Bozeneks - instructions for use, dose, side effects, contraindications

Active substanceBoszentanBoszentan

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Dosage form: & nbspfilm-coated tablets

Composition:

1 tablet, film-coated, contains:

Dosage of 62.5 mg.

Active substance: bosentan monohydrate 64.541 mg (in terms of bosentan 62.500 mg).

Excipients: corn starch, carboxymethyl starch sodium, pregelatinized starch, glyceryl dibehenate, povidone-K90, magnesium stearate. Film Sheath: Opaprai pink [hypromellose, titanium dioxide (E171), talc, ethyl cellulose, triacetin, iron oxide, yellow oxide (E172), iron oxide red (E172).

Dosage of 125 mg.

Active substance: bosentan monohydrate 129.082 mg (in terms of bosentan 125,000 mg).

Excipients: corn starch, sodium carboxymethyl starch, pregelatinized starch, glyceryl dibehenate, povidone-K90, magnesium stearate. Film Sheath: Opaprai pink [hypromellose, titanium dioxide (E171), talc, ethyl cellulose, triacetin, iron oxide, yellow oxide (E172), iron oxide red (E172).

Description:

Round biconvex tablets, covered with a film coating of pink color.On the cross-section the nucleus is white or almost white, a yellowish tint is permissible.

Pharmacotherapeutic group:Vasodilator

ATX: & nbsp

C.02.K.X Other antihypertensive drugs

Pharmacodynamics:

Bozanthan is a non-selective antagonist of endothelin receptors such as ET_A and ET. Boszentan reduces both pulmonary and systemic vascular resistance, leading to an increase in cardiac output without an increase in 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 anti-inflammatory activity. These effects are induced by binding of endothelin-1 (ET-1) to ET receptors_A and ETs located in the endothelium and cells of the smooth muscles of the vessels. The concentrations of ET-1 in tissues and blood plasma are increased in certain cardiovascular diseases and connective tissue diseases, including pulmonary arterial hypertension (PAH), scleroderma, acute and chronic heart failure,myocardial ischemia, systemic hypertension and atherosclerosis, which implies the involvement 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.

Bosentan competes with ET-1 and other ET peptides for binding to ET_A and ETB, with a slightly higher affinity for the ET receptors_A (Ki = 4.1 - 43 nmol) in comparison with the ETB receptors (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 (WHO) bosentan in combination with anticoagulants, vasodilators (calcium channel blockers), diuretics, oxygen and digoxin, but not epoprostenol, was accompanied by a decrease in the severity of symptoms of PAH and a significant increase in exercise tolerance (according to the World Health Organization (WHO)). results of the test with a 6-minute walk). 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 condition of patients was monitored on average for 0.2 ± 0.6 years. In the majority of patients, the diagnosis of primary PAH (72%) was confirmed and the FC III (84%) was classified as WHO. 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.

Study of effectiveness 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 indicators 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) up to 8 mm Hg. Art. and pulmonary vascular resistance (LSS) - up to 389 dyne-s / cm⁵.

Systemic scleroderma with ulcerative lesions of the extremities. The results of two clinical studies in adult patients with systemic scleroderma and ulcerative lesions of the extremities (at the stage of exacerbation or in cases where ulcerative lesions were noted during the last year) showed that during the whole period of bosentan administration a significant decrease in the number of new ulcerative lesions of the limbs was 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:

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 (iv) administration of bosentan, the volume of its distribution (V_d) 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 plasma concentration (C_m_Oh) and AUC (the area under the concentration-time curve) is disproportionate to the dose taken and is achieved at a lower rate.

Suction. Absolute bioavailability of bosentan, in healthy volunteers after ingestion, is about 50%, food intake does not affect bioavailability. FROM_m_Oh in blood plasma is achieved 3-5 hours after taking the drug inside.

Distribution. Boszentan in a 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 administration of IV in a dose of 250 mg V_d is 18 liters.

