What is bosentan used for. Bosentan: Uses, Side Effects, and Important Safety Information

04.09.202112.07.2023 by alexxlab

What is bosentan used for. How does bosentan work. What are the potential side effects of bosentan. Who should not take bosentan. How is bosentan administered. What precautions should be taken when using bosentan.

Содержание

Understanding Bosentan: A Comprehensive Guide

Bosentan is a medication that plays a crucial role in treating certain cardiovascular conditions. This article delves into the various aspects of bosentan, including its uses, mechanism of action, potential side effects, and important safety considerations.

What is Bosentan and How Does It Work?

Bosentan belongs to a class of medications known as endothelin receptor antagonists. It works by blocking the action of endothelin, a substance in the body that causes blood vessels to narrow. By inhibiting this action, bosentan helps to widen blood vessels, particularly in the lungs, improving blood flow and reducing blood pressure in the pulmonary arteries.

Primary Uses of Bosentan

Treatment of pulmonary arterial hypertension (PAH)
Management of systemic sclerosis with ongoing digital ulcer disease
Improving exercise capacity and symptoms in certain PAH patients

Is bosentan effective for all types of hypertension? No, bosentan is specifically indicated for pulmonary arterial hypertension and is not typically used for treating systemic hypertension.

Administration and Dosage of Bosentan

Bosentan is available as an oral tablet for suspension. The typical dosing regimen involves taking the medication twice daily, in the morning and evening. The dosage is determined based on several factors, including the patient’s medical condition, weight, response to treatment, and other medications they may be taking.

How to Take Bosentan

Dissolve the tablet(s) in a small amount of water
Drink the entire mixture immediately after dissolution
Take with or without food, as directed by your healthcare provider
Maintain a consistent schedule, taking the medication at the same times each day

Can bosentan tablets be split? Yes, if half tablets are needed for the prescribed dose, the tablets can be broken along the score line. However, they should not be divided into quarters.

Potential Side Effects and Risks of Bosentan

While bosentan can be highly effective in treating certain conditions, it’s important to be aware of potential side effects. Some common side effects include:

Dizziness
Flushing
Stuffy nose
Joint pain

More serious side effects may occur, although they are less common. These can include:

Liver damage
Fast or pounding heartbeat
Unusual tiredness
Swelling in ankles or feet
Sudden weight gain
Fainting
Shortness of breath
Coughing up blood

Does bosentan affect fertility? In men, bosentan can potentially decrease sperm production, which may impact fertility. It’s important to discuss this with a healthcare provider if there are concerns about fertility.

Critical Safety Warnings for Bosentan Use

Bosentan carries several important safety warnings that patients and healthcare providers must be aware of:

Liver Damage Risk

Bosentan may rarely cause serious, potentially fatal liver damage. Liver function tests are required before starting treatment and monthly during treatment. Patients should be alert for signs of liver problems, such as:

Persistent nausea or vomiting
Loss of appetite
Abdominal pain
Yellowing of eyes or skin
Dark urine

Pregnancy and Bosentan

Bosentan must not be used during pregnancy due to the risk of serious harm to the unborn baby, including birth defects. Women of childbearing age must:

Have a negative pregnancy test before starting bosentan
Undergo monthly pregnancy tests during treatment
Use at least two reliable forms of birth control while taking bosentan and for at least one month after stopping

What should a woman do if she becomes pregnant while taking bosentan? If pregnancy occurs or is suspected, it’s crucial to inform the healthcare provider immediately.

The Bosentan REMS Program

In the United States, patients must participate in the Bosentan REMS (Risk Evaluation and Mitigation Strategy) Program to receive this medication. This program is designed to ensure that the benefits of bosentan outweigh its risks.

Key Components of the REMS Program

Patient education about the risks associated with bosentan
Regular liver function monitoring
Pregnancy prevention and testing for women of childbearing potential
Enrollment of healthcare providers, pharmacies, and patients in the program

Are there similar programs for bosentan use in other countries? While the specific REMS Program is unique to the United States, other countries may have their own regulations and monitoring programs for bosentan use. Patients should consult with their local healthcare providers for country-specific guidelines.

Drug Interactions and Precautions

Bosentan can interact with various medications and substances, potentially altering its effectiveness or increasing the risk of side effects. It’s crucial to inform healthcare providers about all medications, supplements, and herbal products being used.

Notable Drug Interactions

Cyclosporine
Glyburide
Hormonal contraceptives
Certain antifungal medications
HIV protease inhibitors

Can bosentan be taken with over-the-counter pain relievers? While some pain relievers may be safe to use with bosentan, it’s important to consult with a healthcare provider before combining medications, as interactions can occur.

