Tractor® (Tracleer®)

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: & nbspfilm-coated tablets
    Composition:

    1 tablet, film-coated, contains:

    Core: active substance: bosentan 62.5 mg or 125 mg (as monohydrate); Excipients: corn starch 6,959 mg and 13,918 mg, pregelatinized starch 3,125 mg and 6,250 mg, sodium carboxymethyl starch 3,750 mg and 7,500 mg, povidone K90 0.825 mg and 1.650 mg, glyceryl tribehenate 2.475 mg and 4.950 mg, magnesium stearate 0.825 mg and 1.650 mg;

    Film sheath: gipromesellosis 1,560 mg and 2,340 mg, triacetin 0,200 mg and 0,300 mg, talc 0,720 mg and 1,080 mg, titanium dioxide CI 77891, E171 0.991 mg and 1.486 mg, iron oxide yellow CI 77492, E172 0.007 mg and 0.011 mg, iron oxide red CI 77491, E172 0.002 mg and 0.003 mg, ethylcellulose aqueous dispersion (solid) 0.520 mg and 0.780 mg.

    Description:

    Film-coated tablets, 62.5 mg

    Round tablets of orange-white color, cylindrical, biconvex, covered with a film sheath, engraved "62.5" on one side.

    Tablets coated with a film coating, 125 mg

    Oval tablets of orange-white color, cylindrical, biconvex, covered with a film sheath, engraved with "125" on one side.

    Pharmacotherapeutic group:vasodilator
    ATX: & nbsp

    C.02.K.X   Other antihypertensive drugs

    Pharmacodynamics:

    Bozanthan is a non-selective antagonist of endothelin receptors (AER) with affinity for endothelin receptors of types A and B (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 vasoconstrictors, has the ability to induce fibrosis, cell proliferation, hypertrophy and remodeling of the myocardium, and also displays pro-inflammatory activity.

    These effects are caused by binding ET-1 with receptors ETA and ETAT, located in the endothelium and cells of the smooth musculature of the vessels. Concentration ET-1 in tissues and blood plasma increases with certain cardiovascular diseases and pathology of connective tissue, including pulmonary arterial hypertension (PAH), scleroderma, acute and chronic heart failure, myocardial ischemia, arterial hypertension and atherosclerosis, suggesting participation ET-1 in the pathogenesis and development of these diseases.With PAH and heart failure in the absence of receptor antagonism to ET increase in concentration ET-1 strictly correlates with the severity and prognosis of these diseases.

    Boszentan competes with ET-1 and others ET peptides for binding to ETA and ETAT receptors, with a slightly higher affinity for the receptors ETA (Ki=4,1-43 nmol), compared with the receptors ETAT (Ki=38-730 nmol).

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

    Efficiency

    Efficacy in adult patients with PAH

    Results of two clinical trials in adult patients with PAH III-IV functional class (PK) showed that when bosentan is added to standard therapy, which may include anticoagulants, vasodilators (eg, slow calcium channel blockers), diuretics, oxygen therapy, and digoxin, but does not include epoprostenol, tolerance to physical loads increases significantly. The main end point in each study was a change in the distance of the test with 6-minute walking at 12 weeks in the first study and on the 16th - in the second. Improvement in exercise tolerance was observed after 4 weeks of therapy,was evident at week 8 and persisted until 28 weeks of double-blind treatment in a subset of the sample of patients. In patients receiving bosentan treatment, a decrease in the severity of symptoms of PAH has been noted. Also in patients of this subgroup, there was an improvement in the manifestation of dyspnea during a walking test.

    The first study showed that the use of bosentan is accompanied by an increase in the cardiac index and is combined with a significant decrease in pulmonary artery pressure, pulmonary vascular resistance, and medium pressure in the right atrium. The results of a study of the use of bosentan in patients with PAH II FK (mean distance of the test with 6-minute walking - 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 worsening of the course of PAH in the group of patients receiving bosentan, 1 case of hospitalization was noted, while at the same time in the group of patients not receiving bosentan - 3 cases. When observed for 6 months, one case of a lethal outcome in each group was recorded, which does not allow to assess the effect of bosentan on survival.In patients with PAH III FC and Eisenmenger syndrome associated with congenital heart defects, with the use of bosentan in doses of 62.5 mg 2 times / day. and 125 mg 2 times / day. After 16 weeks of therapy, there was no worsening of hypoxemia (oxygen saturation in blood plasma increased by 1%). The average vascular resistance in the pulmonary artery significantly decreased, the tolerance of exercise was improved (the average distance of the test with a 6-minute walk increased by 53 m).

