Bosentan Oral: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing

Warnings:

Bosentan may rarely cause serious (possibly fatal) liver damage. Rarely, liver problems have happened in people after stopping treatment with bosentan. Your doctor will perform liver function tests before you start treatment and once a month during treatment. Tell your doctor right away if you notice nausea/vomiting that doesn’t stop, loss of appetite, stomach/abdominal pain, yellowing eyes/skin, or dark urine.

Bosentan must not be used during pregnancy because it may cause serious harm (such as birth defects) in an unborn baby. Women of childbearing age must have a negative pregnancy test before starting this medication and monthly during treatment. To prevent pregnancy, use at least two reliable forms of birth control as directed by your doctor while taking bosentan and for at least one month after stopping bosentan. If you become pregnant or think you may be pregnant, tell your doctor right away. (See also Precautions section.)

To receive this medication in the United States, you must understand, agree to, and carefully follow the requirements of the Bosentan REMS Program. If you live in Canada or any other country, consult your doctor and pharmacist for your country’s regulations.

Warnings:

Bosentan may rarely cause serious (possibly fatal) liver damage. Rarely, liver problems have happened in people after stopping treatment with bosentan. Your doctor will perform liver function tests before you start treatment and once a month during treatment. Tell your doctor right away if you notice nausea/vomiting that doesn’t stop, loss of appetite, stomach/abdominal pain, yellowing eyes/skin, or dark urine.

Bosentan must not be used during pregnancy because it may cause serious harm (such as birth defects) in an unborn baby. Women of childbearing age must have a negative pregnancy test before starting this medication and monthly during treatment. To prevent pregnancy, use at least two reliable forms of birth control as directed by your doctor while taking bosentan and for at least one month after stopping bosentan. If you become pregnant or think you may be pregnant, tell your doctor right away. (See also Precautions section.)

To receive this medication in the United States, you must understand, agree to, and carefully follow the requirements of the Bosentan REMS Program. If you live in Canada or any other country, consult your doctor and pharmacist for your country’s regulations.

… Show More

Uses

How to use Bosentan Tablet For Suspension

Read the Medication Guide provided by your pharmacist before you start using bosentan and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth with or without food as directed by your doctor, usually twice daily (in the morning and evening). If half tablets are needed for your dose, break the tablets along the score line. Do not break the tablets into quarters. Put the tablet(s) in a small amount of water to dissolve. Once dissolved, drink all the mixture right away. Unused half tablets may be stored back in the opened blister for up to 7 days.

The dosage is based on your medical condition, weight, response to treatment, and other medications you may be taking. Be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same times each day.

Do not stop taking this medication without consulting your doctor. Some conditions may become worse when this drug is suddenly stopped. Your dose may need to be gradually decreased.

Since this drug can be absorbed through the skin and lungs and may harm an unborn baby, women who are pregnant or who may become pregnant should not handle this medication or breathe the dust from the tablets.

Tell your doctor if your condition does not get better or if it gets worse.

Side Effects

See also Warning section.

Dizziness, flushing, stuffy nose, or joint pain may occur. If any of these effects last or get worse, tell your doctor or pharmacist promptly.

Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor right away if you have any serious side effects, including: fast/pounding heartbeat, unusual tiredness, swelling ankles/feet, unusual/sudden weight gain, fainting, shortness of breath, coughing up blood.

In men, this medication can decrease sperm production, which may affect the ability to father a child. Talk to your doctor for more details.

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: fever, swollen lymph nodes, rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US – Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.

In Canada – Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Precautions

See also Warning section.

Before taking bosentan, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease, anemia.

This drug may make you dizzy. Alcohol or marijuana (cannabis) can make you more dizzy. Do not drive, use machinery, or do anything that needs alertness until you can do it safely. Avoid alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis). Alcohol may also increase the risk of serious liver problems.

This medication may contain aspartame. If you have phenylketonuria (PKU) or any other condition that requires you to limit/avoid aspartame (or phenylalanine) in your diet, ask your doctor or pharmacist about using this medication safely.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

This medication must not be used during pregnancy. It may harm an unborn baby. It is important to prevent pregnancy while using this medication. Discuss the use of at least two reliable forms of birth control (such as condoms, birth control pills) with your doctor. If you become pregnant or think you may be pregnant, tell your doctor right away.

