Overview
Farm action
Non-selective antagonist of endothelin receptors such as ETA and ETB. Endothelin 1 (ET1) is a powerful vasoconstrictor that, when bound to the Bosentan and ETB receptors located in the endothelium and smooth muscle cells of blood vessels, induces fibrosis, cell proliferation, hypertrophy and myocardial remodeling, and exhibits pro-inflammatory activity. The concentration of ET1 in tissues and blood plasma increases with some cardiovascular diseases and pathology of connective tissue, including with pulmonary arterial hypertension, scleroderma, acute and chronic heart failure, myocardial ischemia, systemic arterial hypertension and atherosclerosis. Bozentan competitively blocks ET1 receptors and does not bind to other receptors, reduces the resistance of systemic and pulmonary vessels, which leads to an increase in cardiac output without increasing heart rate.
Pharmacokinetics
When ingested at a dose of up to 500 mg, an increase in Cmax and AUC occurs in proportion to the dose, with a higher dose, it is disproportionate and slower. Oral bioavailability is 50%, food intake does not affect bioavailability. TCmax 3-5 hours. Distribution volume after a single iv injection of a dose of 250 mg - 18 liters. Communication with proteins - 98%. It is metabolized in the liver with the participation of isoenzymes of cytochrome P450, CYP2C9 and CYP3A4, with the formation of 3 metabolites (one has pharmacological activity). T1 / 2 - 5.4 h. Ground clearance - 8.2 l / h. It is excreted mainly with bile, less than 3% - with urine. Average AUC in children is lower than in adults suffering from pulmonary arterial hypertension. With a CC of 15-30 ml / min, the concentration of bosentan in the blood plasma decreases by 10%, while the concentration of metabolites increases by 2 times.
Indications
Pulmonary arterial hypertension, including primary and secondary against scleroderma.
Contraindications
Hypersensitivity, moderate and severe liver failure, initial increase in AST and / or ALT activity by more than 3 times, simultaneous use of cycloserine A, women of reproductive age (not using reliable methods of contraception during treatment), pregnancy, lactation, children's age (up to 12 years old).
Dosage
Inside, in the morning and in the evening, regardless of food intake. The initial dose is 62.5 mg 2 times a day for 4 weeks, then the dose is increased to a maintenance dose - 125 mg 2 times a day.
In the case of clinical deterioration (with a decrease in walking distance during the 6-minute test by at least 10% compared with the baseline) despite the use of the drug for at least 8 weeks (of which at a recommended dose of at least 4 weeks), it should consider alternative treatments. Some patients who did not have a therapeutic response after 8 weeks of administration may experience an effect after an additional 4-8 weeks. If a decision is made to discontinue the drug, the dose is canceled gradually with the use of alternative therapy. In the case of clinical deterioration several months after the start of therapy, despite the use of the drug, it is necessary to consider the appropriateness of its continuation. In some patients who do not have a positive effect when taking 125 mg 2 times a day, exercise tolerance may improve with increasing doses up to 250 mg 2 times a day, however, the risk / benefit ratio for the patient should be weighed considering that hepatotoxicity is dose dependent. In order to avoid deterioration of the clinical condition due to the possible "withdrawal" syndrome, it is necessary to gradually reduce the dose, reducing it by half within 3-7 days, under the supervision of a doctor. For children with a body weight of 10-20 kg, the initial dose is 31.25 mg once a day for 4 weeks, and the maintenance dose is 31.25 mg 2 times a day; 20-40 kg - initial dose - 31.25 mg 2 times a day, maintenance - 62.5 mg 2 times a day; over 40 kg - an initial dose of 62.5 mg 2 times a day, supporting - 125 mg 2 times a day.
Experience in patients with low body weight (less than 40 kg) is limited.
Side effects
From the CCC: peripheral edema, severe vasodilation (asymptomatic decrease in blood pressure, flushing of the face, flushing of the face, feeling hot), palpitations. From the nervous system: headache, fatigue. From the digestive system: dry mouth, dyspepsia, impaired liver function, gastroesophageal reflux, rectal bleeding.
Hematopoietic organs: anemia.
On the part of the respiratory system: nasopharyngitis, pneumonia, upper respiratory tract infection. Allergic reactions: itchy skin.
Laboratory indicators: increased activity of "liver" enzymes (in the first 16 weeks of therapy, asymptomatic, returns to the initial within a few days to 9 weeks spontaneously or after a dose reduction or drug withdrawal), a decrease in Hb.
Overdose. Symptoms: headache (mild or moderate), marked decrease in blood pressure.
Treatment: symptomatic.
Interaction
Bozentan is an inducer of cytochrome P450 isoenzymes CYP2C9 and CYP3A4, presumably also induces CYP2C19, i.e. the concentration of substances in the blood plasma metabolized by these isoenzymes will decrease while taking it (dose adjustment is necessary). Concomitant use with potent CYP3A4 inhibitors (including ketoconazole, intraconazole and ritonavir), as well as CYP2C9 inhibitors (including voriconazole) is not recommended.
Possible decrease in the effect of oral contraceptives with simultaneous use because estrogens and progesterone are partially metabolized by CYP 450, so women of childbearing age should use additional or alternative methods of reliable contraception while taking the drug.
Glibenclamide - the risk of increased activity of "hepatic" aminotransferases; concomitant use is not recommended.
Fluconazole significantly increases the concentration of bosentan in blood plasma; concomitant use is not recommended.