    A study of bosentan in patients with PAH III FC associated with HIV infection showed a significant increase in exercise tolerance. Improvement in survival rates in the long-term was noted in all patients receiving bosentan in two placebo-controlled studies, as well as in their extensions. The average duration of bosentan is 1.9 ± 0,7 years (from 0,1 years to 3,3 years), observation was carried out within 2,0 ± 0.6 years. The majority of patients confirmed the diagnosis of primary PAH (72%) and III FK (84%). The overall survival in the population as a whole after the first year of bosentan is 93%, and after 2 years - 84% (Kaplan-Mayer evaluation).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), survival in patients with primary PAH receiving bosentan, is comparable with the corresponding parameters of epoprostenol.

    In patients with systemic scleroderma, the Kaplan-Mayer survival estimate was lower.

    The study of efficacy in children with PAH

    Assessment of the pharmacokinetics parameters in children with PAH was carried out within 12 weeks of using bosentan.

    Analysis of hemodynamic parameters indicates an increase in cardiac index (SI) by 0.5 l / min / m2 , as well as a decrease in pressure in the pulmonary artery (DLA) by 8 mm Hg. Art. and pulmonary vascular resistance (LSS) by 389 dyne * s * cm-5.

    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 ulcerative lesions were noted during the last year) showed that the use of bosentan was accompanied by a significant decrease in the number of new ulcerative lesions of the limbs compared with placebo during of the entire treatment period.

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

    Pharmacokinetics:

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

    Pharmacokinetic parameters in healthy volunteers depend on the dose and time of administration of the drug. After intravenous administration of bosentan, the volume of its distribution and clearance decrease with increasing dose and increase with time. After oral administration, the systemic exposure of bosentan is proportional in doses up to 500 mg. When ingesting a higher dose of bosentan, an increase in the maximum concentration in the blood plasma (CmOh) and AUC (the area under the concentration-time curve) is disproportionate to the dose taken and is achieved at a lower rate.

    Suction

    The absolute bioavailability of bosentan in healthy volunteers after oral administration is about 50%, food intake does not affect the bioavailability. FROMmOh in the blood plasma is achieved 3-5 hours after ingestion.

    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 (Vss ) is 18 liters.

    Metabolism and excretion

    After a single intravenous injection at a dose of 250 mg, the clearance is 8.2 l / h. The half-life (T1/2) - 5.4 h.

    With repeated use, the concentration of bosentan in the blood plasma is reduced gradually and is 50-65% of the concentration for a single application. The decrease in bosentan concentration is probably due to autoinduction of liver enzymes. The equilibrium state is reached within 3-5 days.

    Bozanthan is excreted through the intestine with bile after completion of the metabolism in the liver with the participation of cytochrome P450 isoenzymes CYP2C9 and CYP3A4. Less than 3% of the dose taken inside is excreted by the kidneys.

    In the process of metabolism of bosentan, 3 metabolites are formed, but only one of them has pharmacological activity. The pharmacologically active metabolite is mainly excreted 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, perhaps, isoenzyme CYP2C19 and P-glycoprotein. In vitro bosentan suppresses the activity of BSEP (a pump for the export of bile salts) in hepatocyte cultures.

    In studies in vitro shown, that bosentan does not have a significant inhibitory effect on a number of isoenzymes CYP (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4). Consequently, bosentan does not increase the concentration in the blood plasma of drugs whose metabolism is mediated by these isoenzymes.

    Pharmacokinetics in special groups of patients

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

    Children over 2 years old

    Pharmacokinetic parameters for single and repeated use of bosentan in the dosage form of film-coated tablets were studied in children with PAH, the dose of the drug was selected based on the patient's body weight (AC-052-356 [BREATHE-3]). The effect of bosentan decreased over time with respect to the characteristic curve for bosentane due to the ability of bosentan to autoinduce. Mean values AUC (CV%) in children receiving bosentan 2 times / day. in doses of 31.25 mg, 62.5 mg and 125 mg are 3.496 ng * h / ml (49%), 5.428 ng * h / ml (79%) and 6.124 (27%) ng * h / ml, respectively, and were lower than 8.149 ng * h / ml (47%) in adult patients with PAH who received 125 mg of bosentan. In the equilibrium state, the system exposure in children with a body weight of 10-20 kg, 20-40 kg and more than 40 kg was 43%, 67% and 75% of the corresponding indices in adults.

    Impaired liver function

    In patients with mild violations of liver function (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 violations of hepatic function AUC bosentan in the equilibrium state is higher by 9%, and the active metabolite Ro 48-5033 - by 33%.

    In patients with moderate impairment of liver function (7-9 on the Child-Pugh scale) and PAH associated with portal hypertension, AUC bosentan in the equilibrium state was 4.7 times higher, and the active metabolite Ro 48-5033 - 12.4 times higher than in patients with PAH with preserved renal function.

