Bosentan
Regulatory sources consulted
Approved indications
- Spain: treatment of pulmonary arterial hypertension to improve symptoms and exercise capacity in patients in WHO functional class III. The product information separately reports improvements observed in functional class II patients, without extending the approved indication stated here to that class.
- Spain: reduction in the number of new digital ulcers in patients with systemic sclerosis and active digital ulcer disease; it is not indicated to heal existing ulcers.
- United States: WHO Group 1 pulmonary arterial hypertension in adults; in pediatric patients aged 3 years and older with idiopathic or congenital PAH.
Contraindications
Absolute
- Pregnancy; females of reproductive potential not using reliable contraception.
- Moderate or severe hepatic impairment, elevated baseline aminotransferases, concomitant cyclosporine A or glyburide, or hypersensitivity.
Clinical warnings
- Boxed warning · Risk of hepatotoxicity and embryo-fetal toxicity: perform periodic liver tests, exclude pregnancy, use effective contraception, and stop treatment if pregnancy is detected. — DailyMed label; AEMPS CIMA registro 81567
- Major warning · May cause anemia; measure hemoglobin before treatment, at one month, at three months, and periodically thereafter. — AEMPS CIMA registro 81567
Drug interactions
- HighCyclosporine A
Mechanism: Markedly increases bosentan exposure and bosentan reduces cyclosporine concentration.
Recommendation: Contraindicated: do not use together.
https://cima.aemps.es/cima/dochtml/ft/81567/FT_81567.html
- HighHormonal contraceptives
Mechanism: Bosentan reduces exposure to and effectiveness of hormonal contraceptives.
Recommendation: Do not use as the sole method; use additional or alternative effective contraception.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8444da17-6c31-492b-8842-93740f083d9d
- HighGlyburide
Mechanism: The combination reduces glyburide concentrations and increases the risk of aminotransferase elevations.
Recommendation: Do not use together.
https://cima.aemps.es/cima/dochtml/ft/81567/FT_81567.html
- HighFluconazole or combined CYP2C9 and CYP3A4 inhibition
Mechanism: It may substantially increase bosentan exposure.
Recommendation: The combination is not recommended.
https://cima.aemps.es/cima/dochtml/ft/81567/FT_81567.html
- HighRifampin
Mechanism: CYP2C9 and CYP3A4 induction markedly reduces exposure and may reduce bosentan efficacy.
Recommendation: The combination is not recommended.
https://cima.aemps.es/cima/dochtml/ft/81567/FT_81567.html
- HighTacrolimus or sirolimus
Mechanism: They may increase bosentan exposure, while bosentan may reduce tacrolimus or sirolimus concentrations.
Recommendation: Not recommended; if essential, monitor adverse reactions and immunosuppressant blood concentrations.
https://cima.aemps.es/cima/dochtml/ft/81567/FT_81567.html
Adverse events
Common (≥1%)
Respiratory tract infection · Anemia · Headache · Edema
Rare but serious
Liver failure · Autoimmune hepatitis · Severe anemia
Pregnancy and lactation
FDA category: Contraindicado en el embarazo
May cause fetal harm; use effective contraception before, during, and for one month after treatment. Breastfeeding is not recommended during treatment.
Recent literature (PubMed)
Pulmonary arterial hypertension (PAH) is a subtype of pulmonary hypertension (PH), characterized by pulmonary arterial remodeling. The prevalence of PAH is approximately 10.6 cases per 1 million adults in the US. Untreated, PAH progresses to right heart failure and death. Pulmonary hypertension is defined by a mean pulmonary artery pressure greater than 20 mm Hg and is classified into 5 clinical groups based on etiology, pathophysiology, and treatment. Pulmonary arterial hypertension is 1 of the 5 groups of PH and is hemodynamically defined by right heart catheterization demonstrating a mean pulmonary artery pressure greater than 20 mm Hg, a pulmonary artery wedge pressure of 15 mm Hg or lower, and a pulmonary vascular resistance of 3 Wood units or greater. Pulmonary arterial hypertension is further divided into subgroups based on underlying etiology, consisting of idiopathic PAH, heritable PAH, drug- and toxin-associated PAH, pulmonary veno-occlusive disease, PAH in long-term responders to calcium channel blockers, and persistent PH of the newborn, as well as PAH associated with other medical conditions including connective tissue disease, HIV, and congenital heart disease. Early presenting symptoms are nonspecific and typically consist of dyspnea on exertion and fatigue. Currently approved therapy for PAH consists of drugs that enhance the nitric oxide-cyclic guanosine monophosphate biological pathway (sildenafil, tadalafil, or riociguat), prostacyclin pathway agonists (epoprostenol or treprostinil), and endothelin pathway antagonists (bosentan and ambrisentan). With these PAH-specific therapies, 5-year survival has improved from 34% in 1991 to more than 60% in 2015. Current treatment consists of combination drug therapy that targets more than 1 biological pathway, such as the nitric oxide-cyclic guanosine monophosphate and endothelin pathways (eg, ambrisentan and tadalafil), and has shown demonstrable improvement in morbidity and mortality compared with the previ
Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease with multi-organ involvement, fibrosis and vasculopathy. Treatment in SSc, including early diffuse cutaneous SSc (dcSSc) and the use of organ-specific therapies, has improved, as evident from randomized clinical trials. Treatments for early dcSSc include immunosuppressive agents such as mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab and tocilizumab. Patients with rapidly progressive early dcSSc might be eligible for autologous haematopoietic stem cell transplantation, which can improve survival. Morbidity from interstitial lung disease and pulmonary arterial hypertension is improving with the use of proven therapies. Mycophenolate mofetil has surpassed cyclophosphamide as the initial treatment for SSc-interstitial lung disease. Nintedanib and possibly perfinidone can be considered in SSc pulmonary fibrosis. Pulmonary arterial hypertension is frequently treated with initial combination therapy (for example, with phosphodiesterase 5 inhibitors and endothelin receptor antagonists) and, if necessary, the addition of a prostacyclin analogue. Raynaud phenomenon and digital ulcers are treated with dihydropyridine calcium channel blockers (especially nifedipine), then phosphodiesterase 5 inhibitors or intravenous iloprost. Bosentan can reduce the development of new digital ulcers. Trial data for other manifestations are mostly lacking. Research is needed to develop targeted and highly effective treatments, best practices for organ-specific screening and early intervention, and sensitive outcome measurements. A study in one patient taking bosentan during breastfeeding found very low levels in milk. Another woman breastfed her preterm newborn while taking bosentan and sildenafil with no adverse effects reported. Amounts ingested by the infant are far below doses given to treat infants and would not be expected to cause any adverse effects in breastfed infants.
Raynaud's phenomenon (RP) is a condition characterized by episodic, excessive vasoconstriction in the fingers and toes, triggered by cold or stress. This leads to a distinctive sequence of color changes in the digits. Pallor indicates reduced blood flow due to oxygen deprivation, while erythema appears as reperfusion. RP can be primary, with no identifiable underlying cause, or secondary, associated with other conditions. These conditions include autoimmune diseases, most commonly systemic sclerosis, vascular diseases; and neurological conditions. While the exact cause of RP remains unclear, genetic and hormonal (estrogen) factors are likely contributors. The pathogenesis of RP involves a complex interaction between the vascular wall, nerves, hormones, and humoral factors, disrupting the balance between vasoconstriction and vasodilation. In primary RP, the vascular abnormalities are primarily functional. However, in secondary RP, both functional and structural components occur in blood vessels. This explains why digital tissue damage frequently occurs in secondary RP but not primary RP. Diagnosis of RP is primarily clinical. Recent advancements in imaging techniques have aided in diagnosis and monitoring, but nail fold capillaroscopy remains the gold standard for distinguishing between primary and secondary RP. If there are signs of acute ischemic injury, vascular imaging, particularly preoperatively, is crucial to rule out other vaso-occlusive conditions. Management of RP focuses on alleviating symptoms and preventing tissue damage. Vasodilator medications are the first-line treatment when general measures like warmth and stress management are not sufficient. Dihydropyridine calcium channel blockers (CCBs), such as nifedipine, are commonly used for vasodilation. Phosphodiesterase-5 inhibitors and prostaglandin analogs are alternative options for patients who do not respond to CCBs or have ischemic tissue damage. Bosentan, an endothelin-1 receptor antagonist, has sh
The evidence for the treatment of connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) mostly depends on subgroup or post hoc analysis of randomized controlled trials (RCTs). Thus, we performed a meta-analysis of RCTs that reported outcomes for CTD-PAH. PubMed and EMBASE were searched for CTD-PAH treatment. The selected outcomes were functional class (FC) change, survival rates, 6-min walk distance (6-MWD), clinical worsening (CW), N-terminal prohormone BNP (NT-proBNP), pulmonary vascular resistance (PVR), mean pulmonary arterial pressure (mPAP), right atrial pressure (RAP), and cardiac index (CI). The meta-analysis was conducted according to the PRISMA guidelines and registered in PROSPERO (CRD42020153560). Twelve RCTs conducted with 1837 patients were included. The diagnoses were systemic sclerosis in 59%, SLE in 20%, and other CTDs in 21%. The pharmacological interventions were epoprostenol, treprostinil, sildenafil, tadalafil, bosentan, macitentan, ambrisentan, riociguat, and selexipag. There was a significant difference between interventions and placebo in FC, 6MWD, CW, PVR, RAP, and CI that favored intervention. Our analysis showed a 39% reduction in the CW risk with PAH treatment. The short-term survival rates and mean serum NT-proBNP changes were similar between the study and control groups. Treatment for CTD-PAH had favorable effects on clinical and hemodynamic outcomes but not on survival and NT-proBNP levels. Different from the previous meta-analyses that focused on 6-MWD, time to clinical worsening, and CW as outcomes, this meta-analysis additionally reports the pooled analysis of change in FC, hemodynamic measurements (RAP, PVR, CI), and NT-proBNP, some of which have prognostic value for PAH.