comparison of dosage forms

    In a cross-over study, pharmacokinetics parameters were studied in 16 adult healthy volunteers who were taking bosentan in the form of a tablet coated with film, at a dose of 62.5 mg, or in a dosage form, dispersible tablets at a dose of 64 mg (32 mg x 2). After receiving the dispersible tablets, the concentration of bosentan in the blood plasma was lower than after taking the tablets coated with a film shell (ratio of geometric mean values AUC0-∞ 0.87). The form of the dosage form had no significant effect on the time to reach the maximum concentration and T1/2 bosentan.

    Pharmacokinetics in special patient groups

    The results of the studies suggest that the pharmacokinetics of bosentan in adult patients are not significantly affected by factors such as gender, body weight, race or age.

    Children

    Studies of the pharmacokinetics of bosentan have also been conducted 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 category of patients.

    The results of a pharmacokinetics study in 19 children with PAH aged 3 to 15 years with single and multiple administration of bosentan in the form of a tablet coated with a tablet at a dose of 2 mg / kg of body weight 2 times a day indicate that the exposure of bosentan decreases with time in full accordance with the autoinductive properties of bosentane. Mean values AUC (CV%) of bosentan in children receiving bosentan in doses of 31.25 mg, 62.5 mg or 125 mg twice a day, were 3.496 (49%), 5.228 (79%), and 6.124 (27%) ng * h / ml, respectively, and were below average values ​​of this indicator (8.149 (47%) ng * h / ml) in adult patients with PAH who were taking bosentan in a dose of 125 mg 2 times a day.In an equilibrium state, the system exposure in children with a body weight of 10-20 kg, 20-40 kg and more than 40 kg was, respectively, 43%, 67% and 75%, from the corresponding indicators in adults. The study of dispersible tablets in 36 patients with PAH aged 2 to 11 years did not show a proportional dependence of the pharmacokinetic parameters on the dose value, since in the equilibrium state the concentration of bosentan in the blood plasma and the value AUC were found to be close with the administration of bosentan in a dose of 2 mg / kg and 4 mg / kg of body weight 2 times a day, respectively (AUCτ: 3.577 and 3.371 ng * h / ml). The total systemic exposure to bosentan at a dose of 125 mg 2 times a day in children was approximately 2 times lower than in adult patients, and in most cases, exposure indicators in children and adults coincided.

    In general, in a group of children (n= 31), who took bosentan in a dose of 2 mg / kg of body weight 2 times a day, its average daily exposure was 8.535 ng * h / ml, a AUCτ - 4.268 ng * h / ml (CV: 61%). In children aged 3 months to 2 years, the average daily exposure was 7.899 ng * h / ml, a AUCτ - 3.939 ng * h / ml (CV: 72%). In children from 3 months to 1 year (n=2) - AUCτ was 5.914 ng * h / ml (CV: 85%), and in patients from 1 year to 2 years (n=7) AUCt - 3.507 ng * h / ml (CV: 70%). Patients older than 2 years (n= 22), the average daily exposure of bosentan was 8.820 ng * h / ml, a AUCτ - 4,410 ng * h / ml (CV: 58%). The use of bosentan in a dose of 2 mg / kg 3 times a day did not lead to an increase in the concentration of bosentan in the blood plasma, and the average daily exposure was 7.275 ng * h / mlCV: 83%, n=27).

    The data obtained confirm that the concentration of bosentan in the blood plasma reaches a plateau in children with lower doses compared to adults. In addition, taking the drug at doses above 2 mg / kg 2 times a day (4 mg / kg 2 times a day or 2 mg / kg 3 times a day) does not increase the exposure of bosentan in children.

    In a study in newborns, bosentan concentrations increased slowly and continued to increase after the end of the first dose, demonstrating a low exposure (AUC0-12 at whole blood 164 ng * h / ml, n= 11). In the equilibrium state, AUCτ was 6.165 ng / hr (CV: 133%, n = 7), which is comparable to the exposure in adult patients with PAH when taking bosentan at a dose of 125 mg 2 times a day, taking into account the distribution of the drug in the whole blood and blood plasma, equal to 0.6.

    The significance of the data obtained with regard to the hepatotoxicity of the drug has not been determined.The pharmacokinetics of bosentan are not significantly affected by sex and the concomitant use of epoprostenol.

    Impaired liver function

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

    Influence of hepatic impairment moderate severity (class B according to the Child-Pugh classification) on the pharmacokinetic parameters of bosentan and its main metabolite, Ro 48-5033, were studied in 5 patients with PAH due to portal hypertension and moderate-level liver failure, as well as in 3 patients with PAH due to other causes and normal liver function.

    In patients with hepatic insufficiency of class B, the mean equilibrium value AUC bosentan was 360 (212-613) ng * h / ml, i.e. was 4.7 times higher, and the average AUC active metabolite Ro 48-5033 was 106 (58.4-192) ng * h / ml, i.e. is 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: average AUC: 8.57 [1.28-57.2] ng * h / ml). Despite the small number of patients and the high variability of the data obtained, these results indicate a significant increase in the systemic exposure of bosentan and its main metabolite Ro 48-5033 in patients with hepatic impairment moderate degree of severity (class B according to the Child-Pugh classification).

