It is important to notify your physician if you experience swelling or any other side effects. Treatment may be required including reducing salt and fluid in your diet, as well as a water pill diuretic to promote increased fluid removal through the kidneys. Decreases in sperm count have been observed in men taking bosentan. Because of the potential of damage to the liver, liver function tests LFTs must be obtained before initiating therapy and every month as long as a patient is receiving bosentan.
A physician will guide a patient in managing their liver enzymes if they become elevated. This may require a patient stop the medication.
Bosentan should be stopped if the blood tests for liver enzymes LFTs are accompanied by signs and symptoms of abnormal liver function or injury, or by an increased total bilirubin another blood test for liver function to more than 2 times normal.
Because of the potential harm to the fetus, women must also have a pregnancy test before initiating therapy and on a monthly basis as they are receiving bosentan. Red blood cell counts should be checked at one and three months after initiation of bosentan therapy. This should then be monitored once every three months as long as a patient is receiving bosentan. Bosentan should not be used in pregnancy. Bosentan has been shown to be harmful to the fetus in research studies of rats and rabbits.
Patients should not become pregnant while taking bosentan. Therefore, two forms of contraception are recommended when taking bosentan to prevent pregnancy: Surgical treatment to prevent pregnancy, such as a tubal ligation and; a Copper TA or LNg 20 intrauterine device IUD.
In addition, a pregnancy test prior to the initiation of bosentan and monthly thereafter is advised. If a patient becomes pregnant while taking bosentan, she you should stop the bosentan and immediately notify her doctor. It is not known whether bosentan passes into breast milk; therefore, nursing mothers should not take bosentan. Bosentan is broken down by the body in a way that may result in important interactions with other drugs the patient may be taking at the same time.
Ritonavir or ritonavir-containing combination drugs require a special approach and dose changes if used with bosentan.
The dosing should by adjusted by the doctor. In patients receiving cholesterol-lowering medications, cholesterol levels should be monitored carefully to determine if the cholesterol medication dose requires a change.
For patients taking rifampin and bosentan, drug levels may be altered. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take bosentan exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor. If you are taking the dispersible tablet, place the tablet in a small amount of liquid right before you take it. If your doctor has told you to take a half tablet, break the dispersible tablet carefully on the line.
Take the half tablet as directed, and put the other half back in the opened blister in the package. Use the other half tablet within 7 days. Do not break the dispersible tablet into quarters. Your doctor will probably start you on a low dose of bosentan and increase your dose after 4 weeks.
Bosentan controls the symptoms of PAH but does not cure it. It may take 1 to 2 months or longer before you feel the full benefit of bosentan. Continue to take bosentan even if you feel well. Do not stop taking bosentan without talking to your doctor. If you suddenly stop taking bosentan, your symptoms may get worse. Your doctor may decrease your dose gradually. This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.
Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one. Male laboratory animals who were given medications similar to bosentan developed problems with their testicles and produced fewer sperm male reproductive cells than normal. It is not known if bosentan will damage the testicles or decrease the number of sperm produced in men.
Talk to your doctor about the risks of taking bosentan if you would like to have children in the future. Bosentan may cause other side effects.
Call your doctor if you have any unusual problems while taking this medication. Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture not in the bathroom. Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program.
It is important to keep all medication out of sight and reach of children as many containers such as weekly pill minders and those for eye drops, creams, patches, and inhalers are not child-resistant and young children can open them easily.
To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location — one that is up and away and out of their sight and reach. However, responses are variable and in many patients, disease progresses despite therapy. As a result an increasing number of patients are being considered for combination therapy Hoeper and Dinh-Xuan Current therapies in the treatment of PAH act on the three intracellular pathways, endothelin, nitric oxide and prostacyclin, known to be abnormal in PAH Figure 1.
A logical extension therefore is to use a combination of two or more therapies each acting in synergy through a different pathway Hoeper and Dinh-Xuan The combination of bosentan and sildenafil is of particular interest because both are oral agents, which are generally well tolerated.
