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

Clinical and pharmacological group: & nbsp

Vasodilators

Included in the formulation

Bozenex®

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FarmSirma Soteks, ZAO Russia

Tractor®

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Actelion Pharmaceuticals Co., Ltd. Switzerland

Trakley® DT

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Actelion Pharmaceuticals Co., Ltd. Switzerland

Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

VED

АТХ:

C.02.K.X Other antihypertensive drugs

Pharmacodynamics:

Bozanthan is a non-selective antagonist of endothelin receptors with affinity for endothelin receptors of types A and B (ET_A and ET_AT). Boszentan reduces both pulmonary and systemic vascular resistance, leading to an increase in cardiac output without an increase in the heart rate.

Neurohormone endothelin-1 (ET-1) is one of the most powerful vasoconstrictors, it has the ability to induce fibrosis, cell proliferation, hypertrophy and myocardial remodeling, and also exhibits pro-inflammatory activity. These effects are caused by binding of ET-1 to ET receptors_A and ET_ATlocated in the endothelium and cells of the smooth muscles of the vessels. The concentration of ET-1 in tissues and plasma increases in certain cardiovascular diseases and pathology of connective tissue, including pulmonary arterial hypertension, scleroderma, acute and chronic heart failure, myocardial ischemia,arterial hypertension and atherosclerosis, suggesting the involvement of ET-1 in the pathogenesis and development of these diseases. When pulmonary arterial hypertension and heart failure in the absence of receptor antagonism to ET, increasing the concentration of ET-1 is strongly correlated with the severity and prognosis of these diseases. Boszentan competes with ET-1 and other ET peptides for binding to ET_A and ET_ATreceptors, with a slightly higher affinity for the ET receptors_A (Ki = 4.1-43 nmol), compared with ET receptors_AT(Ki = 38-730 nmol).

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

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 pulmonary arterial hypertension 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 C_maxin blood plasma and AUC in relation to the accepted dose is disproportionate 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. C_maxin blood plasma is achieved 3-5 hours after taking the drug inside.

Distribution

Bozentan in high degree (more than 98%) binds to blood plasma proteins, mainly with albumin. Boszentan does not penetrate into the red blood cells. After a single intravenous dose of 250 mg V_dis 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 is 5.4 hours.

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.

Bosenthan is excreted through the intestine with bile after completion of liver metabolism 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 the isoenzymes CYP2C9 and CYP3A4, and possibly also the isoenzyme CYP2C19 and P-glycoprotein. In vitro bosentan inhibits the activity of BSEP (a pump for the export of bile salts) in hepatocyte cultures. In studies in vitro shown, that bosentan has no significant inhibitory effect on a number of CYP isoenzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4). Consequently, bosentan does not increase the concentration in the blood plasma of drugs, the metabolism of which is mediated by these isoenzymes.

Indications:

Treatment of pulmonary arterial hypertension in order to improve exercise tolerance and clinical symptoms in patients with functional class II-IV WHO classification, adults and children over 3 years, 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 disease and, in particular, with violations of hemodynamic parameters according to the type of Eisenmenger syndrome; a decrease in the number of new digital ulcers in adults with systemic scleroderma and progressive ulcerative lesions of the limbs.

ICD-10

IX.I26-I28.I27.0 Primary pulmonary hypertension

IX.I26-I28.I27.8 Other specified forms of pulmonary heart disease

XIII.M30-M36.M34 Systemic sclerosis

XVII.Q20-Q28.Q21.8 Other congenital malformations of cardiac septum

Contraindications:

Violations of liver function of moderate and severe severity (7 or more points on the Child-Pugh scale); initial increase in hepatic transaminase activity more than 3 times from the upper limit of the norm; simultaneous administration of cyclosporin A; use in women of reproductive age who do not use reliable methods of contraception; age up to 3 years (solid dosage form); hypersensitivity to bosentan or any of the components of the drug.

Carefully:

Severe arterial hypotension (systolic blood pressure less than 85 mm Hg), chronic obstructive pulmonary disease, mild violations of liver function (less than 7 on the Child-Pugh scale); at pulmonary arterial hypertension I functional class (insufficient clinical data on efficacy and safety of use).

No effect of the drug on the healing of existing digital ulcers.

Pregnancy and lactation:

Contraindications to the use of the drug in pregnancy and lactation.

Dosing and Administration:

The initial dose of the drug is 62.5 mg twice a day for 4 weeks, then the dose increases to 125 mg twice a day. In some patients with ineffective use of the drug 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 twice a 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 a sudden discontinuation of drug therapy.Information about clinically significant worsening in the course of pulmonary arterial hypertension as a result of a sharp drug cancellation. 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.

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

The initial dose of the drug is 62.5 mg 2 times a day for 4 weeks, then the dose is increased to a maintenance dose of 125 mg twice a day.

Clinical status of patients should be monitored regularly, carefully assessing the benefit / risk relationship for further drug therapy and taking into account the possibility of a negative effect of the drug on liver function.

Data on the efficacy and safety of the drug children under 18 are absent.

Side effects:

From the side of the blood and lymphatic system: often - anemia, a decrease in hemoglobin; frequency unknown - anemia or a decrease in hemoglobin, when it is necessary to carry out blood transfusion; infrequently - thrombocytopenia, neutropenia, and leukopenia.

From the immune system: often - reactions of hypersensitivity (including dermatitis, pruritus and rash); anaphylactic and / or angioedema.

From the nervous system: very often - a headache.

From the cardiovascular system: often - fainting, palpitations, flushing of blood to the skin of the face, lowering of blood pressure.