    The pharmacokinetics of bosentan in patients with heavy hepatic insufficiency (class C according to the Child-Pugh classification) has not been studied. The use of Traklir® DT is contraindicated in patients with hepatic impairment moderate and severe degrees of severity (class B or C according to the Child-Pugh classification).

    Impaired renal function

    In patients with severe renal insufficiency (creatinine clearance, CK, 15-30 ml / min), the concentration of bosentan in blood plasma is reduced by approximately 10%. The concentration of bosentan metabolites in the blood plasma increases approximately 2-fold compared with patients with normal renal function. Patients with renal insufficiency do not need a dose adjustment. The use of bosentan against hemodialysis was not studied.

    Given the physico-chemical properties of bosentan and its high degree of binding to blood plasma proteins,significant removal of bosentan from the vascular bed during hemodialysis is not expected.

    Indications:

    Pulmonary arterial hypertension (PAH) II-III functional class (PK) by WHO classification in order to increase tolerance to physical activity and improve clinical symptoms, including:

    - primary (idiopathic and hereditary) pulmonary arterial hypertension;

    - secondary pulmonary arterial hypertension against scleroderma in the absence of significant interstitial lung injury;

    - pulmonary arterial hypertension associated with congenital heart defects and with violations of hemodynamic parameters according to the type of Eisenmenger syndrome.

    Reducing the number of new digital ulcers in adults patients with systemic scleroderma and digital ulcers (in cases where patients can not take film-coated tablets).

    Contraindications:

    - Hypersensitivity to bosentan or any of the components of the drug;

    - hepatic insufficiency of moderate and severe severity (classes B and C according to Child-Pugh classification);

    - initial increase in the activity of "liver" transaminases: ACT (aspartate aminotransferase) and / or ALT (alanine aminotransferase) more than 3 times the upper limit of the norm (VGN);

    - severe arterial hypotension (systolic blood pressure, BP, less than 85 mm Hg in adults, systolic blood pressure <80% of the lower limit of the norm corresponding to the age and sex of the child);

    - simultaneous administration of cyclosporin A;

    - pregnancy;

    - use in women with preserved reproductive potential who do not use reliable methods of contraception;

    - the period of breastfeeding (there are no clinical data);

    - use in children under 18 to reduce the number of new digital ulcers (due to the lack of clinical data);

    - persistent neonatal lag (PGHN);

    - children's age up to 3 months under the Arab League;

    - phenylketonuria (the drug contains aspartame).

    Carefully:

    - Arterial hypotension;

    - use in children under 2 years of age (experience in clinical use is limited).

    Pregnancy and lactation:

    Pregnancy

    Pre-clinical studies have established the reproductive toxicity of bosentan (teratogenic and embryotoxic effects). Data on the use of Traklir® DT in pregnant women have not been received.The possible risk to man is unknown. The use of Traklir® DT during pregnancy is contraindicated.

    Use in women with preserved reproductive potential

    PBefore beginning treatment with Traklir® DT, women who have reproductive potential should confirm their absence of pregnancy, discuss reliable methods for preventing pregnancy, and choose appropriate contraceptive methods for the patient. Patients and doctors should take into account the fact that bosentan may reduce the effectiveness of hormonal contraceptives due to pharmacokinetic interaction (see section "Interaction with other drugs"). Therefore, women with preserved reproductive potential are not recommended to use the method of hormonal contraception (including drugs used orally, as injections, transdermal therapeutic systems or implants) as the only method; they need to use an additional or alternative reliable method of contraception. If there is any doubt about the reliability of the selected method of contraception, the patient should consult a gynecologist for an individual method of contraception.Given the possible ineffectiveness of hormonal contraception and the high risk of a negative effect of pregnancy on the course of PAH, it is recommended that a pregnancy test be performed monthly during therapy with Trakli® DT, which will make it possible to diagnose pregnancy in the early stages.

    Breast-feeding

    It is not established whether the bosentan in breast milk. If therapy with Traklir® DT is necessary during lactation, breastfeeding should be discontinued.

    Fertility

    In pre-clinical studies in males revealed changes in the testes. Results of the clinical study showed that 8 out of 24 male patients with PAH after 3 or 6 months of bosentan treatment showed a decrease in sperm concentration by 42% or more from the baseline values. Based on clinical and preclinical data, the risk of the negative influence of bosentan on spermatogenesis in men can not be ruled out. We can not exclude the adverse effect of prolonged treatment with bosentan on spermatogenesis in male patients.

    Dosing and Administration:

    Dispersible tablets should be taken orally in the morning and evening, regardless of the time of meal.

    Preparation for use

    The design of the blister in which Traclyre® DT tablets are placed prevents the children from accessing them randomly.

    In order to remove the dispersible tablet from the blister, it is necessary:

    1. From the perforation line, separate one blister containing one tablet of the preparation from the blister.

    2. Bend off the edges of the foil in the direction of the arrows and remove it.

    3. Squeeze the tablet out of the cell.

    To obtain a liquid form of the drug Traklir®DT, the dispersible tablet should be dissolved in water. For this, a little water is poured into a spoon and a pill is put into it. The tablet should be completely covered with water. With mixing, the tablets are completely dissolved. The resulting solution is taken by the patient. To ensure that there are no traces left on the spoon, some more water is added to it and swallowed again. To make sure that the drug is taken completely, you need, if possible, to drink another glass of water.

    If necessary, the dispersible tablet can be divided into parts, breaking up along the marks put on it. To do this, the tablet is clamped upside down from both sides by the risks of the thumb and forefinger, and broken into equal parts, as shown in the figure (see Fig.below).

