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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. </p></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK542293_"><span class="title" itemprop="name">Bosentan</span></h1><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Omar M. Masarweh</span><sup>1</sup>; <span itemprop="author">Abhishek Bhardwaj</span><sup>2</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup> Kern Medical Center</div><div class="affiliation"><sup>2</sup> University of California</div><p class="small">Last Update: <span itemprop="dateModified">May 29, 2023</span>.</p></div><div class="body-content whole_rhythm" itemprop="text"><div id="article-18462.s1"><h2 id="_article-18462_s1_">Continuing Education Activity</h2><p>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.</p><p>
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<b>Objectives:</b>
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<ul><li class="half_rhythm"><div>Identify the mechanism of action of bosentan.</div></li><li class="half_rhythm"><div>Describe the potential drug-drug interactions of bosentan.</div></li><li class="half_rhythm"><div>Outline appropriate monitoring for patients using bosentan.</div></li><li class="half_rhythm"><div>Explain interprofessional team strategies for improving care coordination and communication to advance the treatment of pulmonary artery hypertension and improve outcomes when using bosentan.</div></li></ul>
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<a href="https://www.statpearls.com/account/trialuserreg/?articleid=18462&utm_source=pubmed&utm_campaign=reviews&utm_content=18462" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Access free multiple choice questions on this topic.</a>
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</p></div><div id="article-18462.s2"><h2 id="_article-18462_s2_">Indications</h2><p>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.<a class="bk_pop" href="#article-18462.r1">[1]</a><a class="bk_pop" href="#article-18462.r2">[2]</a><a class="bk_pop" href="#article-18462.r3">[3]</a> There are several non-FDA-approved uses of bosentan to treat idiopathic or congenital PAH in the pediatric population aged three years and older.<a class="bk_pop" href="#article-18462.r4">[4]</a> 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.<a class="bk_pop" href="#article-18462.r5">[5]</a> Furthermore, non-FDA-approved uses of bosentan include adjunct therapy for thromboangiitis obliterans, also known as Buerger disease.<a class="bk_pop" href="#article-18462.r6">[6]</a></p></div><div id="article-18462.s3"><h2 id="_article-18462_s3_">Mechanism of Action</h2><p>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.<a class="bk_pop" href="#article-18462.r7">[7]</a> 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.<a class="bk_pop" href="#article-18462.r8">[8]</a></p><p>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.<a class="bk_pop" href="#article-18462.r8">[8]</a></p><p>One consequence of antagonizing the ETB receptors results in a relative increase in the amount of circulating ET-1.<a class="bk_pop" href="#article-18462.r8">[8]</a><a class="bk_pop" href="#article-18462.r7">[7]</a></p></div><div id="article-18462.s4"><h2 id="_article-18462_s4_">Administration</h2><p>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.<a class="bk_pop" href="#article-18462.r8">[8]</a></p></div><div id="article-18462.s5"><h2 id="_article-18462_s5_">Adverse Effects</h2><p>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.<a class="bk_pop" href="#article-18462.r8">[8]</a> 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.<a class="bk_pop" href="#article-18462.r8">[8]</a> Additionally, less common adverse effects observed included a transient decrease in sperm count and decreases in hemoglobin and hematocrit.<a class="bk_pop" href="#article-18462.r8">[8]</a></p></div><div id="article-18462.s6"><h2 id="_article-18462_s6_">Contraindications</h2><p>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.<a class="bk_pop" href="#article-18462.r8">[8]</a> 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.<a class="bk_pop" href="#article-18462.r8">[8]</a> 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.<a class="bk_pop" href="#article-18462.r8">[8]</a></p></div><div id="article-18462.s7"><h2 id="_article-18462_s7_">Monitoring</h2><p>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.<a class="bk_pop" href="#article-18462.r7">[7]</a> 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.<a class="bk_pop" href="#article-18462.r8">[8]</a> 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.</p><p>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.<a class="bk_pop" href="#article-18462.r8">[8]</a></p></div><div id="article-18462.s8"><h2 id="_article-18462_s8_">Toxicity</h2><p>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.<a class="bk_pop" href="#article-18462.r8">[8]</a> 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.<a class="bk_pop" href="#article-18462.r8">[8]</a></p></div><div id="article-18462.s9"><h2 id="_article-18462_s9_">Enhancing Healthcare Team Outcomes </h2><p>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.<a class="bk_pop" href="#article-18462.r8">[8]</a></p><p>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]</p></div><div id="article-18462.s10"><h2 id="_article-18462_s10_">Review Questions</h2><ul><li class="half_rhythm"><div>