From the digestive system: often - gastroesophageal reflux disease; infrequently - increased hepatic transaminase activity associated with hepatitis and / or jaundice; rarely - cirrhosis, liver failure.

From the skin and subcutaneous tissues: often - redness of the skin.

General disorders and disorders at the injection site: very often - peripheral edema, fluid retention.

Overdose:

Bozentan was used in a single dose of 2,400 mg in healthy volunteers and 2000 mg per 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 after taking 10,000 mg was recorded, 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 correction of the pronounced decrease blood pressure. Boszentan not removed during hemodialysis.

Interaction:

Bozentan undergoes a metabolism involving cytochrome CYP450 and its isoenzymes CYP2C9 and CYP3A4. Inhibition of the isoenzyme CYP3A4 increases the concentration in the blood plasma of bosentan. The effect of inhibition of the isoenzyme CYP2C9 on the concentration of bosentan in 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 the isozyme 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, simultaneous use of the drug and potent inhibitors of the CYP3A4 isoenzyme (such as ketoconazole, itraconazole or ritonavir) and inhibitor of the isoenzyme CYP2C9 (such as voriconazole).

Bozanthan is the inducer of the isoenzymes CYP2C9 and CYP3A4. According to the research in vitro The role of the inductor of the isoenzyme CYP2C19 is also assumed. Therefore, with simultaneous use of the drug 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 starting the drug, changing its dose or canceling.

Cyclosporine: simultaneous application of the drug 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 hepatocytes. The concentration of cyclosporine in the blood plasma at the same time decreases by almost 50%.

Warfarin: when used simultaneously in healthy volunteers with a drug at a dose of 500 mg twice a day for 6 days, the concentration of S-warfarin (the substrate of the isoenzyme CYP2C9) and R-warfarin (the substrate of the isoenzyme CYP3A4) in the blood plasma is reduced by 29% and 38%, respectively . The experience of simultaneous use of the drug and warfarin in patients with pulmonary arterial hypertension was not accompanied by significant clinical changes international normalized attitude and the dose of warfarin (at the end of the study compared with baseline values). In addition, the frequency of correction of the dose of warfarin during the study due to changes international normalized attitude or due to side effects were not different 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 drug therapy, but mandatory monitoring is recommended international normalized attitude, especially at the beginning of the drug and at the stages of dose increase.

Simvastatin: when the drug is administered 125 mg twice a day for 5 days, the concentration of simvastatin (the substrate of the isoenzyme CYP3A4) and its active form of beta-hydroxy acid in blood plasma is reduced by 34% and 46%, respectively. Simultaneous use of simvastatin does not affect the concentration of bosentan in blood plasma. When joint application of simvastatin and the drug 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 at a dose of 62.5 mg twice 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 the drug is not carried out.

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 of CYP3A4, in patients with a reduced metabolism of the isoenzyme CYP2C9, there is a risk of a significant increase in the concentration of bosentan, which may increase the incidence and severity of the side effects of the drug.

Epoprostenol: limited results of the study, in which 10 children received the drug in combination with epoprostenol, indicate that after a single and repeated intake of these drugs, concentrations of bosentan in the blood plasma C_max and AUC were approximately the same in patients who received and did not receive infusion of epoprostenol.

Sildenafil: while simultaneous use of the drug at 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, a decrease in AUC of sildenafil by 63% and an increase in AUC of bosentan by 50% were noted. Changes in the concentrations of substances in the plasma are not of clinical significance, correction of the doses of the drugs is not required.

Digoxin, nimodipine, losartan: simultaneous application of the drug at a dose of 500 mg twice a day for 7 days is accompanied by a decrease in the concentration of digoxin in the blood plasma AUC, C_max and 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.

Special instructions:

Liver function

An increase in the activity of hepatic transaminases associated with taking the drug is dose-dependent. Changes in hepatic transaminase activity usually occur during the first 26 weeks of therapy, but may occur at a later date. The risk of abnormal liver function may also increase with simultaneous use with the drug of BSEP suppressing agents, such as rifampicin, glibenclamide and ciclosporin, although the data showing this is limited.

It is necessary to monitor the activity of hepatic transaminases before starting therapy with the drug, and then once a month during the treatment period.

Recommendations in case of increased activity of hepatic transaminases

With activity hepatic transaminases 3-5 times higher

Carry out a re-definition of activity hepatic transaminases, with confirmation of increased activity hepatic transaminases should reduce the daily dose of the drug or cancel the drug; monitor the activity of hepatic transaminases every 2 weeks. If the activity of hepatic transaminases returned to the indices observed before the start of therapy, the possibility of continuing or resuming the administration of the drug in the regime indicated below is evaluated.

With activity hepatic transaminases 5-8 times higher

Carry out a re-definition of activity hepatic transaminases, with confirmation of increased activity hepatic transaminases should cancel the drug; monitor the activity of hepatic transaminases every 2 weeks. If the activity of hepatic transaminases returned to the indices observed before the start of therapy, the possibility of recommencement of the drug intake in the mode indicated below.

With activity hepatic transaminases 8 times higher

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

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

Renewal of therapy

You can resume therapy with the drug 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 drug treatment. 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. The activity of liver transaminases should be checked 3 days after the resumption of therapy with the drug, then repeat the control, following the recommendations of the doctor, and then return to the regular monitoring scheme.

Therapy in women of reproductive age

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

Impact on the ability to drive vehicles and manage mechanisms

Effect of the drug on the ability to drive vehicles and engage in other potentially hazardous activities requiring increased concentration and speed of psychomotor reactions, has not been studied, but considering that the drug may cause dizziness, care should be taken when performing such activities.

Instructions

Boszentan (Bosentanum)