    The remaining part of the divided tablet of Trakley® DT can / can be stored at T from 15 ° C to 25 ° C, but should / should be used for 7 days.

    Mode of application

    Pulmonary arterial hypertension

    Treatment and follow-up should only be performed by a physician with experience in the treatment of PAH.

    Use in children

    A study of the parameters of the pharmacokinetics of bosentan in children suggests that the concentration of bosentan in blood plasma in children with PAH aged 1 to 15 years on average is lower than in adult patients and does not increase with an increase in the dose of Tracler® DG more than 2 mg / kg of body weight or frequency of admission from 2 to 3 times a day. The increase in the dose of the drug and the frequency of its administration probably do not give an additional clinical effect. Based on these pharmacokinetic data, in children with PAH aged 1 year and older it is recommended to apply an initial and maintenance dose of 2 mg / kg of body weight in the morning and evening.

    In the case of persistent neonatal pulmonary tuberculosis (PGHN), the effectiveness of Trakley® DT in the standard treatment regimen has not been proven.

    Application in adults

    The use of dispersible tablets has been studied only in children.The results of the comparative bioavailability of tablets, film-coated, tablets and dispersible in adults showed a lower exposure when taking bosentan dispersible tablets (cm. "Pharmacokinetics" section). Thus, use of dispersible tablets for adults may be recommended in cases where patients are unable to take tablets, film-coated.

    In the adult starting dose of 62.5 mg of 2 times / day (morning and evening) for 4 weeks, then the dose can be increased to the maintenance dose, which is 125 mg of 2 times / day.

    These recommendations should be followed when resuming the use of Trakli® DT after a break in treatment.

    Therapy in the case of clinical worsening of PAH

    possibility of using alternative therapies should be considered in case of clinical deterioration (e.g., reduction of walking distance during a 6-minute test not less than 10% compared to baseline) despite the use of the drug Traklir® DT for at least 8 weeks (of them in the recommended dose - at least 4 weeks). However in some patients after failure Traklir® DT formulation after 8 weeks of use, the positive effect can be observed after an additional 4-8 weeks of treatment.At the onset of clinical deterioration after several months of treatment with Trakli® DT, the advisability of its further application should be evaluated anew. An increase in the dose of Traklir® DT to 250 mg twice a day in some patients, with an insufficient dose rate of 125 mg twice a day, may contribute to some increase in exercise tolerance. The benefit / risk ratio should be carefully weighed to decide whether to increase the dose of the drug, taking into account the dependence of the hepatotoxic effect of the drug Trakli® DT from its dose.

    Actions in case of admission

    If the patient forgot to take Traclyre® DT, the missed dose should be taken as soon as possible, after which the treatment is continued as usual. Do not take 2 doses simultaneously to replenish the missed dose.

    Discontinuation of therapy

    There is limited experience with the sudden discontinuation of therapy with Traclyre® DT in patients with PAH, but there is no evidence of a dramatic deterioration in PAH. However, in order to prevent the deterioration of the patient due to the possible development of the syndrome of "withdrawal, a gradual dose reduction (half-way for 3-7 days) is recommended, against the backdrop of alternative therapy.It is recommended that the patient's clinical condition be regularly monitored during the withdrawal period.

    If a decision is made to cancel the drug Traklir® DT, its dose should be reduced gradually, while starting alternative therapy.

    Decrease in the number of new digital ulcers in adults with systemic scleroderma

    The appointment of treatment and supervision of it should be performed only by a doctor who has experience in the treatment of systemic scleroderma.

    In adults, the initial dose of Traklir® DT is 62.5 mg 2 times / day for 4 weeks, then the dose is increased to a maintenance dose of 125 mg 2 times / day. These recommendations should be followed when resuming the use of Trakli® DT after a break in treatment.

    It is necessary to carry out a regular study of the clinical state of the patient to decide whether to continue treatment. A thorough assessment of the benefit / risk ratio is necessary, taking into account the possibility of hepatotoxic action of the drug Trakli® DT.

    The clinical experience of using the drug for this indication does not exceed 6 months.

    Use in children

    Data on the efficacy and safety of the drug Traklir® DT for this indication in patients under 18 years are absent (see the section "Contraindications").The pharmacokinetics of Traklir® DT in children with this disease have not been studied. Use in special patient groups

    Impaired liver function

    No dose adjustment is required for patients with mild hepatic insufficiency (class A according to the Child-Pugh classification, see the section "Pharmacokinetics").

    Traklir® DT is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh classes B and C).

    Impaired renal function

    For patients with impaired renal function and patients on hemodialysis, dose adjustment is not required.

    Application in elderly patients

    Patients over 65 years of age do not need a dose adjustment.

    Side effects:

    In 20 placebo-controlled clinical trials conducted for different indications, 2,486 patients received bosentan in doses from 100 mg to 2000 mg, and 1,838 patients received a placebo. The duration of treatment averaged 45 weeks.

    Unwanted drug reactions (NLR) were considered events that were observed in 1% or more patients who received bosentan, with a frequency of at least 0.5% higher than in patients receiving placebo.Headache (11.5%), edema of the lower extremities or fluid retention (13.2%), changes in functional liver function tests (10.9%) and anemia / decrease in hemoglobin (9.9%) were most often reported.