Hoeper and colleagues reported the clinical course of 9 patients with severe idiopathic PAH, in whom bosentan caused transient clinical improvement, eventually followed by a decline in exercise tolerance, who then received adjunct treatment with sildenafil. Bosentan was associated with an initial improvement in six minute walk test distance but this effect was not sustained. Three months later, the six minute walk test distance had increased by a mean of m and this improvement persisted for a median follow up of nine months Hoeper et al In a small German study, involving eleven patients with different forms of pulmonary hypertension, but including idiopathic PAH and congenital heart disease, Lunze and co-authors Lunze et al found that the combination of sildenafil and bosentan was associated with improvements in exercise capacity and reduction in mean pulmonary artery pressure.
They found that the combination was well tolerated although one patient died suddenly for reasons that are not evident in the paper. There is a pharmacological interaction between bosentan and sildenafil in that bosentan decreases the plasma concentration of sildenafil and sildenafil increases the plasma concentration of bosentan when they are co-prescribed in PAH Paul et al However, this interaction does not appear to be associated with significant problems and the combination of bosentan and sildenafil does not appear to be associated with an increased risk of abnormal elevation of liver transaminases when compared to the use of bosentan alone Hoeper, Kiely et al Humbert and colleagues reported the results of a double blind placebo controlled prospective study in which 33 patients with PAH were commenced on intravenous epoprostenol treatment and were randomized to receive either bosentan or placebo.
Hemodynamics, exercise capacity and functional class improved in both groups at week 16 and in the combination treatment group there was a trend for a greater although non significant improvement in all measured hemodynamic parameters. The addition of iloprost was also associated with significant improvement in NYHA functional class and increased time to clinical worsening when compared with placebo.
The authors concluded that within the limitations of the relatively small sample size, the addition of inhaled iloprost in patients with PAH with reduced exercise capacity on bosentan monotherapy was both safe and efficacious.
It has become increasingly clear that where it has been used, combination therapy with two or more agents has been associated with improvements in exercise capacity and functional class in patients with PAH. The question of which combination should be used and when remains unclear Hoeper and Dinh-Xuan Some authors have recommended adding increasing number of agents in combination, when specific treatment goals have not been met.
Hoeper and colleagues have shown Hoeper, Markevych et al that this goal oriented approach to therapy, based on achieving set functional criteria, has been associated with improved survival and less requirement for transplantation than in a historical cohort treated with monotherapy alone. In summary, whilst ongoing studies are required in assessing bosentan as part of combination therapy it appears that such a strategy can be associated with improvements in exercise capacity, functional class and possibly survival in patients with PAH Hoeper et al ; Hoeper and Dinh-Xuan ; Humbert, Barst et al ; Hoeper, Kiely et al ; Hoeper, Markevych et al ; Paul et al ; Lunze et al ; McLaughlin et al Atrial septostomy and lung transplantation are potential lifesaving therapies, which are reserved for a small number of patients who are deemed likely to benefit from them and in whom the selective PAH therapies discussed above are ineffective.
A detailed discussion of these therapies is beyond the scope of this article and the reader is referred elsewhere for a detailed discussion of surgical therapies in PAH including atrial septostomy and lung transplantation ASTP et al ; Doyle et al Sitbon and colleagues have described the criteria that they use to categorize patients as failing to respond to 3-months of intravenous epoprostenol therapy Sitbon et al These patients were then considered for lung transplantation.
Although no such criteria have been described for bosentan, alone or in combination with other agents, the reader is referred to the general principles prescribed by Sitbon and others when considering timing for referral for transplantation ASTP et al ; Sitbon et al ; Doyle et al There is limited data on the cost-effectiveness of bosentan or other specific PAH therapies Wlodarczyk et al , despite the importance that health authorities appropriately place on such data.
These drugs are generally expensive and availability is limited in most countries. This may reflect the resistance of some health authorities to subsidise therapy for patients in other functional classes. It is our view that part of the responsibility of health care professionals is to advocate for reduced costs and greater availability of these therapies especially in developing countries.
The dual endothelin receptor antagonist bosentan given at a dose in adults of The use of bosentan as part of a comprehensive management plan has resulted in improvements in exercise capacity, functional class, quality of life and survival.
Patients require regular monthly monitoring of liver function tests and clear guidelines are in place in terms of reducing or stopping bosentan therapy depending upon the results of these liver function tests. Bosentan has been extensively used as monotherapy in PAH especially in patients with idiopathic PAH and scleroderma associated PAH but also appears to be efficacious in other forms of pulmonary hypertension including other connective tissue disease associated PAH, HIV associated PAH and Eisenmenger syndrome as well as in selected cases of chronic thromboembolic pulmonary hypertension.