Metabolism and excretion. After a single IV administration at a dose of 250 mg, the clearance is 8.2 l / h. The half-life (T_1/2) -5.4h. 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. Boszentan 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 the inducer of isoenzymes CYP2C9 and CYP3A4, and, possibly, isoenzyme CYP2C19 and P-glycoprotein. In vitro bosentan suppresses activity BSEP (Bile Salt Export Pump, a pump for removing 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, the metabolism of which is mediated by these isoenzymes.

Pharmacokinetics in special patient groups

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

Children older than 2 years. Pharmacokinetic parameters for single and repeated use of bosentan in the drug form of the film-coated tablet 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 a day in doses of 31.25 mg, 62.5 mg and 125 mg were 3.496 ng / hr (49%), 5.428 ng / hr (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.

Violation of the function of the liver. In patients with mild violations of liver function (class A in the Child-Pugh classification), no significant changes in the pharmacokinetics of bosentan were observed. 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 hepatic impairment (Child-Pugh class B) 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 PAH patients with preserved renal function.

The pharmacokinetics of bosentan in patients with severe hepatic impairment (Child-Pugh class C) has not been studied.It is recommended to avoid the use of Bozenex ® in patients with moderate and severe liver function disorders (Child-Pugh class B and C).

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 physicochemical 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) 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, in particular, with violations of hemodynamic parameters according to 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;

- violation of liver function of moderate and severe severity (class B and C according to the Child-Pugh classification);

- initial 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);

- simultaneous application with cyclosporin A;

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

- pregnancy;

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

- the period of breastfeeding;

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

- children's age up to 3 years (solid dosage form);

- It is not recommended simultaneous use of the drug with glibenclamide, fluconazole, rifampicin, potent inhibitors of isoenzymes CYP3A4 and CYP2C9 (see the sections "Interaction with other medicinal products" and "Special instructions").

Carefully:

Arterial hypotension; chronic obstructive pulmonary disease (COPD); mild violations of liver function (Class A Child-Pugh classification); with PAH I FC (insufficient clinical data on efficacy and safety of use); concomitant left ventricular failure.

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 bosentan during pregnancy has not been studied. The use of Bozeneks® during pregnancy is contraindicated.

Use in women with preserved reproductive potential. Before starting treatment with Bozeneks®, women who have a reproductive potential should confirm the absence of pregnancy, doctors are required to give recommendations for the prevention of pregnancy, and patients should start using reliable contraceptive methods. Patients and physicians who prescribe the treatment should take into account that due to pharmacokinetic interaction, the Bozenex® preparation may reduce the effectiveness of hormonal contraceptives. For this reason, women with preserved reproductive potential 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 decline in efficiency hormonal contraception and the possible negative effect of pregnancy on the course of PAH, during therapy with Bozeneks® it is recommended that a pregnancy test be performed 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 in breast milk. During the treatment with Bozeneks®, breastfeeding should be discontinued.

Fertility. In preclinical studies, the effect on the testes was revealed. 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:

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 PAH in order to improve exercise tolerance and clinical symptoms the patients II-IV FC on WHO classification

Application in adults

The initial dose of Bozeneks® is 62.5 mg twice a day for 4 weeks, then the dose is increased to 125 mg twice a day.

Therapy in the case of clinical worsening of PAH. Consideration should be given to the possibility of using alternative therapies in case of clinical impairment (for example, if the distance from the 6-minute walk test is reduced by at least 10% compared to baseline), despite the use of Bozeneks® for at least 8 weeks (of them in the recommended dose - at least 4 weeks). However, in some patients with Bosezenks ineffective after 8 weeks of use, a positive effect can be observed after an additional 4-8 weeks of treatment. If clinical deterioration occurs after several months of treatment with Bozeneks®, the advisability of its further application should be evaluated anew. An increase in the dose of BOSENEX ® 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 Bozeneks® drug on its dose.