The simultaneous use of bosentan and warfarin does not lead to clinically significant changes in the international normalized ratio (INR); dose adjustment of warfarin or similar oral anticoagulants at the beginning of bosentan therapy is not required, however, more intensive monitoring of INR at the beginning of use and at the stage of increasing the dose of bosentan is recommended.
The simultaneous use of 125 mg of bosentan 2 times a day for 5 days reduces the concentration of simvastatin and its active metabolite in blood plasma by 34% and 46%, respectively, the concentration of bosentan in blood plasma does not change (it is recommended to control cholesterol concentration with subsequent dose adjustment). The simultaneous use of bosentan in a dose of 62.5 mg of the drug 2 times a day for 6 days and ketoconazole increases the concentration of bosentan in 2 times, however, dose adjustment of Bosentan is not required. When using combination therapy in combination with a CYP2C9 inhibitor, in patients with impaired metabolism of CYP3A4, the risk of a significant increase in the concentration of bosentan in the blood plasma increases, which can lead to the development of potentially serious side effects. The simultaneous use of digoxin and bosentan at a dose of 500 mg 2 times a day for 7 days reduces the AUC, Cmax and Cmin of digoxin by 12.9 and 23%, respectively, which is not clinically significant.
special instructions
An increase in the activity of “hepatic” aminotransferases (AST and / or ALT) associated with taking bosentan is dose-dependent in nature and is observed during the first 16 weeks of therapy. Monitoring the activity of “liver” enzymes must be carried out before the start of actually and every month during treatment, as well as 2 weeks after each increase in dose. If ALT / AST activity increases, it is necessary to confirm these results by re-examination; upon confirmation, the daily dose Bosentan reduced (by monitoring the activity of enzymes every 2 weeks) or therapy is stopped, followed by monitoring the activity of enzymes if the activity of enzymes increases by 3-5 times; in case of exceeding 5-8 times - cancel the drug. Mylan the activity of aminotransferases returned to the indicators before the start of therapy, it is necessary to assess the possibility of continuing or resuming treatment with the drug. With an increase in the activity of aminotransferases by 9 or more times, treatment should be discontinued and the resumption of treatment is excluded. With associated clinical symptoms of liver Mylan (nausea, vomiting, fever, abdominal pain, jaundice, excessive fatigue, apathy, flu-like symptoms, including arthralgia, myalgia, fever), treatment should be discontinued. The resumption of therapy with bosentan is possible only if the expected effect of the therapy exceeds the potential risk, and if the activity of the liver enzymes does not exceed the indicators before treatment. Hepatologist consultation is recommended. It is necessary to control the activity of aminotransferases 3 days and 2 weeks after the resumption of therapy, and then according to the above recommendations.
Treatment with bosentan is associated with a dose-dependent, moderate, non-progressive decrease in Hb, which stabilizes after the first 4-12 weeks of therapy. It is recommended to determine Hb before starting therapy, monthly for the first 4 months, then every 3 months. If a clinically significant decrease in Hb is observed, further research should be conducted to establish the causes and the need for specific therapy.
For women of childbearing age, bosentan can only be used if reliable contraceptive methods and a negative pregnancy test are used, which is recommended to be performed monthly during treatment.
When signs of pulmonary edema appear while taking the drug, the possibility of the presence of a concomitant veno-occlusive disease should be considered.
It is recommended to monitor patients with signs of fluid retention, especially in the case of concomitant LV systolic dysfunction. In such cases, the use of diuretics or an increase in the dose of diuretics already in use is recommended.
During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require an increased concentration of attention and speed of psychomotor reactions.
There is no specific clinical experience in the treatment of patients on dialysis.
Content
Latin name
Pharmacological group
Other cardiovascular products
Characterization of the substance
Pharmacology
Bozentan - non-selective antagonist of endothelin receptors type ETBUT and ETAT. Endothelin 1 (ETone) - a powerful vasoconstrictor, when bound to ET receptorsBUT and ETAT, located in the endothelium and vascular smooth muscle cells, induces fibrosis, cell proliferation, hypertrophy and myocardial remodeling, and exhibits pro-inflammatory activity. ET concentrationone in tissues and blood plasma increases with some cardiovascular diseases and pathology of connective tissue, including with pulmonary arterial hypertension, scleroderma, acute and chronic heart failure, myocardial ischemia, systemic arterial hypertension and atherosclerosis. Bozentan competitively blocks ET receptorsone and does not bind to other receptors, reduces the resistance of systemic and pulmonary vessels, which leads to an increase in cardiac output without increasing heart rate.
When taking bosentan orally in a dose of up to 500 mg, an increase in Cmax and AUC occurs in proportion to the dose, with the introduction of a higher dose - disproportionately and more slowly. The oral bioavailability of bosentan is 50%, food intake does not affect bioavailability. TCmax 3-5 hours. The volume of distribution after a single iv injection of a dose of 250 mg is 18 liters. Communication with proteins - 98%. Bozentan is metabolized in the liver with the participation of isoenzymes of cytochrome P450, CYP2C9 and Mylan, with the formation of 3 metabolites (one has pharmacological activity). T1/2 - 5.4 h. Ground clearance - 8.2 l / h. Bozentan is excreted mainly with bile, less than 3% - with urine. Average AUC in children is lower than in adults suffering from pulmonary arterial hypertension. With a CC of 15-30 ml / min, the concentration of bosentan in blood plasma decreases by 10%, while the concentration of metabolites increases by 2 times.
Application
Bozentan: Contraindications