    The use of bosentan was associated with a dose-dependent increase in the activity of "liver" transaminases and a decrease in hemoglobin (see section "Special instructions").

    The safety profile of bosentan in uncontrolled clinical trials in children did not differ from the drug safety profile in adult patients with PAH in baseline studies, except for the incidence of infectious diseases that was higher in children (69.0%) than in adults (41.3% ). This difference in the incidence of infectious diseases can be partially explained by the longer average duration of bosentan therapy in children (71.8 weeks) than adults (17.4 weeks). Among the most frequent cases of infectious diseases of the upper respiratory tract (25%), pulmonary (arterial) hypertension (20%), nasopharyngitis (17%), hypertension (15%), vomiting (13%), bronchitis (10%) , abdominal pain (10%) and diarrhea (10%).

    The following NLRs are registered in clinical trials and post-marketing period and are presented according to the terminology of the medical vocabulary for regulatory activities MEDDRA. Depending on the frequency of occurrence, NLPs are grouped as follows: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10 000, <1/1000); very rarely (<1/10 000), the frequency is unknown (can not be estimated from available data).

    In each frequency group, NLRs are presented in order of decreasing severity. There were no clinically significant differences between NLR in the common database and separately from the recorded indications.

    Infectious and parasitic diseases

    Very often: upper respiratory tract infections6, nasopharyngitis6, bronchitis6.

    Violations of the blood and lymphatic system

    Often: anemia6, decreased hemoglobin6;

    Infrequently: thrombocytopenia1, neutropenia, leukopenia1;

    The frequency is unknown: anemia or a decrease in hemoglobin, requiring blood transfusion1.

    Immune system disorders

    Often: hypersensitivity reactions (including dermatitis, skin itching and rash)2;

    Rarely: anaphylactic reactions and / or angioedema1.

    Disturbances from the nervous system

    Very often: headache3,6;

    Often: faint1’4.

    Heart Disease

    Often: a feeling of heartbeat1’4.

    Vascular disorders

    Often: "tides" of blood to the skin of the face6, a decrease in blood pressure1’4.

    Disorders from the gastrointestinal tract

    Very often: vomiting6, abdominal pain6, diarrhea6;

    Often: gastroesophageal reflux disease, diarrhea.

    Disturbances from the liver and bile ducts

    Very often: change in the indicators of functional "liver" tests (see section "Special instructions") 6;

    Infrequently: increased activity of "liver" transaminases (ACT, ALT) due to hepatitis or jaundice1 (see section "Special instructions");

    Rarely: cirrhosis, liver failure1.

    Disturbances from the skin and subcutaneous tissues

    Often: erythema.

    General disorders and disorders at the site of administration

    Very often: peripheral edema6, fluid retention5, fever6.

    1The data were obtained from post-registration observations, the frequency was determined by statistical modeling of data from placebo-controlled clinical trials.

    2Hypersensitivity reactions were noted in 9.9% of patients who received bosentan and 9.1% had a placebo.

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

    4These reactions can be due to the underlying disease.

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

    6Data are obtained from uncontrolled clinical trials in children.

    In the post-marketing period, rare cases of liver cirrhosis of unknown etiology were noted against long-term therapy with bosentan in patients with severe concomitant diseases, while using other medications. Also, rare cases of hepatic insufficiency develop. These observations confirm the need for mandatory monthly monitoring of liver function during the entire period of treatment with Trakli® DT (see section "Special instructions").

    Additional Information

    Use in children

    The safety profile of bosentan in children in the first uncontrolled study of film-coated tablets did not differ from the corresponding safety profile in adult patients with PAH in baseline studies. The most frequent cases in children were "hot flushes" of blood (21%), headache and changes in functional "liver" tests (16% for each NLR).

    A generalized analysis of the results of bosentan studies in the dosage form of a dispersible tablet of 32 mg included data from 100 children with PAH. Boszentan was administered at a dose of 2 mg / kg body weight 2 times / day (n= 33), 2 mg / kg body weight 3 times / day (n= 31) or 4 mg / kg body weight 2 times / day (n= 36). At the time of enrollment, the age of six patients ranged from 3 months to 1 year, 15 patients from 1 to 2 years and 79 patients from 2 to 12 years. The average duration of treatment was 71.8 weeks (0.4 to 258 weeks).

    The incidence of HLR did not differ significantly in patients younger or older than 2 years, but this finding is based on data from only 21 patients under 2 years of age and 6 patients aged 3 months to 1 year. NLR as a violation of liver function and anemia / hemoglobin reduction were observed in 9% and 5% of patients, respectively.

    In addition, 13 newborns received dispersible bosentan tablets at a dose of 2 mg / kg body weight 2 times / day (8 patients received a placebo). The average duration of treatment with bosentan and placebo was 4.5 days (0.5 to 10 days) and 4.0 days (2.5 to 6.5 days), respectively. The most frequent NLDs in children who received bosentan and placebo, were respectively anemia or a decrease in hemoglobin (7 and 2 patients), generalized edema (3 and 0 patients), and vomiting (2 and 0 patients).

