Index of drugs

Treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and alleviate symptoms in patients with class III functional disturbances according to the WHO classification. Effectiveness was demonstrated in the following diseases: primary (idiopathic and hereditary) arterial pulmonary hypertension; pulmonary arterial hypertension resulting from systemic sclerosis without significant pulmonary changes; pulmonary arterial hypertension with congenital left to right leel and Eisenmenger syndrome. There was also some improvement in patients with functional class II WHO according to WHO classification. The drug is also indicated in reducing the number of new ulcers on the fingertips of patients with systemic sclerosis and current digital ulcers.

1 tabl powl. contains 125 mg bosentan (as a monohydrate).

Bosentan is a dual endothelin receptor (ERA) antagonist with affinity for type A and B receptors (ET_AND and ET_B). Competing for binding to ET receptors_AND, ET_B with endothelin 1 (ET-1), which is one of the most potent vasoconstrictors and may also promote fibrosis, cell proliferation, cardiac hypertrophy, remodeling and has proinflammatory effects. Bosentan selectively blocks ET receptors and does not bind to other receptors. It reduces vascular resistance both pulmonary and systemic, resulting in increased cardiac output without increasing heart rate. The total bioavailability of bosentan is about 50% and does not change in the presence of food. C_max is achieved within 3-5 h. After repeated administration, the concentration of bosentan in the blood decreases gradually to 50% -65% of the concentration observed after single dose administration, which is probably due to autoinduction of metabolizing enzymes. The stationary state is reached within 3-5 days. Bosentan> 98% bound to plasma proteins. It is metabolized in the liver with the participation of CYP2C9 and CYP3A4 (one metabolite has pharmacological activity) and excreted mainly in the bile. T_0,5 in the final phase of elimination is 5.4 hours.

Hypersensitivity to the active substance or to any of the excipients. Moderate and severe hepatic impairment (Child-Pugh B or C). Initial values ​​of hepatic transaminases (AST and / or ALT)> 3-fold upper limit of normal (ULN). Co-administration of ciclosporin A. Pregnancy. Women of childbearing potential not using effective methods of contraception.

The efficacy of the preparation has not been established in patients with severe pulmonary hypertension. In the event of clinical deterioration, a switch to treatment that is recommended in the advanced stage of the disease (eg epoprostenol) should be considered. The benefit-risk ratio for bosentan in patients with class I pulmonary hypertension in class I WHO functional disorders has not been established. Treatment with the product can only be started if the systemic systolic blood pressure is> 85 mmHg. The beneficial effect of the preparation on the healing of existing ulcers on the fingertips has not been demonstrated. Treatment with bosentan is associated with a dose-dependent increase in liver transaminases. The aminotransferase activity should be determined before starting treatment and monthly intervals during treatment. In addition, aminotransferase levels should be measured at 2 weeks after each dose increase. If the ALT and AST> 3 and ≤5 x ULN are increased, the result should be confirmed by repeating the test; if confirmed, a decision should be made on a case-by-case basis for each patient to continue the use of the preparation (optionally at a reduced dose) or discontinue treatment; monitoring of aminotransferase levels should be continued at least every 2 weeks; if aminotransferase levels return to pre-treatment values, treatment should be considered or restarted with bosentan.If ALT and AST are> 5 and ≤8 x ULN, this should be confirmed by repeating the test; if confirmed, treatment should be discontinued and aminotransferase levels monitored at least every 2 weeks; if aminotransferase levels return to pre-treatment values, re-initiation of bosentan should be considered. If ALT and AST> 8 x ULN are increased, treatment should be discontinued; you should not consider restarting treatment with bosentan. In the case of clinical signs of liver damage, i.e. nausea, vomiting, fever, abdominal pain, jaundice, unusual drowsiness or fatigue, flu-like symptoms, treatment should be discontinued and re-start of treatment with bosentan should not be considered. The reintroduction of bosentan should only be considered if the potential benefits of treatment with the product outweigh the potential risks and aminotransferase levels are within pre-treatment values. A consultation with a hepatologist is recommended. The aminotransferase levels should be checked within 3 days of starting treatment again, then again after a further 2 weeks, and then as described above. The risk of liver dysfunction may also be increased when bosentan is used as a bile acid inhibitor (eg rifampicin, glibenclamide, cyclosporin A). Treatment with bosentan is associated with a dose-related decrease in hemoglobin. Hemoglobin levels should be monitored before starting treatment, monthly during the first 4 months of treatment, and then once a quarter. If there is a clinically significant reduction in hemoglobin concentration, further evaluation and testing should be performed to determine the cause and need for specialist treatment. If symptoms of pulmonary edema occur when using bosentan in patients with pulmonary arterial hypertension, the possibility of a related veno-mitochondral disease should be considered. Specific tests have not been performed in patients with pulmonary hypertension with concomitant left ventricular dysfunction. It is recommended to monitor patients for symptoms of fluid retention (eg weight gain, edema), especially if they have severe systolic failure at the same time. If the symptoms described above occur, it is recommended to start treatment with diuretics or to increase the dose of diuretics used. Treatment with diuretics should be considered in patients with symptoms of fluid retention in the body before treatment with bosentan. There is limited experience in the use of bosentan in patients with pulmonary hypertension associated with HIV infection treated with antiretroviral agents. When initiating treatment with bosentan in patients requiring ritonavir-boosted protease inhibitors, bosentan tolerance (especially at the onset of the initial phase) should be closely monitored to detect hypotension, and liver function tests should be performed; an increased long-term risk of hepatotoxicity and haematological adverse reactions of bosentan and antiretroviral therapies and the risk of interactions that could affect the efficacy of antiretroviral treatment (CYP induction by bosentan) can not be excluded; you should monitor the course of HIV infection. In patients with pulmonary hypertension occurring in the course of chronic obstructive pulmonary disease (COPD) an increase in minute ventilation and a decrease in oxygen saturation were observed; the most common side effect was dyspnoea, which resolved after discontinuation of bosentan.