Since this drug can be absorbed through the skin and lungs and may harm an unborn baby, women who are pregnant or who may become pregnant should not handle this medication or breathe the dust from the tablets.

It is unknown if this medication passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this medication is not recommended. Consult your doctor before breast-feeding.

Interactions

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor’s approval.

A product that may interact with this drug is: sparsentan.

Other medications can affect the removal of bosentan from your body, which may affect how bosentan works. Examples include cyclosporine, HIV protease inhibitors (such as atazanavir), among others.

This drug can speed up the removal of other drugs from your body, which may affect how they work. Examples of affected drugs include daridorexant, elacestrant, glyburide, certain products used to treat chronic hepatitis C (asunaprevir, ombitasvir/paritaprevir/ritonavir), among others.

This medication may decrease the effectiveness of hormonal birth control such as pills, patch, or ring. This could cause pregnancy. Talk to your doctor or pharmacist about using an additional reliable birth control method while using this medication. Also tell your doctor if you have any new spotting or breakthrough bleeding, because these may be signs that your birth control is not working well.

Does Bosentan Tablet For Suspension interact with other drugs you are taking?

Enter your medication into the WebMD interaction checker

Overdose

If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: severe headache, severe dizziness, nausea, vomiting.

Do not share this medication with others.

Lab and/or medical tests (such as liver function, pregnancy tests, hemoglobin/hematocrit) should be done before you start taking this medication and while you are taking it. Keep all medical and lab appointments. Consult your doctor for more details.

If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up.

Store at room temperature away from light and moisture. Keep the tablets stored in the blister package until right before use. Tablets or half tablets from the open blisters may be stored back in the opened blister for up to 7 days. Do not store in the bathroom. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

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CONDITIONS OF USE: The information in this database is intended to supplement, not substitute for, the expertise and judgment of healthcare professionals. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for you or anyone else. A healthcare professional should be consulted before taking any drug, changing any diet or commencing or discontinuing any course of treatment.

Bosentan – StatPearls – NCBI Bookshelf

Omar M. Masarweh; Abhishek Bhardwaj.

Author Information and Affiliations

Last Update: May 29, 2023.

Continuing Education Activity

Pulmonary artery hypertension has proven to cause significant mortality and morbidity worldwide. The first-line treatment option for pulmonary artery hypertension has been an endothelin 1 antagonist, such as bosentan. Bosentan is a medication used in the management and treatment of pulmonary artery hypertension. This activity will highlight the mechanism of action, adverse event profile, toxicity, off-label use, dosing, pharmacodynamics, and monitoring pertinent for members of the interprofessional team to treat patients with pulmonary artery hypertension.

Objectives:

• Identify the mechanism of action of bosentan.

• Describe the potential drug-drug interactions of bosentan.

• Outline appropriate monitoring for patients using bosentan.

• Explain interprofessional team strategies for improving care coordination and communication to advance the treatment of pulmonary artery hypertension and improve outcomes when using bosentan.

Access free multiple choice questions on this topic.

Indications

Bosentan is FDA approved for the treatment of patients with pulmonary arterial hypertension (PAH) with significant physical limitations to increase their exercise ability and decrease the rate of clinical worsening.[1][2][3] There are several non-FDA-approved uses of bosentan to treat idiopathic or congenital PAH in the pediatric population aged three years and older.[4] New studies have shown that it may be useful in treating chronic thromboembolic pulmonary hypertension (CTEPH). Clinical trials in the use of endothelial receptor antagonists, such as bosentan, for the treatment of Eisenmenger syndrome have shown some promise, with further research necessary to investigate its safety profile and efficacy. [5] Furthermore, non-FDA-approved uses of bosentan include adjunct therapy for thromboangiitis obliterans, also known as Buerger disease.[6]