    Changes in laboratory indicators

    Increased activity of "liver" transaminases (ACT and ALT)

    The use of bosentan was accompanied by a dose-dependent increase in the activity of "hepatic" transaminases (ACT and ALT) for 26 weeks of treatment, developed gradually and, as a rule, is asymptomatic. In the post-marketing period, rare cases of liver cirrhosis and liver failure are noted. The mechanism of development of these NLRs is unclear. This increased activity of "hepatic" transaminases can spontaneously normalize with the use of the drug Trakli® DT in a maintenance dose or after its reduction. However, discontinuation of treatment or a brief interruption in therapy may still be required (see section "Special instructions").

    In 20 placebo-controlled studies, an increase in the activity of "hepatic" transaminases at 3 times or more of the upper limit of the norm (VGN) was noted in 11.2% of patients who received bosentan, and 2.4% had a placebo. An increase of 8 or more times higher than ULN was registered in 3.6% of patients receiving bosentan, and in 0.4% - placebo. It was noted that against the background of bosentan treatment, an increase in the activity of "hepatic" transaminases was combined with an increase in the concentration of bilirubin in the blood plasma (2 and more times higher than UGN) in the absence of bile duct obstruction in patients in 0.2% of cases (5 patients),and against the background of placebo - in 0.3% of cases (6 patients).

    In a generalized analysis of the data obtained in 100 children, an increase in the activity of "hepatic" transaminases in 3 times or more of IGN was observed in 2% of patients.

    In 13 newborns with PGHN who received bosentan in a dose of 2 mg / kg body weight 2 times / day for less than 10 days (0.5 to 10 days), no increase in the activity of "liver" transaminases was observed 3 times or more, but 3 days after the cancellation of bosentan in one patient was hepatitis is diagnosed.

    Hemoglobin

    Reduction of hemoglobin was observed in 8.0% patients receiving bosentan, and y 3,9% - Placebo. In a generalized analysis of the data obtained in 100 children, a decrease in the initial hemoglobin below 100 g / l was observed in 10% of patients. A decrease in hemoglobin below 80 g / l was not observed.

    In 6 out of 13 newborns with PGHN, a decrease in baseline normal hemoglobin was lower than the lower limit of the norm when treated with bosentan.

    Overdose:

    Bozentan was used in a single dose of 2,400 mg in healthy volunteers and in a dose of up to 2000 mg / day for 2 months in patients with other than PAH diseases. The most common symptom of an overdose was mild or moderate headache.

    Severe overdose can lead to a marked decrease in blood pressure, which requires active cardiovascular therapy. In the post-registration period, an overdose was registered in a teenage boy after taking 10,000 mg of bosentan, which was manifested by nausea, vomiting, marked decrease in blood pressure, dizziness, increased sweating, and impaired clarity of visual perception. The condition completely normalized within 24 hours against the background of maintenance hypertensive therapy.

    Bozentan is not removed during hemodialysis.

    Interaction:

    Bozemanin is an inducer of the isoenzymes of the cytochrome P450 system CYP2C9 and CYP3A4, and possibly, CYP2C19. Therefore, with the simultaneous use of bosentan and drugs whose metabolism is mediated by these isoenzymes, their concentration in the blood plasma is reduced. One should consider the possibility of reducing the effectiveness of drugs, the metabolism of which is carried out with the participation of the above isoenzymes. Perhaps after the start of taking bosentan, changing its dose or canceling it, you will need to change the dose of concomitant medications.

    Bozental is metabolized with the participation of isoenzymes CYP2C9 and CYP3A4. Inhibition of these isoenzymes may be accompanied by an increase in the concentration of bosentan in the blood plasma (see Fig. ketoconazole). Effect of inhibitors of isoenzymes CYP2C9 on the concentration of bosentan in blood plasma was not studied. When combined with them, use caution.

    Fluconazole and other isozyme inhibitors CYP2C9 and CYP3A4: The simultaneous use of bosentan with fluconazole, which inhibits, mainly, isoenzyme CYP2C9 and, only slightly, isoenzyme CYP3A4, may be accompanied by a marked increase in the concentration of bosentan in the blood plasma. This combination is not recommended. For the same reason, the simultaneous use of Tracler® DT and potent inhibitors of isoenzyme CYP3A4 (ketoconazole, itraconazole or ritonavir) and an isoenzyme inhibitor CYP2C9 (voriconazole).

    Cyclosporin A: simultaneous use of bosentan and cyclosporin A (calcineurin inhibitor) it is contraindicated. With a combination of these drugs, the minimum initial concentration of bosentan in the blood plasma increases by a factor of 30 compared with the use of a single bosentan.The equilibrium concentration of bosentan in blood plasma increases 3-4 times compared with the concentration of bosentan in monotherapy. The mechanism of this interaction may be explained by the inhibition of cyclosporin transport protein, responsible for the transfer of bosentan to hepatocytes. The concentration of cyclosporin A (substrate isoenzyme CYP3A4) in the blood plasma is reduced by almost 50%. This change is most likely due to induction of the isoenzyme CYP3A4 bosentan.

    Tacrolimus, sirolimus: simultaneous use with bosentan in clinical studies has not been studied, but it is assumed that the concentration of bosentan in blood plasma may increase by analogy with the simultaneous use with cyclosporine A. When combined with bosentan, the concentration of tacrolimus and sirolimus in blood plasma may decrease. Concerning, bosentan do not do it apply simultaneously with tacrolimus or sirolimus. If it is necessary to simultaneously use these drugs, it is necessary to monitor the possible development of boventane-derived NLP and to control the concentration of tacrolimus and sirolimus in the blood plasma.