    The pharmacokinetics of bosentan in patients with severe impairment of liver function (10 points and higher on the Child-Pugh scale) has not been studied. It is recommended to avoid the use of Trakley® in patients with moderate and severe liver disorders (7 points and higher on the Child-Pugh scale).

    Impaired renal function

    In patients with severe impairment of renal function (creatinine clearance (CK) 15-30 ml / min), the concentration in the blood plasma of bosentan decreases by approximately 10%. The concentration of bosentan metabolites in the blood plasma increases approximately 2-fold compared to patients with preserved renal function. In patients with impaired renal function, dose adjustment is not required. 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 blood plasma proteins, significant removal of bosentan from the vascular bed during hemodialysis is not expected.

    Indications:

    Treatment of pulmonary arterial hypertension (PAH) in order to improve exercise tolerance and clinical symptoms in patients II-IV functional class (PK) by WHO classification, adults and children over 3 years old, including:

    - primary (idiopathic and hereditary) LAS;

    - secondary PAH against scleroderma in the absence of significant interstitial lung injury;

    - PAH, associated with congenital heart disease, and, in particular, with violations of 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;

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

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

    - aboutsimultaneous application with cyclosporine;

    - PChanging the drug in women reproductive age, who do not use reliable methods of contraception;

    - atozrast to 3 years (solid dosage form).

    Carefully:

    Severe arterial hypotension (systolic blood pressure less than 85 mm Hg), chronic obstructive pulmonary disease (COPD), mild liver dysfunction (less than 7 on the Child-Pugh scale); with PAH I FC (not enough clinical data on efficacy and safety of use).

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

    Pregnancy and lactation:

    Pregnancy

    Pre-clinical studies established the reproductive toxicity of bosentan (teratogenic and fetotoxic effect). Clinical studies on the use of the drug in women during pregnancy have not been conducted. The possible risk of using Traklir® during pregnancy has not been studied. The use of Trakley® during pregnancy is contraindicated.

    Use in women of childbearing age

    Before beginning treatment with Trakley®, women of reproductive age should be confirmed with no pregnancy, doctors are obliged to give recommendations on prevention pregnancy, and patients should begin to use reliable methods of contraception. Patients and physicians who prescribe the treatment should take into account that due to the pharmacokinetic interaction, the drug Trakley ® can reduce the effectiveness of hormonal contraceptives. For this reason, women of reproductive age are not recommended to use the method of hormonal contraception (medications used orally, as injections, transdermal therapeutic systems (TTS) or implants), as the only; they need to use an additional or alternative method of reliable contraception. If there is any doubt about the contraceptive method used, the patient should consult a gynecologist for an individual selection of a reliable contraceptive method. Given the decrease in the effectiveness of hormonal contraception and the possible negative effect of pregnancy on the course of PAH, during therapy with Trakley® it is recommended to carry out a pregnancy test on a monthly basis, which will make it possible to diagnose pregnancy in the early stages.

    Breast-feeding

    It is not established whether the bosentan with breast milk.Breastfeeding is not recommended during the treatment with Trakley®.

    Dosing and Administration:

    The tablets covered with a film cover, it is necessary to accept inside in the morning and in the evening, irrespective of time of reception of food, without chewing and washing down with water.

    Treatment of pulmonary arterial hypertension (PAH) in order to improve exercise tolerance and clinical symptoms in patients II-IV functional class (PK) according to WHO classification

    Application in adults

    The initial dose of Trakley® is 62.5 mg 2 times / day. for 4 weeks, then the dose increases to 125 mg twice a day.

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

    Discontinuation of therapy

    There is limited experience in observing patients after the sudden discontinuation of therapy with Trakley®. There is no information about clinically significant worsening during PAH as a result of abrupt withdrawal of the drug.Nevertheless, in order to reduce the risk of clinical deterioration of patients and prevent the syndrome of "withdrawal", the dose of the drug is recommended to be reduced gradually (reducing it by half for 3-7 days), while initiating alternative therapy.

    Decrease in the number of new digital ulcers in adults with systemic scleroderma and progressive ulcerative lesions of the limbs

    The initial dose of Trakley® is 62.5 mg 2 times / day. for 4 weeks, then increase the dose to a maintenance -125 mg 2 times / day. Clinical status of patients should be monitored regularly, carefully assessing the benefit / risk relationship for further therapy with Trakley® and taking into account the potential adverse effects of the drug on liver function.

    Data on the effectiveness and safety of the drug in children under 18 years are absent.