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

Reduction of new digital ulcers the 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 Bozeneks ® 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 also be followed when the BOSENEX® is resumed after a break in treatment.The clinical experience of using bosentan preparations for this indication does not exceed 6 months. It is necessary to regularly evaluate the effectiveness of therapy and the need for its continuation. An appropriate analysis of the relationship between the benefits of therapy and the potential risk of adverse reactions should be carried out, taking into account the hepatotoxicity of bosentan.

Use in children. Data on the effectiveness and safety of the use of bosentan preparations for this indication in patients younger than 18 years are absent.

Use in special patient groups

Violation of the function of the liver. Patients with mild violations of liver function (class A according to the Child-Pugh classification) do not need a dose adjustment. The use of BOSENEX ® in patients with moderate or severe hepatic insufficiency should be avoided (Child-Pugh class B and C).

Impaired renal function. In patients with impaired renal function, dose adjustment is not required. Patients on hemodialysis do not need a dose adjustment.

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

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 patients with a low body weight (less than 40 kg), Bozeneks® is used in doses, based on the calculation of the child's body weight / patient.

Macca bodies	Initial dose (4 weeks)	Maintenance 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

Data on the use of the drug in patients with a body weight of up to 40 kg are limited. To select a dose for such patients, please use the information given in the table of dosing 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 0.5% of patients receiving placebo), headache (11.5% vs. 9.8%), lower limb edema and / or fluid retention (13.2% vs. 10.9%), increased activity of "liver" transaminases ACT and / or 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 frequency of occurrence, 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); frequency is unknown (can not be estimated from available data). Adverse reactions reported at the post-marketing phase of the drug are included with the frequency of occurrence reported in 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
On the part of the blood and lymphatic system	often	anemia, decreased hemoglobin
	frequency unknown	anemia or a decrease in hemoglobin, when it is necessary to carry out blood transfusion
	infrequently	thrombocytopenia, neutropenia, leukopenia
From the immune system	often	reactions of hypersensitivity (including dermatitis, pruritus, skin rash)¹
From the immune system	rarely	anaphylactic reactions and / or angioedema
From the nervous system	Often	headache²
From the nervous system	often	fainting³
From the side of the cardiovascular system	often	heart palpitations³, "tides" of blood to the skin of the face, BP reduction³
From the gastrointestinal tract	often	gastroesophageal reflux disease, diarrhea
Disturbance of the liver and bile ducts	Often	change in liver function
	infrequently	increased activity of "liver" transaminases (ACT, ALT) due to hepatitis (including possible exacerbation of existing hepatitis) and / or jaundice
	rarely	cirrhosis of the liver, hepatic impairment
From the skin and subcutaneous tissues	often	erythema
On the part of the respiratory system, the organs of the thorax and the mediastinum	often	swelling of the nasal mucosa
General disorders and disorders at the site of administration	Often	peripheral edema, fluid retention⁴

¹The sensitivity reaction was noted in 9.9% of patients who received bosentan, and 9.1% had a placebo.

²Headache was noted by 11.5% of patients who received bosentan and 9.8% - placebo.

³ These reactions can be due to the underlying disease.

⁴ 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 bosentan in patients with severe

concomitant diseases, simultaneously using numerous 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 the Bozeneks® drug.

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

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

Change in laboratory indicators

Change in the activity of "liver" transaminases. In the clinical program, a dose-dependent increase in the activity of "liver" transaminases was observed during 26 weeks of treatment, developed gradually, as a rule, asymptomatically. In the postmarketing period, reports were received of rare cases of development in patients with cirrhosis of the liver and insufficiency of liver function. The mechanism of occurrence of the above-mentioned adverse reactions is unclear. The activity of "hepatic" transaminases can spontaneously decrease with the continuation of treatment without changing the dose of Bozeneks® or after its reduction, nevertheless, discontinuation of treatment or a short-term interruption in therapy may still be required.

In 20 studies, an increase in the activity of "liver" transaminases was observed 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 y 0.4 % - 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. A decrease in hemoglobin below 1 g / l from the baseline was observed in 8% 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 pulmonary arterial hypertension. 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 was registered after taking 10,000 mg, which resulted in nausea, vomiting, marked decrease in blood pressure, dizziness, increased sweating, impaired clearness of visual perception.The condition was completely normalized within 24 hours, while a pronounced decrease in blood pressure was corrected. Boszentan not removed during hemodialysis.