    Glibenclamide: simultaneous use of bosentan in a dose of 125 mg 2 times / day for 5 days was accompanied by a decrease in the concentration of glibenclamide (substrate isoenzyme CYP3A4) in blood plasma by 40% and possible significant decrease in the hypoglycemic effect of the drug. The concentration of bosentan in blood plasma also decreased by 29%. In addition, the frequency of increased activity of "hepatic" transaminases increased in patients receiving co-therapy. AND glibenclamide, and bosentan have an inhibitory effect on the export pump of bile salts (BSEP), which may explain the increased activity of "liver" transaminases. This combination is not recommended. There is no data on the drug interaction of bosentan with other derivatives of sulfonylurea.

    Rifampicin: while simultaneous use of bosentan in a dose of 125 mg 2 times / day and rifampicin, which is a powerful inducer of isoenzymes CYP2C9 and CYP3A4, in 9 healthy volunteers for 7 days the concentration of bosentan in blood plasma decreased by 58%, and in individual patients - by 90%. As a result, a significant reduction in the effectiveness of bosentan when combined with rifampicin can be expected. The simultaneous use of rifampicin and bosentan Not recommended. Data on the joint use of bosentan with other isoenzyme inducers CYP3A4, such as carbamazepine, phenobarbital, phenytoin and St. John's wort, not enough. Nevertheless, with their joint application, we can expect a decrease in the systemic exposure of bosentan. We can not exclude a significant reduction in the effectiveness of treatment.

    Lopinavir / ritonavir (and other protease inhibitors whose action enhances ritonavir): while simultaneous use of bosentan in a dose of 125 mg 2 times / day and combination lopinavir + ritonavir 400 + 100 mg 2 times / day for 9.5 days in healthy volunteers, the minimum initial concentration of bosentan in blood plasma was approximately 48 times higher than the concentration when using one bosentan. At day 9, the concentration of bosentan in the blood plasma was 5 times higher than when only bosentan was taken. Inhibition of isoenzyme by ritonavir CYP3A4 and the protein responsible for the transport of bosentan to hepatocytes leads to a decrease in the clearance of bosentan, and is likely to underlie this interaction. In patients who simultaneously take bosentan and lopinavir + ritonavir or other protease inhibitors, the action of which enhances ritonavir, it is necessary to control the tolerability of the drug Trakli® DT.

    When combined with bosentan for 9.5 days, there was a clinically insignificant decrease in the concentration of lopinavir and ritonavir (approximately 14% and 17%, respectively). Nevertheless, complete induction with bosentan could not be achieved, so the possibility of further lowering the concentration of protease inhibitors can not be ruled out. Appropriate monitoring of HIV therapy is recommended. Similar effects can be expected with other protease inhibitors, the action of which enhances ritonavir.

    Other antiretroviral drugs: due to the lack of data, specific recommendations for other antiretroviral drugs can not be provided. Considering the pronounced toxic effect of nevirapine on the liver, which can increase the hepatotoxicity of bosentan, the joint use of these drugs Not recommended.

    Hormonal contraceptives: with the simultaneous use within 7 days of bosentan in a dose of 125 mg 2 times / day and a single dose of oral contraceptive,containing 1 mg norethisterone and 35 μg ethinyl estradiol, there was a decrease AUC both components (by 14% and 31%, respectively). Individual patients decreased the exposure of norethisterone and ethinyl estradiol to 56% and 66%, respectively. Thus, only hormonal contraception, regardless of the route of administration (oral, injectable, transdermal or implant), can not be considered a reliable contraceptive.

    Warfarin: simultaneous use of bosentan at a dose of 500 mg 2 times / day for 6 days leads to a decrease in plasma concentrations of both S-warfarin (the substrate of the isoenzyme CYP2C9) and R-warfarin (the substrate of the isoenzyme CYP3A4) by 29% and 38% respectively. The simultaneous use of bosentan and warfarin in patients with PAH did not reveal clinically significant changes in the international normalized ratio (INR) or the dose of warfarin (the initial dose compared with the maintenance dose). In addition, the frequency of changes in warfarin dose during studies due to fluctuations in INR or due to the development of NLR did not differ in patients who received bosentan or placebo. There is no need to change the dose of warfarin or other similar anticoagulants for oral administration when added to the therapy of bosentan.Nevertheless, more frequent control of INR is recommended, especially at the beginning of the use of bosentan and with an increase in its dose.

    Simvastatin: with the simultaneous use of bosentan at a dose of 125 mg 2 times / day for 5 days, the concentration of simvastatin (the substrate of the isoenzyme CYP3A4) and its active metabolite of beta-hydroxy acid decreases in blood plasma by 34% and 46%, respectively. Simultaneous use of simvastatin does not affect the concentration of bosentan in blood plasma. It is recommended to monitor the concentration of cholesterol in the blood plasma and the corresponding correction of the dose of simvastatin.

    Ketoconazole: simultaneous administration of bosentan in a dose of 62.5 mg 2 times / day for 6 days and ketoconazole, a potent inhibitor of isoenzyme CYP3A4, is accompanied by a twofold increase in the concentration of bosentan in blood plasma. A change in the dose of Traclyre® DT is not required. Despite the lack of research data in vivo, it is assumed that a similar increase in bosentan concentration in the blood plasma can be observed with simultaneous use of other potent inhibitors of the isoenzyme CYP3A, for example, itraconazole and ritonavir.Nevertheless, with the simultaneous use of bosentan and an isoenzyme inhibitor CYP3A4, in patients with reduced isoenzyme metabolism CYP2C9 there is a risk of a significant increase in the concentration of bosentan, which may contribute to an increase in the frequency and severity of NLP.