    Use in special groups of patients

    Impaired liver function

    In patients with mild violations of liver function (5-6 points on the Child-Pugh scale), there is no need for correction of the dose of the drug. The use of Traclyr® in patients with moderate to severe and severe impairment of liver function should be avoided (7 points or higher on the Child-I drink).

    Impaired renal function

    In patients with impaired renal function, no dose adjustment is required.

    Patients on hemodialysis do not need a dose adjustment.

    Application in elderly patients

    Patients over 65 years of age are not required correction of the dose of the drug.

    Use in children older than 3 years and in patients with low body weight

    Pulmonary arterial hypertension

    In children with PAH older than 3 years, as well as in patients with low body weight (less than 40 kg), Trakley® is used in doses based on the weight of the child / patient:

    Body weight (kg)

    Initial dose

    (4 weeks)

    Supportive

    dose

    from 10 to 20 kg

    1 time a day 31.25 mg (1/2 tablets of 62.5 mg)

    2 times a day 31.25 mg (1/2 tablets of 62.5 mg)

    from 20 to 40 kg

    2 times a day 31.25 mg (1/2 tablets of 62.5 mg)

    2 times a day 62.5 mg

    more than 40 kg

    2 times a day 62.5 mg

    2 times a day 125 mg

    Decrease in the number of new digital ulcers in systemic scleroderma and progressive ulcerative lesions of the limbs

    Data on efficacy and safety of use in patients under 18 years are absent.

    Data on the use of the drug in patients with a body weight of up to 40 kg are limited.

    For dose selection in such patients, please use the information given in the table of dose selection in children with PAH.

    Side effects:

    In 20 placebo-controlled studies conducted according to different indications, 2,486 patients received bosentan in doses from 100 mg to 2000 mg and 1838 patients received a placebo.

    The duration of treatment averaged 45 weeks.

    Most often (in 1% or more recipients bosentan and in 0.5% of those receiving placebo) had headache (11.5% vs. 9.8%), lower limb edema and / or fluid retention (13.2% vs. 10.9%), increased activity of "liver" transaminases aspartate aminotransferase (ACT) and / or alanine aminotransferase (ALT) (10.9% versus 4.6%) and anemia / hemoglobin reduction (9.9% vs. 4.9%).

    The use of bosentan is associated with a dose-dependent increase in the activity of "hepatic" transaminases 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, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10000, <1/1000); very rarely (<1/10000).

    Adverse reactions reported at the post-marketing phase of the drug are included with the frequency of the 20-placebo-controlled trials and marked italics.

    The frequency categories do not take into account such factors as the duration of bosentan administration, the history data, the initial clinical data. In each group, adverse reactions are indicated in order of severity. Clinically significant differences in the adverse reactions indicated in the common database and separately according to the recorded indications were not noted.

    System-Organ Class

    Frequency

    Adverse Reactions

    From the side of the blood and lymphatic system

    often

    anemia, decreased hemoglobin;

    frequency unknown1

    anemia or a decrease in hemoglobin, when it is necessary to carry out blood transfusion;

    infrequently

    thrombocytopenia;

    infrequently

    neutropenia, leukopenia;

    From the immune system

    often

    reactions of hypersensitivity (including dermatitis, pruritus and rash)2

    rarely

    anaphylactic reactions and / or angioedema

    From the nervous system

    Often

    headache3

    often

    fainting4

    From the side of the cardiovascular system

    often

    heart palpitations4, "tides" of blood to the skin of the face, BP reduction4

    From the digestive system

    often

    gastroesophageal reflux disease, diarrhea

    infrequently

    increased activity of "hepatic" transaminases, associated with hepatic and / or jaundice

    rarely

    cirrhosis, liver failure

    From the skin and subcutaneous tissues

    often

    redness of the skin

    General disorders and disorders at the site of administration

    Often

    peripheral edema, fluid retention

    1 The frequency can not be estimated from the available data.

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

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

    4 These reactions can be due to the underlying disease.

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

    In the postmarketing period there are reports of rare cases of cirrhosis of the unclear etiology with prolonged use of Trakley® in patients with severe concomitant diseases that simultaneously use multiple medications. Also, rare cases of the development of liver failure are noted. These cases increase the importance of strict adherence to monthly monitoring of liver function during the entire treatment period with Trakley®.

    Uncontrolled studies in children with PAH (AC-052-356 [BREATN-3])

    Application Safety Profile bosentan in children (BREATH-3: n=19, bosentan 2 mg / kg 2 times / day; for 12 weeks) did not differ from the corresponding safety profile in adult patients with PAH in baseline studies. The most frequently observed in children were "hot flashes" of blood to the skin of the face (21%), headache and increased activity of "liver" transaminases (16% for each adverse reaction).