Interaction:

Bosanzan undergoes metabolism with the participation of cytochrome SUS 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 bosentan and potent inhibitors of isoenzyme CYP3A4 (eg, ketoconazole, itraconazole or ritonavir) and an isoenzyme inhibitor CYP2C9 (eg, voriconazole). Boszentan is the inducer of isoenzymes CYP2C9 and CYP3A4. According to research in vitro It is also assumed that the role of the isoenzyme inducer CYP2C19. Therefore, with the simultaneous use of the drug Bozeneks® and drugs, the metabolism of which is mediated by these isoenzymes, their concentration in the blood plasma is reduced. One should consider the possibility of reducing the effectiveness of drugs that are metabolized with the same isoenzymes. It may be necessary to adjust the dose of concomitant medications once BOSENEX® is taken, the dose is changed, or if it is withdrawn.

Cyclosporine: simultaneous use of the drug Bozeneks® 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 (C_ss) 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 intake bosentan in hepatocytes. The concentration of cyclosporine in the blood plasma at the same time decreases by almost 50%.

Tacrolimus, sirolimus: simultaneous use with bosentan in clinical studies has not been studied, but it is assumed that the concentration of bosentan in the blood plasma can increase by analogy with cyclosporine. The concentration in blood plasma of tacrolimus and sirolimus can decrease with joint application with bosentan. In this regard, the Bozeneks® preparation 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 bosentan in a dose of 125 mg twice a day for 5 days, the concentration of glibenclamide (substrate 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 the above, Bozenex® should not be used simultaneously with glibenclamide. There is no data on the possible drug interaction with other sulfonylurea derivatives.

Hormonal contraceptives: while simultaneous use of bosentan in a dose of 125 mg twice a day for 7 days and an oral contraceptive for a single dose, a combined preparation containing 1 mg of norethisterone and 35 μg of ethinyl estradiol, there was a decrease AUC for its components 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 (inward, injection, transdermal, or implant) during the administration of the Bozeneks® preparation.

Warfarin: when used simultaneously in healthy volunteers with bosentan at a dose of 500 mg twice a day for 6 days, the concentration decreases S-varfarin (substrate isoenzyme CYP2C9) and R-varfarin (substrate isoenzyme CYP3A4) in blood plasma by 29% and 38%, respectively.The simultaneous use of bosentan and warfarin in patients with PAH was not accompanied by significant clinical changes in the International Normalized Relationship (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 BOSENEX® therapy. However, obligatory control of INR is recommended, especially at the beginning of BOSENEX® application and at the stages of dose increase.

Simvastatin: with the simultaneous use within 5 days of bosentan in a dose of 125 mg 2 times a day, the concentration of simvastatin decreases (substrate isoenzyme CYP3A4) and its active form β-hydroxy acids 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 Bozeneks ® 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 bosentan in a dose of 62.5 mg 2 times a day and ketoconazole, a potent inhibitor of isoenzyme CYP3A4, is accompanied by a twofold increase in the concentration of bosentan in the blood plasma. Correction of the dose of Bozeneks® is not performed.

An increase in the concentration of bosentan in blood plasma is also contemplated with the simultaneous use of itraconazole and ritonavir, despite the lack of confirmation in 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: while simultaneous use in healthy volunteers for 7 days bosentan in a dose of 125 mg 2 times a 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%. Because of this, a significant reduction in the effect of the Bozeneks® preparation when combined with rifampicin is possible. Data on the combined use with other isoenzyme inducers CYP3A4, such as carbamazepine, phenobarbital, phenytoin, as well as preparations containing St. John's wort, is not enough, nevertheless, with a high probability of their joint application, one can not exclude a significant decrease in the effectiveness of treatment with Bozenex®.