Mechanism of Action

Endothelins consists of a group of 21 amino acid peptides with three different isoforms, ET-1, ET-2, and ET-3, with ET-1 being the most abundant and found in sites such as the airway epithelium, parenchymal cells of the lung, pulmonary tumors, pulmonary vasculature, kidneys, small intestine, and cardiac myocytes.[7] Once produced and secreted, endothelins bind to endothelin G protein-coupled receptors, of which two primary forms exist, endothelin A and endothelin B (ETA and ETB, respectively). Although these receptors are present throughout the lung tissue, ETA receptors have their highest concentrations in the pulmonary vasculature and airway smooth muscle. In contrast, ETB receptors are most abundantly present in the endothelium.[8]

The binding of endothelin to the ETA receptors causes vasoconstriction, while binding to the ETB receptors causes bronchoconstriction. Due to the location and function of endothelins, implications point to them in many respiratory diseases such as asthma, pulmonary hypertension, COPD, connective tissue diseases, bronchiolitis obliterans, and lung transplant rejection. The intended role of bosentan is to antagonize these receptors in lung tissue, causing the smooth muscle along the pulmonary vasculature to relax, decreasing pulmonary pressures and resistance. In clinical studies, bosentan proved to prevent ET-1 mediated cellular proliferation.[8]

One consequence of antagonizing the ETB receptors results in a relative increase in the amount of circulating ET-1.[8][7]

Administration

Bosentan is administered orally as a film-coated tablet or as an oral suspension. When used in the treatment of pulmonary artery hypertension, bosentan is given twice daily at either 125 mg or 250 mg doses for adults. In the pediatric population, patients less than 12 years old, bosentan dosage ranges from 31.25 mg to 125 mg twice daily. [8]

Adverse Effects

In clinical trials with bosentan for the treatment of pulmonary artery hypertension, the most common adverse effects included headache (22%), flushing (9%), syncope (7%), and hepatic dysfunction (8%). In these clinical trials, less common adverse effects included cough, dyspnea, respiratory tract infections, chest pain, hypotension, sinusitis, dizziness, and in some cases worsening of PAH.[8] According to the FDA labeling of bosentan, embryo-fetal toxicity occurred in animal studies. Therefore pregnancy testing should be conducted on any female of reproductive age or any female that thinks she could be pregnant. Other less common adverse effects include fluid retention, which may lead to hospitalization of patients with preexisting heart failure.[8] Additionally, less common adverse effects observed included a transient decrease in sperm count and decreases in hemoglobin and hematocrit.[8]

Contraindications

Contraindications to bosentan include females who are or may become pregnant due to the risk of embryo-fetal toxicity. Due to the high risk, any female who is eligible for bosentan must be on two or more forms of reliable contraception during treatment, as well as for one month following completion of therapy.[8] Additional contraindications include using bosentan while taking cyclosporin A. Clinical studies have shown concomitant use of bosentan and cyclosporin A has resulted in drastic increases in the plasma level of bosentan, increasing the risk for adverse effects and toxicity. Further contraindication includes the use of bosentan in patients taking glyburide due to the increased risk of hepatotoxicity, resulting in increased levels of liver enzymes.[8] Finally, anyone allergic to bosentan or any of its parts should not take bosentan due to the risk of hypersensitivity reactions resulting in DRESS syndrome, anaphylaxis, rash, and angioedema.[8]

Monitoring

When given at therapeutic doses, bosentan levels reach steady-state after 3 to 5 days of therapy. The hepatic cytochrome P450 enzyme system metabolizes bosentan into two active metabolites. Only one of the metabolites (Ro 48-5033) can exert effects similar to bosentan, however, with only less than 20% of the effect.[7] Due to the hepatic clearance of the drug and interaction with the cytochrome P450 system, bosentan is contraindicated with any CYP2C9 and 3A4 substrates, inducers, or inhibitors, as well as glyburide and cyclosporine. Other drug-drug interactions that may require careful monitoring due to bosentan’s ability to increase drug metabolism by the cytochrome P450 system include protease inhibitors, certain azole antifungals, erythromycin, and amiodarone.[8] One crucial drug-drug interaction occurs with warfarin. In one clinical trial, co-administration of bosentan and warfarin resulted in a significant decrease in warfarin’s anticoagulation effects; therefore, careful INR monitoring may be necessary.