    Changes in laboratory indicators

    Change in the activity of "hepatic" transaminase

    In the clinical program, a dose-dependent increase in the activity of "hepatic" transaminase was observed within 26 weeks of treatment, developed gradually, as a rule, asymptomatic. AT post-marketing period, reports of rare cases of patients with liver cirrhosis and insufficiency of liver function.

    The mechanism of occurrence of the above-mentioned adverse reactions is unclear. Activity of "hepatic" transaminases can spontaneously decrease with continued treatment without changing the dose of the drug Traklir® or after its reduction, nevertheless, discontinuation of treatment or a short-term interruption in therapy may still be required.

    In 20 studies, there was an increase in activity of "liver" transaminases in 3 times or more in 11.2% of patients who received bosentan and 2.4% had a placebo. An increase of 8 or more times the upper limit of the norm (VGN) was noted in 3.6% of patients receiving bosentan and 0.4% had a placebo. It was noted that an increase in the activity of "hepatic" transaminases is associated with an increase in the concentration of bilirubin in the blood plasma (2 and more times higher than UGN) in patients with no obstruction of bile ducts in 0.2% of cases (5 patients) receiving bosentan and in 0.3% of cases (6 patients) - placebo.

    Hemoglobin

    Reduction of hemoglobin below 1 g / l from the baseline values ​​was observed in 8.0% of patients receiving bosentan and 3.9% had a placebo.

    Overdose:

    Bosentan was used in a single dose of 2,400 mg in healthy volunteers and 2000 mg / day for 2 months in patients with other diseases other than PAH. The most common symptom of an overdose was a headache of mild to moderate intensity. Overdose can lead to a marked decrease in blood pressure, which may require drug treatment. The case of an overdose of bosentan in a teenage boy after taking 10,000 mg was recorded, which resulted in nausea, vomiting,marked decrease in blood pressure, dizziness, increased sweating, impaired clarity of visual perception.

    The condition was completely normalized within 24 hours, while a correction of pronounced blood pressure reduction was performed. Boszentan not removed during hemodialysis.

    Interaction:

    Bozental is metabolized with cytochrome CYP and its isoenzymes CYP2C9 and CYP3A4. Inhibition of isoenzyme CYP3A4 increases the concentration in the blood plasma of bosentan (see Fig. ketoconazole). Effect of inhibition of the isoenzyme CYP2C9 the concentration of bosentan in blood plasma was not studied. With combined use, use caution. Simultaneous use with fluconazole, which mainly has an inhibitory effect on the isoenzyme CYP2C9 and only insignificant - on isoenzyme CYP3A4, may be accompanied by an increase in the concentration of bosentan in the blood plasma. This combination is not recommended. For the same reason, the simultaneous use of Trakley® and potent inhibitors of isoenzyme CYP3A4 (such as ketoconazole, itraconazole or ritonavir) and an isoenzyme inhibitor CYP2C9 (such as voriconazole).

    Boszentan is an isoenzyme inducer CYP2C9 and CYP3A4. According to the research in vitro It is also assumed that the role of the isoenzyme inductor CYP2C19. Therefore, with the simultaneous use of the drug Traklir® and drugs, the metabolism of which is mediated by these isoenzymes, their concentration in the blood plasma is reduced. It is necessary to take into account the possibility of reducing the effectiveness of drugs, the metabolism of which is carried out with the participation of these isoenzymes. It may be necessary to adjust the dose of concomitant medications after the beginning of taking Trakli®, changing its dose or canceling.

    Cyclosporine: simultaneous use of Trakley® and cyclosporine (calcineurin inhibitor) is contraindicated. With this combination of drugs, the minimum initial concentration of bosentan in the blood plasma rises by a factor of 30 compared with the use of bosentan in monotherapy. The equilibrium concentration of bosentan in blood plasma increases 3-4 times compared with the concentration of bosentan in monotherapy. A possible mechanism of this interaction is the inhibition of the cyclosporin transport protein responsible for the supply of bosentan to hepatodites.The concentration of cyclosporine in the blood plasma at the same time decreases by almost 50%.

    Tacrolimus, sirolimus: simultaneous use with the drug Traklyar ® in clinical studies has not been studied, but it is assumed that the concentration of bosentan in blood plasma can increase by analogy with cyclosporine. The concentration in the blood plasma of tacrolimus and sirolimus may decrease with a joint application with Trakley®. In this regard, Trakley® should not be used simultaneously with tacrolimus or sirolimus. If this combination is necessary, monitoring of the patient's condition and concentration of tacrolimus and sirolimus in the blood plasma is mandatory.