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<a href="https://www.statpearls.com/account/trialuserreg/?articleid=18462&utm_source=pubmed&utm_campaign=reviews&utm_content=18462" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Access free multiple choice questions on this topic.</a>
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</div></li><li class="half_rhythm"><div>
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<a href="https://www.statpearls.com/articlelibrary/commentarticle/18462/?utm_source=pubmed&utm_campaign=comments&utm_content=18462" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Comment on this article.</a>
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</div></li></ul></div><div id="article-18462.s11"><h2 id="_article-18462_s11_">References</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="article-18462.r1">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. <span><span class="ref-journal">Clin Respir J. </span>2018 Jun;<span class="ref-vol">12</span>(6):2065-2074.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/29393580" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29393580</span></a>]</div></dd><dt>2.</dt><dd><div class="bk_ref" id="article-18462.r2">Daizadeh I. Pulmonary Arterial Hypertension: A Case Study in FDA Expedited Program Designations. <span><span class="ref-journal">Ther Innov Regul Sci. </span>2019 Mar;<span class="ref-vol">53</span>(2):264-269.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/29874936" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29874936</span></a>]</div></dd><dt>3.</dt><dd><div class="bk_ref" id="article-18462.r3">Oldfield V, Lyseng-Williamson KA. Bosentan: a review of its use in pulmonary arterial hypertension and systemic sclerosis. <span><span class="ref-journal">Am J Cardiovasc Drugs. </span>2006;<span class="ref-vol">6</span>(3):189-208.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16780392" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16780392</span></a>]</div></dd><dt>4.</dt><dd><div class="bk_ref" id="article-18462.r4">Pedersen J, Hedegaard ER, Simonsen U, Krüger M, Infanger M, Grimm D. Current and Future Treatments for Persistent Pulmonary Hypertension in the Newborn. <span><span class="ref-journal">Basic Clin Pharmacol Toxicol. </span>2018 Oct;<span class="ref-vol">123</span>(4):392-406.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/29855164" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29855164</span></a>]</div></dd><dt>5.</dt><dd><div class="bk_ref" id="article-18462.r5">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. <span><span class="ref-journal">Am J Cardiovasc Drugs. </span>2018 Apr;<span class="ref-vol">18</span>(2):93-102.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28660556" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28660556</span></a>]</div></dd><dt>6.</dt><dd><div class="bk_ref" id="article-18462.r6">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. <span><span class="ref-journal">Medicine (Baltimore). </span>2016 Nov;<span class="ref-vol">95</span>(48):e5511.</span> [<a href="/pmc/articles/PMC5134796/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5134796</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27902617" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27902617</span></a>]</div></dd><dt>7.</dt><dd><div class="bk_ref" id="article-18462.r7">Boss C, Bolli MH, Gatfield J. From bosentan (Tracleer®) to macitentan (Opsumit®): The medicinal chemistry perspective. <span><span class="ref-journal">Bioorg Med Chem Lett. </span>2016 Aug 01;<span class="ref-vol">26</span>(15):3381-94.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27321813" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27321813</span></a>]</div></dd><dt>8.</dt><dd><div class="bk_ref" id="article-18462.r8">Mathier MA, Ishizawar D. Bosentan. <span><span class="ref-journal">Expert Opin Pharmacother. </span>2010 Apr;<span class="ref-vol">11</span>(6):1023-34.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20307226" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20307226</span></a>]</div></dd></dl></div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_top_margin">
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<b>Disclosure: </b>Omar Masarweh declares no relevant financial relationships with ineligible companies.</p></div></dd><dt></dt><dd><div><p class="no_top_margin">
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<b>Disclosure: </b>Abhishek Bhardwaj declares no relevant financial relationships with ineligible companies.</p></div></dd></dl></div></div></div>
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<div class="post-content"><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 2025, StatPearls Publishing LLC.<p class="small">
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</p></div><div class="small"><span class="label">Bookshelf ID: NBK542293</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/31194433" title="PubMed record of this page" ref="pagearea=meta&targetsite=entrez&targetcat=link&targettype=pubmed">31194433</a></span></div></div></div>
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