Due to bosentan’s embryo-fetal toxicity, female patients must be on more than one form of contraception before starting therapy and for one month following termination of treatment. [8]

Toxicity

Bosentan is well tolerated, and when patients receive appropriate monitoring presents a very low risk for toxicity. However, when given with cyclosporin A, bosentan’s plasma levels increased 30-fold and resulted in severe headaches, nausea, and vomiting.[8] However, no serious adverse effects or toxicity were present in these patients. In one postmarket period, one episode of overdose by a male patient who took 10000 mg of bosentan resulted in nausea, vomiting, hypotension, blurred vision, and sweating. The patient was able to make a full recovery following adequate blood pressure support.[8]

Enhancing Healthcare Team Outcomes

Before bosentan emerged as a treatment for pulmonary arterial hypertension, the only other available treatments were intravenous medications, such as epoprostenol. Bosentan has since become first-line therapy for patients with pulmonary artery hypertension and has been shown in clinical trials to be effective as monotherapy or more widely used as part of combination therapy. Due to its relatively low possibility of toxicity, ease of administration, effectiveness, and disease-modifying abilities, bosentan remains one of the go-to medications when treating patients with pulmonary artery hypertension. Continued research is needed to understand which combination therapy proves to have the best outcomes while maintaining little to no toxicity.[8]

When using bosentan for pulmonary arterial hypertension, it is best to employ an interprofessional team approach with clinicians (including mid-level practitioners), specialists, specialty-trained nursing staff, and pharmacists, all collaborating across disciplines to guide cases to optimal outcomes with minimal adverse effects or drug interactions. [Level 5]

Review Questions

• Access free multiple choice questions on this topic.

• Comment on this article.

References

1.

Chen X, Zhai Z, Huang K, Xie W, Wan J, Wang C. Bosentan therapy for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: A systemic review and meta-analysis. Clin Respir J. 2018 Jun;12(6):2065-2074. [PubMed: 29393580]

2.

Daizadeh I. Pulmonary Arterial Hypertension: A Case Study in FDA Expedited Program Designations. Ther Innov Regul Sci. 2019 Mar;53(2):264-269. [PubMed: 29874936]

3.

Oldfield V, Lyseng-Williamson KA. Bosentan: a review of its use in pulmonary arterial hypertension and systemic sclerosis. Am J Cardiovasc Drugs. 2006;6(3):189-208. [PubMed: 16780392]

4.

Pedersen J, Hedegaard ER, Simonsen U, Krüger M, Infanger M, Grimm D. Current and Future Treatments for Persistent Pulmonary Hypertension in the Newborn. Basic Clin Pharmacol Toxicol. 2018 Oct;123(4):392-406. [PubMed: 29855164]

5.

Elshafay A, Truong DH, AboElnas MM, Idrees H, Metwali HG, Vuong NL, Saad OA, Hirayama K, Huy NT. The Effect of Endothelin Receptor Antagonists in Patients with Eisenmenger Syndrome: A Systematic Review. Am J Cardiovasc Drugs. 2018 Apr;18(2):93-102. [PubMed: 28660556]

6.

Narváez J, García-Gómez C, Álvarez L, Santo P, Aparicio M, Pascual M, López de Recalde M, Borrell H, Nolla JM. Efficacy of bosentan in patients with refractory thromboangiitis obliterans (Buerger disease): A case series and review of the literature. Medicine (Baltimore). 2016 Nov;95(48):e5511. [PMC free article: PMC5134796] [PubMed: 27902617]

7.

Boss C, Bolli MH, Gatfield J. From bosentan (Tracleer®) to macitentan (Opsumit®): The medicinal chemistry perspective. Bioorg Med Chem Lett. 2016 Aug 01;26(15):3381-94. [PubMed: 27321813]

8.

Mathier MA, Ishizawar D. Bosentan. Expert Opin Pharmacother. 2010 Apr;11(6):1023-34. [PubMed: 20307226]

Disclosure: Omar Masarweh declares no relevant financial relationships with ineligible companies.

Disclosure: Abhishek Bhardwaj declares no relevant financial relationships with ineligible companies.