Bosentan may also have a role as part of combination therapy in patients who have responded sub optimally to monotherapy.
National Center for Biotechnology Information , U. Vasc Health Risk Manag. Author information Copyright and License information Disclaimer. All rights reserved. This article has been cited by other articles in PMC. Abstract The dual endothelin receptor antagonist, bosentan, is an orally active therapy, which is effective in the treatment of pulmonary arterial hypertension PAH.
Keywords: bosentan, pulmonary arterial hypertension, review. Introduction Pulmonary arterial hypertension PAH is a condition characterized by dyspnea, fatigue, chest pain and syncope Gaine and Rubin ; Runo and Loyd ; Galie ; Rubin Definition and classification Pulmonary hypertension is defined as a sustained elevation of mean pulmonary artery pressure to a level greater than 25 mmHg at rest or greater than 30 mmHg during exercise Runo and Loyd ; Galie ; Rubin Open in a separate window.
Pathogenesis and rationale for PAH therapies A detailed discussion of the pathogenesis of PAH is beyond the scope of this article and readers are referred elsewhere Voelkel et al ; Humbert, Morrell et al Epidemiology and genetics The incidence and prevalence of idiopathic pulmonary arterial hypertension is uncertain. Treatment of PAH Conventional therapy for PAH General measures including management of underlying or contributing factors, avoidance of pregnancy, early treatment of intercurrent respiratory infections with antibiotics and the use of influenza and anti-pneumococcal vaccines are recommended Galie ; Rubin Figure 1.
Table 2 Specific PAH therapies and method of delivery. Table 3 Impact of bosentan therapy in patients with idiopathic pulmonary arterial hypertension. Placebo-controlled pivotal studies and open labeled extension In the first placebo controlled study of bosentan in PAH Channick et al Channick and co-authors reported on 32 patients with either idiopathic PAH or scleroderma associated PAH who were randomly assigned to receive bosentan Effect of bosentan on survival in idiopathic PAH None of the placebo-controlled trials of bosentan in PAH were powered to show survival benefit.
Figure 2. Effect of bosentan on quality of life of patients with PAH In an uncontrolled Australian study bosentan monotherapy was associated with significant improvements in quality of life, as measured by the SF questionnaire, which persisted for months Keogh et al Recommendations for role of bosentan monotherapy in PAH The data from the studies in idiopathic, familial and Scleroderma-associated PAH has led to the recommendation that bosentan monotherapy is indicated for patients in WHO functional class III in these conditions Galie Bosentan in other forms of associated PAH Most of the clinical studies of bosentan in PAH have concentrated on patients with idiopathic and familial PAH as well as those with PAH in association with connective tissue disease especially scleroderma.
Table 4 Impact of bosentan therapy in pulmonary arterial hypertension PAH subgroups. Pediatrics The data on efficacy and safety of bosentan in pediatric patients with PAH is not as extensive as that in adults.
Dose of bosentan in treatment of PAH The large placebo controlled study of two bosentan dosing regimes in adult patients with PAH Rubin et al found that the dose of bosentan of Table 6 Recommended dosing regimens for bosentan in adults and children. Safety and tolerability The most significant adverse event in patients on bosentan treatment is the potential development of abnormal hepatic function and specifically a rise in hepatic amino transaminases.
Table 7 Monitoring and management of elevated liver enzymes for patients treated with bosentan. Bosentan as part of combination therapy The newer specific PAH therapies such as bosentan have resulted in significant improvements in exercise capacity, cardiopulmonary hemodynamics and survival.
Goal oriented combination therapy It has become increasingly clear that where it has been used, combination therapy with two or more agents has been associated with improvements in exercise capacity and functional class in patients with PAH. Atrial septostomy and lung transplantation Atrial septostomy and lung transplantation are potential lifesaving therapies, which are reserved for a small number of patients who are deemed likely to benefit from them and in whom the selective PAH therapies discussed above are ineffective.
Cost-effectiveness and access to specific PAH therapies There is limited data on the cost-effectiveness of bosentan or other specific PAH therapies Wlodarczyk et al , despite the importance that health authorities appropriately place on such data. Summary The dual endothelin receptor antagonist bosentan given at a dose in adults of International guidelines for the selection of lung transplant patients.
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