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

    Hormonal contraceptives: at simultaneous application within 7 days of Traklir® in a dose of 125 mg 2 times / day and oral contraceptive for a single dose, a combined preparation containing 1 mg of norethisterone and 35 μg ethinylestradiol, the AUC for its components decreased by 14% and 31%, respectively. Individual patients decreased the exposure of norethisterone and ethinyl estradiol to 56% and 66%, respectively. Thus, hormonal contraception can not be considered sufficiently effective, regardless of the route of administration of the drug-inwardly, injectively, transdermally or as implants.

    Warfarin: with simultaneous use in healthy volunteers with the drug Traklir® at a dose of 500 mg 2 times / day. within 6 days the concentration decreases S-varfarin (substrate isoenzyme CYP2C9) and R- warfarin (substrate isoenzyme CYP3A4) in blood plasma by 29% and 38%, respectively. The experience of simultaneous use of Trakley® and warfarin in patients with PAH was not accompanied by significant clinical changes in the International Normalized Ratio (INR) and the dose of warfarin (at the end of the study compared to baseline values). In addition, the frequency of correction of warfarin dose during the study due to changes in INR or due to side effects did not differ in patients who received bosentan or placebo. There is no need to adjust the dose of warfarin or other oral anticoagulants at the beginning of therapy with Trakley®. However, mandatory monitoring of INR is recommended, especially at the beginning of the use of Trakley® and at the stages of dose increase.

    Simvastatin: with simultaneous application within 5 days of 125 mg of Trakley ® 2 times / day, the concentration of simvastatin decreases (substrate of isoenzyme CYP3A4) and its active form of beta-hydroxy acid in blood plasma by 34% and 46%, respectively. Simultaneous use of simvastatin does not affect the concentration of bosentan in blood plasma.When joint use of simvastatin and Trakley® is recommended to control the concentration of cholesterol in the blood plasma with subsequent correction of the dose of simvastatin.

    Ketoconazole: simultaneous application within 6 days of the drug Traklir® at a dose of 62.5 mg 2 times a day and ketoconazole, a potent inhibitor of the isoenzyme CYP3A4, is accompanied by a twofold increase in the concentration of bosentan in the blood plasma. Correction of the dose of Trakley® is not performed.

    An increase in the concentration of bosentan in blood plasma is also contemplated with simultaneous application of itraconazole and ritonavir, Despite the lack of confirmation in the studies in vivo. Nevertheless, with the combination of bosentan with an inhibitor CYP3A4, in patients with reduced isoenzyme metabolism CYP2C9 There is a risk of a significant increase in the concentration of bosentan, which can increase the frequency and severity of the side effects of the drug.

    Rifampicin: with simultaneous application in healthy volunteers for 7 days of Trakley® in a dose of 125 mg 2 times / day and rifampicin, which is an inducer of isoenzymes CYP2C9 and CYP3A4, the concentration of bosentan in blood plasma decreased by 58%, and in individual patients - by 90%. As a result, a significant reduction in the effect of Trakley® can be achieved when combined with rifampicin. Data on the combined use with other isoenzyme inducers CYP3A4, such as carbamazepine, phenobarbital, phenytoinAnd drugs, which include St. John's wort, insufficient, however with high probability at their joint use is impossible to exclude a significant reduction in the effectiveness of treatment Traklir®.

    Epoprostenol: limited results study (AC-052-356 [BREATH-3]), in which 10 children received Traklir® combined with epoprostenol indicate that after single and multiple administration of these drugs in the blood plasma concentration of bosentan Cmax and AUC were approximately the same in patients who received and did not receive infusion of epoprostenol.

    Sildenafil: with the simultaneous use of the drug Trakley ® at a dose of 125 mg 2 times / day. (equilibrium state) and sildenafil in 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%. Changes in the concentrations of substances in the plasma are not of clinical significance, correction of doses of drugs is not required.

    Digoxin, nimodipine, losartan:

    simultaneous application of the drug Trakli® in a dose of 500 mg 2 times / day for 7 days is accompanied by a decrease in the concentration of digoxin in the blood plasma AUC, FROMmOh and Cmin by 12%, 9% and 23% respectively. The mechanism of this interaction may be related to the effect on glycoprotein R. The clinical significance of this interaction is insignificant.

    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 Trakley ® at a dose of 125 mg 2 times / day. and combinations 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 only one bosentan was used. The equilibrium concentration of bosentan in the blood plasma at day 9 was 5 times higher than when only bosentan was taken. Inhibition of isoenzyme by ritonavir CYP3A4 and the transport protein responsible for the transport of bosentan to hepatocytes, thereby reducing the clearance of bosentan, and probably in this way it is possible to explain the mechanism of this interaction. In patients receiving both tracler® and preparations containing lopinavir + ritonavir or other protease inhibitors of increased activity, it is necessary to control the tolerability of Trakley®.