Bosentan instructions, price in pharmacies of Ukraine

There are no products on the site with the trade name “Bosentan”

Editorial team

Creation date: 04/27/2021
Update date: 07/12/2023

Bosentan – zasіb for treatment of legenous arterial hypertension. It decreases like a legenevium, so it is a systemic judgmental operation, which leads to an increase in the heart rate without an increase in the frequency of the heart rates.

Indications

Treatment of legenous arterial hypertension for increased tolerance to physical intensification and clinical symptoms in patients of class III for functional WHO classification. Efficiency has been demonstrated in the following conditions:

Contraindications

• Increased susceptibility to bosentan or to any additional drug indications.
• Hepatic insufficiency of mild to severe form (class B or C according to the Child-Pugh scale).
• Changes in the activity of hepatic transferases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)), greater than lower in 3 times higher than the upper mean of normal.
• One-hour infusion of cyclosporine A.
• Vagity.
• Women of reproductive age who do not win over the best methods of contraception.

Side effects

Most common side reactions:

• head count;
• snag
• liver dysfunction test;
• anemia/decreased hemoglobin (9.9%).

Contraindications during pregnancy and breastfeeding

Bosentan is contraindicated for women of reproductive age, during pregnancy and breastfeeding.

Children

Relief of spontaneous reactions in case of caring for motor transport or other mechanisms more inconsistency, which can be pushed into the building by car transport or by other mechanisms.

Overdose

The most widespread unacceptable reaction – headache from the lung to the death stage.
Severe overdose can lead to pronounced arterial hypotension, which affects the active support of the cardiovascular system.

Take care of the safety

Save at a temperature not higher than 25 °C in an area inaccessible to children.

Bosentan instructions

BOZENTAN ACCORD 125 MG TABLETS
(UA/19077/01/02)

Release form:

tablets, covered with plaid membrane, 125 mg each, 14 tablets, covered with plaited membrane, in a blister, 4 blisters in a pack

Stock:

1 tablet to take: bosentan (seemingly monohydrate) – 125,000 mg

Manufacturer:

India/Malta

BOSENTAN ACCORD 125 MG FILM-COATED TABLETS
(UA/19783/01/02)

Release form:

tablets, covered with plaid membrane, 14 tablets, covered with plaid membrane, in a blister, 4 blisters in a pack

Stock:

1 tablet, coated with a plaited shell, mixed with: bosentan (looks like monohydrate) 125 mg

Manufacturer:

Netherlands/Poland

BOZENTAN ACCORD 62. 5 MG TABLETS
(UA/19077/01/01)

Release form:

tablets, covered with plaid membrane, 62.5 mg each, 14 tablets, covered with plaid membrane, in a blister, 4 blisters in a pack

Stock:

1 tablet to take: bosentan (seemingly monohydrate) – 62.500 mg

Manufacturer:

India/Malta

BOSENTAN ACCORD 62. 5 MG FILM-COATED TABLETS
(UA/19783/01/01)

Release form:

tablets, covered with plaid membrane, 14 tablets, covered with plaid membrane, in a blister, 4 blisters in a pack

Stock:

1 tablet, coated with a plaited shell, mixed with: bosentan (looks like monohydrate) 62.5 mg

Manufacturer:

Netherlands/Poland

BOZENTAN ZENTIVA
(UA/16744/01/01)

Release form:

tablets, coated with a plaited shell, 62. 5 mg, 14 tablets in a blister, 1, 4 or 8 blister in a cardboard pack

Stock:

1 tablet, coated with a plaited shell, vengeance for bosentan (looks like monohydrate) 62.5 mg

Manufacturer:

Cyprus

BOZENTAN ZENTIVA
(UA/16744/01/02)

Release form:

tablets, coated with a plaited shell, 125 mg, 14 tablets in a blister, 1, 4 or 8 blister in a cardboard pack

Stock:

1 tablet, coated with velvet shell, to bosentan (looks like monohydrate) 125 mg

Manufacturer:

Cyprus

BOZENTAN SANDOZ® (BOSENTAN SANDOZ®)
(UA/16618/01/01)

Release form:

tablets, coated with plaid membrane, 62. 5 mg each, blister, to be filled 14 tablets, covered with plaited membrane, cardboard box, to be covered 4 blisters

Stock:

1 tablet to take: bosentan (in the form of bosentan monohydrate) 62.5 mg

Manufacturer:

Turechchina

BOZENTAN SANDOZ® (BOSENTAN SANDOZ®)
(UA/16618/01/02)

Release form:

tablets, coated with plaid shell, 125 mg each, blister, 14 tablets, packed with plaid shell, cardboard box, 4 blisters

Stock:

1 tablet to take: bosentan (in the form of bosentan monohydrate) 125 mg

Manufacturer:

Turechchina

BOZENTAN SANDOS® 125
(UA/17011/01/02)

Release form:

tablets, coated with plaid membrane, 125 mg each, blister, to be filled 14 tablets, covered with plaited membrane, 4 blisters in a cardboard box

Stock:

1 lozenge: bosentan monohydrate 129. 082 mg (equivalent to 125 mg bosentan)

Manufacturer:

Turechchina

BOZENTAN SANDOS® 62.5
(UA/17011/01/01)

Release form:

tablets, covered with plaid membrane, 62. 5 mg each, blister, to be filled 14 tablets, covered with plaited membrane, 4 blisters in a cardboard box

Stock:

1 lozenge: bosentan monohydrate 64.541 mg (equivalent to 62.5 mg bosentan)

Manufacturer:

Turechchina

BOZENTAN 125mg N60 tabs b.p.o. ASPECTUS PHARMA – Pharm-ID – Unified nomenclature guide for drug packages

Bosentan is metabolized with the participation of CYP2C9 and CYP3A4 isoenzymes. With simultaneous use with inhibitors of the CYP3A4 isoenzyme (for example, ketoconazole), the concentration of bosentan in the blood plasma increases. The effect of inhibition of the CYP2C9 isoenzyme on the concentration of bosentan in plasma has not been studied; such combinations require caution. Simultaneous use with fluconazole, which mainly inhibits the CYP2C9 isoenzymeand slightly – the CYP3A4 isoenzyme, may be accompanied by an increase in the concentration of bosentan in the blood plasma; this combination is not recommended. For the same reason, concomitant use of bosentan with strong inhibitors of the CYP3A4 isoenzyme (such as ketoconazole, itraconazole or ritonavir) and an inhibitor of the CYP2C9 isoenzyme (such as voriconazole) is not recommended.

Bosentan is an inducer of CYP2C9 and CYP3A4 isoenzymes, and CYP2C19 is also suspected in vitro. Therefore, with the simultaneous use of bosentan and drugs, the metabolism of which is mediated by these isoenzymes, their concentration in blood plasma decreases. Consideration should be given to the possibility of reducing the effectiveness of drugs, the metabolism of which is carried out with the participation of the same isoenzymes. It may be necessary to adjust the dose of concomitantly used medicinal products after starting bosentan, changing its dose or discontinuing it.

Co-administration of bosentan and cyclosporine (a calcineurin inhibitor) is contraindicated. With this combination, the minimum initial concentration of bosentan in the blood plasma increases by 30 times compared with the use of bosentan in monotherapy. C _ss bosentan in plasma increases by 3-4 times compared with the concentration of bosentan in monotherapy. A possible mechanism for this interaction is the inhibition of the transport protein responsible for the entry of bosentan into hepatocytes by cyclosporine. The concentration of cyclosporine in the blood plasma is reduced by almost 50%.

Co-administration of tacrolimus and sirolimus with bosentan has not been studied in clinical studies, but it is expected that plasma concentrations of bosentan may increase in a manner similar to cyclosporine. Plasma concentrations of tacrolimus and sirolimus may decrease when co-administered with bosentan. Therefore, bosentan should not be co-administered with tacrolimus or sirolimus. If it is necessary to use this combination, it is necessary to monitor the patient’s condition and the concentrations of tacrolimus and sirolimus in the blood plasma.

With the simultaneous use of bosentan at a dose of 125 mg 2 times / day for 5 days, the concentration of glibenclamide (CYP3A4 isoenzyme substrate) in blood plasma decreases by 40%, which may be accompanied by a significant decrease in the hypoglycemic effect of glibenclamide. The plasma concentration of bosentan is also reduced by 29%. In addition, in patients receiving concomitant treatment, the risk of increased activity of hepatic transaminases increases. Both active substances, glibenclamide and bosentan, have an inhibitory effect on the bile salt transport pump, which may explain the increase in liver transaminase activity. In connection with the above, bosentan should not be used simultaneously with glibenclamide. There are no data on possible drug interactions with other sulfonylurea derivatives.