    Epoprostenol: limited results of a study in which 10 children received bosentan in combination with epoprostenol, indicate that after a single and repeated use of CmOh and AUC bosentan were approximately the same in patients who received and did not receive infusion of epoprostenol (see the section "Pharmacokinetics").

    Sildenafil: while simultaneous use of bosentan in a dose of 125 mg 2 times / day (equilibrium) and sildenafil at a dose of 80 mg 3 times / day for 6 days in healthy volunteers, there was a decrease AUC sildenafil by 63% and increased AUC bosentan - by 50%. Care should be taken when applying simultaneously.

    Digoxin: simultaneous application of bosentan in a dose of 500 mg 2 times / day for 7 days is accompanied by a decrease AUC, FROMmOh and Cmin digoxin by 12%, 9% and 23%, respectively. Induction of glycoprotein P may be the basis of the mechanism of this interaction.The clinical significance of this interaction is negligible.

    Children

    Studies on the study of inter-drug interaction were conducted only in adults.

    Special instructions:

    In patients with severe PAH, the effectiveness of bosentan is not established. It is advisable to consider the appointment of other drugs recommended for a serious stage of the disease (for example, epoprostenol) in the event of a worsening of the clinical condition of the patient (see section "Method of administration and dose").

    The benefit / risk ratio was not established in patients with PAH I of the functional class according to the WHO classification.

    Traklir® DT can be prescribed only if the systolic blood pressure is above 85 mm Hg. (see the "Caution" section).

    The ability of bosentan to influence the healing of already existing digital ulcers has not been established.

    Liver function

    Increased activity ACT and / or ALT on the background of the use of bosentan is dose-dependent. Changes in the activity of "hepatic" transaminases are usually noted during the first 26 weeks of therapy, but may occur at a later time (see section "Side effect"). These increases can partly be explained by competitive inhibition of the excretion of bile salts from hepatocytes, but there may be other mechanisms that are not fully understood,leading to a violation of liver function. We can not exclude the accumulation of bosentan in hepatocytes, leading to cytolysis and potentially severe liver damage, as well as immunological mechanisms. The risk of impaired liver function may also increase with simultaneous use of bosentan with drugs, inhibitors BSEP, such as rifampicin, glibenclamide and ciclosporin And, although these data are limited (see the section "Interaction with other drugs").

    It is necessary to monitor the activity of "liver" transaminases before starting therapy with Trakley® DT, and then once a month during the treatment period. In addition, the activity of "liver" transaminases should be determined 2 weeks after each dose increase.

    Recommendations for monitoring and treatment in case of increased activity of LLT / AST

    ALT / AST activity is 3-5 times higher than ULN

    Conduct a re-determination of the AST / ALT activity. When confirming the increase in activity ACT and ALT the decision to continue treatment with Traklir® DT, possibly in a reduced dose, or its discontinuation should be taken in each specific case.Control of the activity of "liver" transaminases should be carried out at least every 2 weeks. If the activity of "liver" enzymes returned to the initial performance, it is necessary to evaluate the possibility of continuation or renewal of the drug Traklir® PTP mode described below.

    ALT / AST activity is 5-8 times higher than ULN

    Conduct a re-determination of the AST / ALT activity. When confirming the increase in activity ACT and ALT should be discontinued with Traclyre® DT, and the activity of "liver" transaminases should be monitored at least every 2 weeks. If the activity of "liver" enzymes returned to the initial performance, it is necessary to evaluate the possibility of resuming the drug Traklir® PTP mode described below.

    ALT / AST activity is 8 or more times higher than ULN

    Therapy should be discontinued, the resumption of the drug Traklir® DT is excluded.

    With concomitant clinical symptoms of liver damage, those. in the presence of: nausea, vomiting, fever, abdominal pain, jaundice, increased sleepiness and weakness, flu-like syndrome (arthralgia, myalgia, fever), therapy with Traklir® DT should be discontinued, and the resumption of Traklir® DT is excluded.

    Renewal of therapy

    To resume therapy with Traklir® DT is possible only if the expected therapeutic effect of the treatment exceeds the potential risk, and the activity of the "liver" transaminases returned to the initial (before treatment) indicators. It is recommended to consult a doctor-hepatologist. Therapy should be resumed according to the recommendations in the "Application and dose" section of this manual. Activity of "liver" transaminases should be checked 3 days after the resumption of therapy with Trakli® DT, then repeat the control after 2 weeks, then follow the recommendations outlined above.

    Hemoglobin

    On the background of bosentan treatment, a dose-dependent decrease in hemoglobin was noted (see the "Side effect" section). The decrease in hemoglobin associated with the use of bosentan was not progressive, the hemoglobin values ​​stabilized after the first 4-12 weeks of therapy. It is recommended to determine hemoglobin before the beginning of therapy with Trakli® DT once a month for the first 4 months of therapy and thereafter - once in 3 months. If a clinically significant decrease in hemoglobin is observed,a further examination of the patient should be carried out to establish the cause of the anemia and to decide whether appropriate therapy is necessary. In the post-marketing period, cases of anemia requiring transfusion of erythrocyte mass were reported.