The drug is contraindicated in pregnancy (in animals, it is teratogenic and embryotoxic). Before starting treatment in women of childbearing potential, pregnancy should be ruled out (a negative pregnancy test performed prior to treatment) and effective contraception should be implemented. Due to potential pharmacokinetic interactions, bosentan may result in the ineffectiveness of hormonal contraceptives, therefore women of childbearing potential must not be used as the only method of contraception, hormonal contraception (including oral agents, injectable, transdermal patches or implants), but they must use an additional or alternative effective method of contraception.During the treatment with bosentan, a monthly pregnancy test is recommended for early detection of pregnancy. It is not known whether bosentan is excreted in human milk - breast-feeding is not recommended during treatment.

Very common: headache, abnormal liver function tests, edema, fluid retention in the body. Common: anemia, decreased hemoglobin, hypersensitivity reactions (including dermatitis, pruritus and rash), fainting, palpitations, flushing (especially of the face), hypotension, gastroesophageal reflux disease, diarrhea, erythema. Uncommon: thrombocytopenia, neutropenia, leukopenia, elevated aminotransferases associated with hepatitis and / or jaundice. Rare: anaphylaxis and / or angioedema, hepatic cirrhosis, liver failure. Not known: anemia or a reduction in hemoglobin that requires red blood cell transfusion. In the post-marketing setting, (rarely) pulmonary edema has been reported in patients receiving bosentans suspected of obliterating fine venous lungs.

Orally.Pulmonary arterial hypertension (PAH). Adults: initially 62.5 mg 2 times a day for 4 weeks, then increase the dose to a maintenance dose of 125 mg 2 times a day. The same recommendation applies to the resumption of treatment with the preparation.Children and youth: the initial and maintenance dose in children ≥ 2 years is 2 mg / kg. 2 times a day. Studies on comparing the efficacy and safety of 2 mg / kg have not been performed. and 4 mg / kg 2 times a day in children. Clinical experience in children <2 years of age is limited.Proceedings in cases of clinical deterioration of PAH. If TNP deteriorates (eg shortening the distance traveled during a 6-minute walk test by at least 10% compared to the measurement made before treatment) despite administration of bosentan for at least 8 weeks (target dose for at least 4 weeks), alternative treatment options should be considered. However, some patients who have not responded after 8 weeks of treatment with the product may respond positively only after an additional 4-8 weeks of treatment. In case of late clinical worsening, despite treatment with bosentan (eg after several months of treatment), the treatment should be re-assessed. In some patients who do not respond to a 125 mg dose twice a day, exercise capacity may be improved slightly when the dose is increased to 250 mg 2 times a day. The benefit / risk ratio should be carefully assessed, considering that hepatic toxicity is dose-dependent.Discontinuation of treatment. There is limited experience with the abrupt discontinuation of bosentan in patients with PAH. There were no signs of acute relapse of the disease, however, a gradual dose reduction (dose reduction by half for 3-7 days) should be considered. During the withdrawal period, more intensive monitoring of the patient is recommended. At the same time, another treatment for PAH should be introduced.Systemic sclerosis with present finger ulcers. Adults: initially 62.5 mg 2 times a day for 4 weeks, then increased to a maintenance dose of 125 mg 2 times a day. The same recommendation applies to the resumption of treatment with the preparation. The experience of a controlled clinical trial in this indication is limited to a period of 6 months. The patient's response to treatment and the need for further treatment should be regularly evaluated.Children and youth: no data on the efficacy and safety of bosentan in patients <18 years of age in this indication.Special groups of patients. In the elderly, in patients with impaired renal function, including those undergoing hemodialysis and in patients with mild hepatic impairment (A according to Child-Pugh) no dose adjustment is necessary. Do not use in patients with moderate or severe hepatic impairment.Way of giving. The tablets should be taken in the morning and evening, with or without food, with water.