With simultaneous use of bosentan for 7 days at a dose of 125 mg 2 times / day and oral contraceptive for a single dose – a combined preparation containing 1 mg of norethisterone and 35 μg of ethinyl estradiol, there was a decrease in AUC for its components by 14% and 31%, respectively . In some patients, the reduction in exposure to norethisterone and ethinylestradiol reached 56% and 66%, respectively. Thus, hormonal contraception cannot be considered sufficiently effective, regardless of the route of administration of the drug – orally, by injection, transdermally, or in the form of implants.

With simultaneous use in healthy volunteers with bosentan at a dose of 500 mg 2 times / day for 6 days, the concentration of S-warfarin (CYP2C9 isoenzyme substrate) and R-warfarin (CYP3A4 isoenzyme substrate) in blood plasma decreases by 29% and 38% respectively. The experience of the simultaneous use of bosentan and warfarin in patients with PAH was not accompanied by clinically significant changes in the MHO and the dose of warfarin (at the end of the study compared with baseline values). In addition, the frequency of dose adjustments of warfarin during the study due to changes in INR or due to side effects did not differ between patients receiving bosentan or placebo. Dose adjustment of warfarin or other oral anticoagulants is not required at the beginning of bosentan therapy, however, mandatory monitoring of INR is recommended, especially at the beginning of bosentan use and during the stages of dose increase.

With simultaneous use of bosentan at a dose of 125 mg 2 times / day for 5 days, the concentration of simvastatin (a substrate of the CYP3A4 isoenzyme) and its active form of beta-hydroxy acid in blood plasma decreases by 34% and 46%, respectively. The simultaneous use of simvastatin does not affect the concentration of bosentan in plasma. With the combined use of simvastatin and bosentan, it is recommended to control the concentration of cholesterol in the blood plasma, followed by dose adjustment of simvastatin.

Simultaneous use for 6 days of bosentan at a dose of 62. 5 mg 2 times / day and ketoconazole, a potent inhibitor of the CYP3A4 isoenzyme, is accompanied by an increase in the concentration of bosentan in blood plasma by 2 times. Dose adjustment of bosentan is not required.

An increase in plasma concentrations of bosentan is also expected with the simultaneous use of itraconazole and ritonavir, despite the lack of confirmation in in vivo studies. However, when bosentan is combined with a CYP3A4 inhibitor, in patients with reduced metabolism of the CYP2C9 isoenzymethere is a risk of a significant increase in the concentration of bosentan, which may increase the frequency and severity of its side effects.

With simultaneous use in healthy volunteers for 7 days of bosentan at a dose of 125 mg 2 times / day and rifampicin, which is an inducer of CYP2C9 and CYP3A4 isoenzymes, the concentration of bosentan in blood plasma decreased by 58%, and in some patients by 90% . As a result, a clinically significant decrease in the effect of bosentan is possible when used together with rifampicin; this combination is not recommended. Data on the combined use with other inducers of the CYP3A4 isoenzyme, such as carbamazepine, phenobarbital, phenytoin, as well as drugs that include St. .

Co-administration of bosentan 125 mg twice daily with lopinavir + ritonavir 400 + 100 mg twice daily for 9.5 days in healthy volunteers resulted in an approximately 48-fold higher trough plasma concentration of bosentan compared to concentration when using only one bosentan. C _ss of bosentan in blood plasma on day 9 was 5 times higher than when taking bosentan alone. The mechanism of interaction is probably due to the inhibition of the CYP3A4 isoenzyme and the transport protein responsible for the transport of bosentan into hepatocytes by ritonavir, which leads to a decrease in the clearance of bosentan. In patients receiving concomitant treatment with bosentan and drugs containing lopinavir + ritonavir or other overactive protease inhibitors, it is necessary to monitor the tolerability of bosentan. When used together with bosentan for 9.