Special Precautions

Certain groups of people may need special monitoring or dosage adjustments when taking bosentan:

Patients with liver disease
Individuals with anemia
Those with fluid retention or heart failure
Patients undergoing dialysis

Long-term Use and Monitoring

Bosentan is typically used as a long-term treatment for chronic conditions. Regular monitoring is essential to ensure its safe and effective use over time.

Ongoing Assessments

Monthly liver function tests
Regular blood pressure checks
Periodic complete blood counts
Assessment of fluid retention and edema
Evaluation of exercise capacity and symptom improvement

How long can a patient safely take bosentan? The duration of bosentan treatment varies depending on the individual’s condition and response to the medication. Some patients may require long-term therapy, while others might eventually be able to discontinue use under medical supervision.

Alternative Treatments and Combination Therapy

While bosentan is an effective treatment for pulmonary arterial hypertension and certain other conditions, it’s not the only option available. Healthcare providers may consider alternative or additional treatments based on individual patient needs.

Other PAH Treatments

Phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil)
Prostacyclin analogues (e.g., epoprostenol, iloprost)
Soluble guanylate cyclase stimulators (e.g., riociguat)
Calcium channel blockers (for a subset of PAH patients)

Is combination therapy with bosentan common in PAH treatment? Yes, combination therapy is increasingly used in PAH management. Bosentan may be combined with other PAH-specific medications to achieve better outcomes in some patients.

Considerations for Treatment Selection

The choice of treatment depends on various factors, including:

The specific type and severity of PAH
Patient’s overall health and comorbidities
Potential drug interactions
Patient preferences and lifestyle considerations
Cost and availability of different treatment options

Research and Future Directions

The field of pulmonary hypertension treatment, including the use of bosentan, continues to evolve as new research emerges. Ongoing studies are exploring various aspects of bosentan therapy and potential new applications.

Current Research Areas

Long-term outcomes of bosentan treatment
Optimal combination therapies including bosentan
Use of bosentan in pediatric PAH patients
Potential applications in other cardiovascular and pulmonary conditions
Development of new endothelin receptor antagonists with improved efficacy or safety profiles

Are there new endothelin receptor antagonists in development? Yes, researchers are continually working on developing new medications in this class, aiming to improve upon the benefits of existing drugs like bosentan while potentially reducing side effects or offering more convenient dosing regimens.

Implications for Future Treatment

As research progresses, it’s likely that treatment strategies for PAH and related conditions will become more personalized. This may involve:

Tailoring treatment combinations based on genetic or biomarker profiles
Development of novel drug delivery methods
Integration of advanced monitoring technologies for better disease management
Exploration of bosentan’s potential in treating other rare diseases

Patient Education and Support

Effective management of conditions treated with bosentan requires more than just medication. Patient education and support play crucial roles in ensuring optimal outcomes and quality of life for those taking bosentan.

Key Areas of Patient Education

Understanding the medication’s purpose and mechanism of action
Proper administration techniques
Recognition of potential side effects and when to seek medical attention
Importance of adherence to the treatment regimen
Lifestyle modifications to support overall health
Pregnancy prevention and family planning considerations

How can patients best manage the potential side effects of bosentan? Patients should maintain open communication with their healthcare providers, report any new or worsening symptoms promptly, and follow recommended monitoring schedules. Additionally, adopting a healthy lifestyle, including proper nutrition and appropriate exercise as advised by their doctor, can help manage some side effects and support overall well-being.

Support Resources

Various resources are available to support patients taking bosentan:

Patient support programs offered by pharmaceutical companies
Pulmonary hypertension patient associations and support groups
Educational materials provided by healthcare institutions
Online forums and communities for patients with PAH or related conditions
Financial assistance programs for medication costs

Conclusion and Key Takeaways

Bosentan represents a significant advancement in the treatment of pulmonary arterial hypertension and certain other cardiovascular conditions. While it offers substantial benefits for many patients, its use requires careful consideration of potential risks and adherence to safety protocols.

Essential Points to Remember

Bosentan is primarily used to treat pulmonary arterial hypertension
Regular liver function monitoring is crucial during treatment
Pregnancy must be avoided due to the risk of serious birth defects
Participation in the REMS program is required for patients in the United States
Long-term use necessitates ongoing medical supervision and assessments
Combination therapy with other PAH medications may be beneficial for some patients
Patient education and support are integral to successful treatment outcomes

As research continues and medical knowledge advances, the role of bosentan in treating various conditions may evolve. Patients and healthcare providers should stay informed about the latest developments to ensure the most effective and safe use of this medication.

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:

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

Precautions

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.

Images

Available coupons

Save up to 80% on your prescription with WebMDRx

Drug Survey

Are you currently using Bosentan Tablet For Suspension?

This survey is being conducted by the WebMD marketing sciences department.

Selected from data included with permission and copyrighted by First Databank, Inc. This copyrighted material has been downloaded from a licensed data provider and is not for distribution, except as may be authorized by the applicable terms of use.

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.

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.