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5/12/2019 3:04:10 PM


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 for the treatment of idiopathic or congenital PAH in the pediatric population ages 3 years and older.[4] New studies have shown that it may be useful in the treatment of 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 needs to be conducted 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 consist 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, whereas 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]


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 125mg or 250mg doses for adults. In the pediatric population, patients less than 12 years old bosentan dosage ranges from 31.25mg-125mg 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, and 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] Additional, less common adverse effects observed included a transient decrease in sperm count and decreases in hemoglobin and hematocrit.[8]


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 treatment.[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]


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, in addition to glyburide and cyclosporine. Other drug-drug interactions that may require careful monitoring due to bosentan 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 therapy.[8]


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 of toxicity presented. In one postmarket period, one episode of overdose by a male patient who took 10000mg 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’s emergence as a treatment for pulmonary arterial hypertension, the only other available treatments were intravenous medications, such as epoprostenol. Bosentan since has 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 relative low possibility of toxicity, ease of administration, effectiveness and its disease-modifying abilities, bosentan remains as 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 physicians, specialists, specialty-trained nursing staff, and pharmacists, all collaborating across disciplines to guide cases to optimal outcomes. [Level V]

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Bosentan - Questions

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What molecule does bosentan mimic?

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A 60-year-old male complains of shortness of breath while doing minimal yard work. He has little information about his condition from his previous visit with his pulmonologist from a different state. He states he recently had a test that showed a right ventricular systolic pressure of 45 mmHg and his mean pulmonary artery pressure was 58 mmHg. His current medications include warfarin and a diuretic. What is the mechanism of action of the drug that would most likely be recommended?

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Bosentan - References


Pedersen J,Hedegaard ER,Simonsen U,Krüger M,Infanger M,Grimm D, Current and Future Treatments for Persistent Pulmonary Hypertension in the Newborn. Basic     [PubMed]
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. American journal of cardiovascular drugs : drugs, devices, and other interventions. 2018 Apr;     [PubMed]
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. 2016 Nov;     [PubMed]
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. The clinical respiratory journal. 2018 Jun;     [PubMed]
Mathier MA,Ishizawar D, Bosentan. Expert opinion on pharmacotherapy. 2010 Apr;     [PubMed]
Daizadeh I, Pulmonary Arterial Hypertension: A Case Study in FDA Expedited Program Designations. Therapeutic innovation     [PubMed]
Oldfield V,Lyseng-Williamson KA, Bosentan: a review of its use in pulmonary arterial hypertension and systemic sclerosis. American journal of cardiovascular drugs : drugs, devices, and other interventions. 2006;     [PubMed]
Boss C,Bolli MH,Gatfield J, From bosentan (Tracleer®) to macitentan (Opsumit®): The medicinal chemistry perspective. Bioorganic     [PubMed]


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