    When combined with Traclyr® 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 suggested 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 in this group can not be given. Due to the pronounced toxic effect on the liver of nevirapine, which can also increase the adverse effect on the liver of bosentan, the combined use of this combination is not recommended.

    Special instructions:

    Function liver

    Increased activity ACT, ALT, associated with the use of the drug Traklir®, is dose-dependent. Changes in the activity of "liver" transaminases usually occur during the first 26 weeks of therapy, but may occur at a later date. The risk of liver dysfunction may also increase with the simultaneous use of medicines suppressing BSEP, such as rifampicin, glibenclamide and ciclosporin, although the data showing this is limited.

    It is necessary to control the activity of "liver" transaminases (ACT and ALT) before starting therapy with Trakley®, and then once a month during treatment.

    Recommendations in case of increased ALT / AST activity

    With ACT / ALT activity

    3-5 times higher than the upper limit of the norm (VGN):

    Recommendations for monitoring and treatment

    Conduct a re-determination of the activity of AST / ALT, with confirmation of increased activity of ACT and ALT, the daily dose of Trakley® should be reduced or the drug should be withdrawn; Control the activity of "liver" transaminases every 2 weeks.

    If the activity of the "liver" transaminases returned to the indicators observed before the start of therapy, the possibility of continuing or resuming the administration of Trakley® in the mode indicated below is evaluated.

    5-8 times higher than UGN

    Conduct a re-determination of the activity of AST / ALT, when confirming the increase in activity of ACT and ALT, the drug Traclear® should be discontinued; Control the activity of "liver" transaminases every 2 weeks.

    If the activity of the "liver" transaminases returned to the indices observed before the start of therapy, the possibility of resuming the administration of the drug Tractlir® in the mode indicated below is evaluated.

    8 and more times higher than UGN

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

    With associated clinical symptoms of liver damage, those. In case of nausea, vomiting, fever, abdominal pain, jaundice, increased fatigue and apathy, with flu-like symptoms (arthralgia, myalgia, fever), therapy with Trakley® should be discontinued and the use of Traclyr® should not be recommenced.

    Renewal of therapy

    Therapy with Traklir® can be resumed only if the expected therapeutic effect of therapy exceeds the potential risk of side effects, and if the activity of "hepatic" transaminases does not exceed the values ​​recorded before the beginning of treatment with Trakley®.It is recommended to consult a gastroenterologist, specializing in liver and bile duct disease. Therapy should be resumed following the recommendations in the instructions for use of the drug in the section "Method of administration and dose". The activity of "liver" transaminases should be checked 3 days after the resumption of therapy with Trakley®, then repeat the monitoring, following the recommendations of the doctor, and then return to the regular monitoring schedule.

    VGN - the upper limit of the norm

    Hemoglobin

    Therapy with Traclir® is associated with a dose-dependent decrease in hemoglobin. In placebo-controlled studies, the reduction of hemoglobin associated with the use of bosentan is not progressive, hemoglobin is stabilized after the first 4-12 weeks of therapy. It is recommended that this indicator be monitored before the beginning of therapy with Trakley®, at 1 and 3 months of therapy and thereafter - once in 3 months. If a clinically significant decrease in hemoglobin is observed, further examination of patients should be carried out in order to establish the reasons and the need for appropriate therapy.

    Therapy in women of reproductive age

    The use of Traklir® in women of reproductive age is possible only if before the start of treatment the absence of pregnancy is confirmed by a negative test and reliable methods of contraception are selected.

    Before beginning treatment with Tracler®, women of reproductive age should be examined to confirm that they are not pregnant and, on the recommendation of a gynecologist, they should use reliable contraceptive methods.

    It is necessary to inform patients that, due to pharmacokinetic interaction, the use of Trakley® can reduce the effectiveness of oral hormonal contraceptives. For this reason, women of reproductive age should not use the method of hormonal contraception, as the only; It is necessary to use an additional or alternative method of reliable contraception (oral, injectable and transdermal therapeutic systems (TTS), implantable intrauterine devices). You should consult a gynecologist for an individual selection of a reliable contraceptive.Given the decrease in the effectiveness of hormonal contraception, and the possible negative impact of pregnancy on the course of PAH, during therapy with Trakley® it is recommended that a pregnancy test be performed once a month for the earliest possible pregnancy diagnosis.