    Therapy in women with preserved reproductive potential

    Since the effectiveness of hormonal contraceptives may decrease with the use of Traklir® DT, and pregnancy contributes to worsening of the course of PAH, and taking into account the data on the teratogenic effect found in animals:

    - Drug Traklir® DT can be prescribed to women with preserved reproductive potential ONLY against the background of applying reliable methods of contraception and in the case of a negative pregnancy test result before the start of treatment

    - The method of hormonal contraception should not be used as the only method during the treatment with Trakli® DT

    - A pregnancy test is recommended once a month for early pregnancy.

    Venousocclusion disease of the lungs

    Cases of life-threatening pulmonary edema have been reported in patients with venous occlusion disease of the lungs using vasodilators (mainly prostacyclin).Thus, if signs of pulmonary edema appear in patients with PAH during treatment with Traklir® DT, the concomitant veno-occlusive disease should be considered. In the post-marketing period, there were reports of rare cases of pulmonary edema with bosentan in patients with suspected veno-occlusive lung disease.

    Patients with PAH and concomitant left ventricular failure

    Special studies in patients with PAH and concomitant left ventricular dysfunction were not performed. Nevertheless, 1611 patients (804 of them received bosentan, and 807 placebo) with severe chronic heart failure (CHF) were observed on average for 1.5 years in a placebo-controlled study. This study noted an increase in the number of hospitalizations due to CHF during the first 4-8 weeks of treatment with bosentan, the cause of which could be an increase in fluid retention in the body. A rapid increase in body weight, a decrease in hemoglobin and an increase in edema of the lower extremities may be symptoms of fluid retention in the body. At the end of the study, there was no difference in the number of hospitalizations due to heart failure and mortality in patients who took bosentan or placebo.Therefore, the examination of patients should be aimed at identifying fluid retention (eg, weight gain), especially in the case of concomitant severe systolic dysfunction. If symptoms of fluid retention occur, the patient should be prescribed diuretics or increase their dose. The decision to use diuretics due to a delay in the patient's fluid should be taken before starting treatment with Trakli® DT.

    LAS and HIV infection

    The experience of using bosentan in patients with PAH and HIV infection who received antiretroviral therapy is limited. Results of studying the interaction of bosentan and combination lopinavir + ritonavir when they were used together in healthy volunteers, an increase in the concentration of bosentan was observed, which reached the maximum values ​​during the first 4 days (see the section "Interaction with other drugs"). When the drug Traklir® DT is administered to patients taking protease inhibitors whose action enhances ritonavir, special attention should be paid to the tolerability of Traklir® DT, especially at the beginning of treatment, taking into account the risk of developing arterial hypotension and changing functional "hepatic" tests.

    When the drug Traklir® DT and antiretroviral drugs are used together, the delayed negative effects on the liver and NLR on the part of the blood can not be ruled out. In view of the possible interaction associated with the induction of trabecler® DT isoenzymes of the cytochrome P450 system, the activity of antiretroviral therapy may be reduced, and therefore the effectiveness of HIV therapy should be carefully monitored in such patients.

    LH as a consequence of severe chronic obstructive pulmonary disease (COPD)

    The efficacy and safety of bosentan was studied in a 12-week study involving 11 patients with secondary LH as a result of severe COPD. The results of the study indicate an increase in the rate of minute ventilation of the lungs and a decrease in oxygen saturation; Of the NLRs, dyspnoea was observed most frequently, the severity of which decreased with the cancellation of bosentan.

    Simultaneous use with other medicinal products

    The simultaneous use of the drug Traklir® DT and cyclosporin A is not recommended (see the section "Contraindications").

    The simultaneous use of Tracler® DT with glibenclamide, fluconazole and rifampicin is not recommended.For more information, see "Interaction with Other Drugs".

    Joint therapy with Traklir® DT and inhibitors of isoenzymes CYP3A4 and CYP2C9 should be avoided.

    Dispersible tablet Traclyre® DT is a source of phenylalanine (1 tablet contains 3,700 mg of aspartame), which can harm patients with phenylketonuria (see section "Contraindications").

    Effect on the ability to drive transp. cf. and fur:

    The effect of Trakli® DT on the ability to drive vehicles has not been studied. Nevertheless, the drug Traklir® DT can cause a marked decrease in blood pressure, accompanied by dizziness or loss of consciousness and, as a consequence, have a negative impact on the management of vehicles and working with mechanisms.

    Form release / dosage:

    Tablets are dispersible, 32 mg.

    Packaging:

    For 14 tablets in a blister of aluminum (Al / Al) foil.

    For 4 blisters together with instructions for use in a pack of cardboard with the control of the first opening (in the form of a sticker with the logo of the owner of the RU).

    Storage conditions:

    At a temperature of no higher than 25 ° C.

    Keep out of the reach of children.
    Shelf life:

    3 years.

    Do not use after the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-003496
    Date of registration:14.03.2016
    Expiration Date:14.03.2021
    The owner of the registration certificate:Actelion Pharmaceuticals Co., Ltd.Actelion Pharmaceuticals Co., Ltd. Switzerland
    Manufacturer: & nbsp
    Representation: & nbspActelion Pharmaceuticals RUS, LLCActelion Pharmaceuticals RUS, LLCRussia
    Information update date: & nbsp07.08.2016
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