Epoprostenol: limited research results (AC-052-356 [BREATH-3]), during which 10 children received bosentan in combination with epoprostenol, indicate that after a single and repeated intake of these drugs C_m_Oh bosentan in blood plasma and AUC were approximately the same in patients who received and did not receive infusion of epoprostenol.

Sildenafil: with the simultaneous use of bosentan in a dose of 125 mg twice a day (equilibrium) and sildenafil at a dose of 80 mg 3 times a day for 6 days in healthy volunteers, there was a decrease AUC sildenafil by 63% and increased AUC bosentan - by 50%. Changes in the concentrations of substances in the plasma are not clinically relevant, dosage adjustment is not required.

Digoxin, nimodipine, losartan: simultaneous use of bosentan in a dose of 500 mg 2 times a day for 7 days is accompanied by a decrease in the concentration of digoxin in the blood plasma AUC, FROM_m_Oh and a minimum initial concentration (C_min) 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): while simultaneous use of bosentan in a dose of 125 mg twice a day and combinations lopinavir + ritonavir 400 + 100 mg twice daily for 9.5 days in healthy volunteers C_min bosentan in blood plasma was approximately 48 times higher than the concentration when only bosentan was used. C_ss bosentan in the blood plasma on the 9th day was 5 times higher than when taking only bosentan. 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 BOSENEX® simultaneously and preparations containing a combination lopinavir + ritonavir or other protease inhibitors of increased activity, it is necessary to control the tolerability of the Bozenex® preparation.When combined with bosentan for 9.5 days, the concentrations of lopinavir and ritonavir decrease 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 of this group can not be given. In connection with the pronounced toxic effect on the liver of nevirapine, which can also enhance the adverse effects of bosentan on the liver, the combined use of this combination is not recommended.

Special instructions:

In patients with severe PAH, the effectiveness of bosentan preparations has not been established. If the patient's clinical condition worsens, it is advisable to consider the appointment of other drugs recommended for a serious stage of the disease (for example, epoprostenol) (see the "Method of administration and dose" section). The ratio of benefit and risk of using bosentan in patients with PAH I FCWHO classification. The drug Bozeneks ® can be prescribed only if the systolic blood pressure is not higher than 85 mm Hg. Art. The ability of bosentan preparations to influence the healing of already existing digital ulcers has not been established.

Function of the liver. Increased activity ACT, ALT in connection with the reception of bosentan 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 impaired liver function may also increase with the simultaneous administration of BOSENEX® medications with bosentan, suppressive drugs 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 Bozeneks®, and then once a month during the treatment period.

Recommendations in case of increased ALT / AST activity

When the activity of LST / ALT is 3-5 times higher than VGN: to re-determine the activity of AST / ALT, with confirmation of an increase in activity ACT and ALT should reduce the daily dose or abolish the drug Bozeneks®; 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 the therapy, the possibility of continuing or resuming the administration of the Bozeneks® preparation in the mode indicated below is evaluated.

When ACT / ALT activity is 5-8 times higher than IGN: to re-determine the activity of AST / ALT, with confirmation of an increase in activity ACT and ALT should be discontinued with Bozenex®; 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 Bozeneks® preparation in the mode indicated below is evaluated.

When the activity of LST / LLT is 8 or more times higher than VGN: The therapy should be discontinued, the resumption of BOSENEX® treatment is excluded.

With associated clinical symptoms of liver damage, that is, in the case of nausea, vomiting, fever, abdominal pain, jaundice, increased fatigue and apathy, with flu-like symptoms (arthralgia, myalgia, fever) BOSENEX® therapy should be discontinued, and the recommencement of BOSENEX® is not recommended.

Renewal of therapy

Therapy with Bozenex ® can be resumed only if the expected therapeutic effect of therapy exceeds the potential risk of developing adverse events and the activity of "hepatic" transaminases does not exceed the values recorded before the start of treatment with Bozeneks®. It is recommended to consult with 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". Activity of "liver" transaminases should be checked 3 days after the resumption of therapy with Bozeneks®, then repeat the control, following the recommendations of the doctor, and then return to the regular monitoring schedule.