    Possible effect on spermatogenesis in adults

    In the study AC-052-402, the influence on the spermatogenesis of Traclyr® was studied at a dose of 62.5 mg twice a day for 4 weeks, and then 125 mg per day for 5 months. The study included 25 adult men with PAH III and IV FC with initially unchanged spermogram; Analyzed data from 23 patients were analyzed, two patients were excluded due to side effects not related to the change in spermatogenesis. In the majority of patients (n = 22) after 6 months of treatment, the total amount of semen was observed within the limits of normal values, no changes in morphology, motility of spermatozoa, changes in hormonal status. Only one patient in the spermogram had signs of oligospermia after 3 months of treatment with Trakley®, the total amount of sperm remained lower in the two subsequent analyzes for the next 6 weeks.Two months after the drug was discontinued, Trakley® the total amount of sperm in this patient returned to baseline before the study. The significance of the described observation is not determined, especially considering the high interindividual variability of the total amount of sperm in patients. Nevertheless, the obtained data do not allow to exclude the possibility of the effect of antagonists of endothelin receptors, to which the preparation Traklir® belongs, on spermatogenesis in men, and the absence of a systematic effect with prolonged use does not contradict the results of toxicological studies of the preparation.

    Venousocclusion disease of the lungs

    It should be taken into account the possibility of concomitant veno-occlusive disease, if signs of pulmonary edema appear in patients with PAH in the presence of Trakley®.

    Fluid retention and deterioration of flow LAS

    Peripheral edema is one of the clinical symptoms of PAH, while at the same time, with the use of endothelin receptor antagonists, worsening of PAH is often observed. In 20 placebo-controlled studies conducted according to indications of PAH and digital ulcers, peripheral edema and fluid retention in the body were noted in 13.2% of patients receiving bosentan and 10.9% had a placebo.

    In addition, in the postmarketing period, numerous reports of fluid retention in the body were obtained in patients during the first weeks of use of Trakley®. In this regard, patients are prescribed diuretics, monitor fluid intake and diuresis, and with worsening of heart failure, hospitalization is necessary. If there is a clinically significant fluid retention in the body, regardless of whether it is accompanied by an increase in body weight or not, a check should be conducted to clarify the cause of fluid retention in the body (use of Trakley® or heart failure) and assess the need for continued treatment with Trakley® or its cancellation.

    LAS associated with HIV infection

    Data on the use of Trakley® in HIV-infected patients receiving antiretroviral therapy are limited.

    The results of studying the interaction in the joint application of bosentan and combination lopinavir + ritonavir in healthy volunteers showed that the concentration of bosentan increases, reaching the maximum values ​​within 4 days.It is necessary to control the tolerability of therapy with Trakley® in patients receiving ritonavir in combination with protease inhibitors of increased activity, especially at the beginning of treatment, since it is possible to lower blood pressure, as well as a change in the activity of liver transaminases. With long-term combined use of Trakley® and antiretroviral drugs, an increased risk of adverse effects on liver function and clinical blood counts may be possible. In view of the possible interaction associated with the induction of bosentan isoenzymes of cytochrome P450 (CYP), the activity of antiretroviral therapy may decrease, in such patients, the effectiveness of HIV therapy must be carefully monitored.

    PAH as a result of severe chronic obstructive pulmonary disease

    The efficacy and safety of the use of bosentan was studied in a 12-week search trial involving 11 patients with secondary PAH as a result of severe COPD (stage 3 according to the international classification of GOLD (Global Initiative for 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 side effects, dyspnoea is most often noted, the severity of which decreased with the cancellation of bosentan.

    Simultaneous use with other medicinal products

    Glibenclamide: It is not recommended simultaneous use of Trakley® and glibenclamide in connection with the risk of increased activity of "liver" transaminases. For the treatment of diabetes in patients using the drug Trakley®, other hypoglycemic agents should be used for ingestion or insulin injection.

    Fluconazole: The simultaneous use of fluconazole and Traclyr® is not recommended. Combined treatment was not studied, but with simultaneous use, a significant increase in the concentration of bosentan in blood plasma is possible.

    Rifampicin: the simultaneous use of Trakley® and rifampicin is not recommended.

    The use of the combination of Trakley® and inhibitors of the CYP3A4 and CYP2C9 isoenzymes should be avoided.

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

    The effect of Traklir® on the ability to drive vehicles and engage in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions has not been studied, but given that Tractlir® can cause dizziness,Care should be taken when carrying out such activities.

    Form release / dosage:

    Film-coated tablets, 62.5 mg and 125 mg.

    Packaging:

    For 14 tablets in a blister of PVC / PE / PVDC film / and aluminum foil.

    For 4 blisters in a cardboard pack together with instructions for use.

    Storage conditions:

    At a temperature of no higher than 30 ° C.

    Keep out of the reach of children.

    Shelf life:

    5 years.

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

    Terms of leave from pharmacies:On prescription
    Registration number:LS-002509
    Date of registration:27.07.2011
    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: & nbsp29.11.2015
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