Hemoglobin. Therapy with bosentan 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 start of therapy with Bozeneks®, at 1 and 3 months of therapy, and then 1 time in 3 months. If a clinically significant decrease in hemoglobin is observed, further examination should be conducted to establish the reasons for and the need for appropriate therapy.

Therapy in women with preserved reproductive potential. Since the effectiveness of hormonal contraceptives can decrease with the use of Bozeneks®, and pregnancy contributes to worsening of the course of PAH, and taking into account the data on the teratogenic effect found in animals:

- Bozeneks ® can be prescribed to women with preserved reproductive potential ONLY against the background of applying reliable contraceptive methods and in case of negative pregnancy test result before treatment;

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

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

Possible effects on spermatogenesis in adults. In the study AC-052-402, the effect on spermatogenesis of bosentan 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 most patients (n = 22) after 6 months of treatment, the total amount of sperm was observed within the limits of normal values, no changes in morphology, sperm motility, changes in hormonal status were established. Only one patient in the spermogram had signs of oligospermia after 3 months of bosentan treatment, the total amount of sperm remained lower in the two subsequent analyzes for the next 6 weeks. Two months after the cancellation of bosentan, 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. THowever, the obtained data do not allow to exclude the possibility of the effect of antagonists of endothelin receptors, to which the preparation Bosenex®, relates, on spermatogenesis in men, and the absence of a systematic effect with prolonged use does not contradict the results of toxicological studies of bosentan.

Venous-occlusive disease of the lungs. Consider the possibility of concomitant veno-occlusive disease, if signs of pulmonary edema appear in patients with PAH when taking Bozenex®.

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. In this study, there was an increase in hospitalization 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.Rapid weight gain, decreased hemoglobin, and increased edema of the lower extremities may be symptoms of fluid retention in the organism. 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 Bozeneks®.

Fluid retention and deterioration of PAH. 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 in patients during the first weeks of using bosentan were received. 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 pronounced fluid retention in the body, whether it is accompanied by an increase in body weight or not, a check should be conducted to clarify the cause of fluid retention (BOSENEX® or heart failure) and assess the need for continued BOSENEX® or its cancellation.

LAS associated with HIV infection. Data on the use of bosentan 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.

The control of the tolerability of BOSENEX® therapy 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 joint use of the drug Bozeneks® and antiretroviral drugs, there may be an increased risk of adverse effects on liver function and clinical blood count. In view of the possible interaction associated with the induction of bosentan isoenzymes of cytochrome P450 (RLS), the activity of antiretroviral therapy may decrease, in such patients, the effectiveness of HIV therapy must be carefully monitored.

LAS as a result of COPD. 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 GOLD (Global Initiative on 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 most often noted shortness of breath,the severity of which decreased with the cancellation of bosentan.

Simultaneous use with other medicinal products

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

Fluconazole: simultaneous use of fluconazole and BOSENEX ® 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: simultaneous use of Bozeneks® and rifampicin is not recommended.

Use of the combination of Bozenex® and isozyme inhibitors CYP3A4 and CYP2C9 should be avoided.

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

The effect of Bozeneks® on the ability to drive and engage in other potentially dangerous activities that require increased concentration and speed of psychomotor reactions has not been studied, but,that Bozenex® can cause dizziness, care must be taken when performing such activities.

Form release / dosage:

Tablets, film-coated, 62.5 mg and 125 mg.

Packaging:

For 14 tablets in a contoured cell pack of PVC / PE / PVDC film of white color and aluminum foil.

Four contour packs with instructions for use in a pack of cardboard.

Storage conditions:In dry, dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:2 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004208

Date of registration:21.03.2017

Expiration Date:21.03.2022

The owner of the registration certificate:FarmSirma Soteks, ZAO FarmSirma Soteks, ZAO Russia

Manufacturer: & nbsp

Research Institute of Chemical Diversity, JSC Russia

Information update date: & nbsp17.04.2017

Illustrated instructions

Instructions

Bozenex® (Bozenex)