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Bosentan

Therapeutic Indications

Bosentan is indicated for:

Pulmonary arterial hypertension (PAH)

Irrespective of gender only Adults (18 years old or older)

Bosentan is indicated for the treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in patients with WHO functional class III. Efficacy has been shown in:

  • Primary (idiopathic and heritable) PAH
  • PAH secondary to scleroderma without significant interstitial pulmonary disease
  • PAH associated with congenital systemic-to-pulmonary shunts and Eisenmenger’s physiology

Some improvements have also been shown in patients with PAH WHO functional class II.

For this indication, the medical literature mentions below treatments (click for details):

Treatment 1: Oral - 125-250 mg in 2 divided doses daily

Systemic sclerosis

Irrespective of gender only Adults (18 years old or older)

Bosentan is also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease.

For this indication, the medical literature mentions below treatments (click for details):

Treatment 1: Oral - 125-250 mg in 2 divided doses daily

Contraindications

Active ingredient Bosentan is contraindicated in the following cases:

Moderate to severe hepatic impairment

No gender/age discrimination

Bosentan is contraindicated in patients with moderate to severe liver dysfunction.

Elevations in liver aminotransferases, i.e. aspartate and alanine aminotransferases (AST and/or ALT), associated with bosentan are dose dependent. Liver enzyme changes typically occur within the first 26 weeks of treatment but may also occur late in treatment. These increases may be partly due to competitive inhibition of the elimination of bile salts from hepatocytes but other mechanisms, which have not been clearly established, are probably also involved in the occurrence of liver dysfunction. The accumulation of bosentan in hepatocytes leading to cytolysis with potentially severe damage of the liver, or an immunological mechanism, are not excluded. Liver dysfunction risk may also be increased when medicinal products that are inhibitors of the bile salt export pump, e.g. rifampicin, glibenclamide and cyclosporine A, are co-administered with bosentan, but limited data are available.

Liver aminotransferase levels must be measured prior to initiation of treatment and subsequently at monthly intervals for the duration of treatment with bosentan. In addition, liver aminotransferase levels must be measured 2 weeks after any dose increase.

Recommendations in the event of ALT/AST elevations:

ALT/AST levelsTreatment and monitoring recommendations
>3 and ≤5 × ULNThe result should be confirmed by a second liver test; if confirmed, a decision should be made on an individual basis to continue bosentan, possibly at a reduced dose, or to stop bosentan administration. Monitoring of aminotransferase levels should be continued at least every 2 weeks. If the aminotransferase levels return to pre-treatment values continuing or re-introducing bosentan according to the conditions described below should be considered.
>5 and ≤8 × ULNThe result should be confirmed by a second liver test; if confirmed, treatment should be stopped and aminotransferase levels monitored at least every 2 weeks. If the aminotransferase levels return to pre-treatment values re-introducing bosentan according to the conditions described below should be considered.
>8 × ULNTreatment must be stopped and re-introduction of bosentan is not to be considered.

In the event of associated clinical symptoms of liver injury, i.e. nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue, flu-like syndrome (arthralgia, myalgia, fever), treatment must be stopped and re-introduction of bosentan is not to be considered.

Re-introduction of treatment

Re-introduction of treatment with bosentan should only be considered if the potential benefits of treatment with bosentan outweigh the potential risks and when liver aminotransferase levels are within pre-treatment values.

Aminotransferase levels must then be checked within 3 days after re-introduction, then again after a further 2 weeks, and thereafter according to the recommendations above.

ULN = upper limit of normal

Lactation

No gender/age discrimination

It is not known whether bosentan is excreted into human breast milk. Breast-feeding is not recommended during treatment with bosentan.

Pregnancy

No gender/age discrimination

Studies in animals have shown reproductive toxicity (teratogenicity, embryotoxicity). There are no reliable data on the use of bosentan in pregnant women. The potential risk for humans is still unknown. Bosentan is contraindicated in pregnancy.

Ciclosporine A

No gender/age discrimination

Co-administration of bosentan and cyclosporine A (a calcineurin inhibitor) is contraindicated. When co-administered, initial trough concentrations of bosentan were approximately 30-fold higher than those measured after bosentan alone. At steady state, bosentan plasma concentrations were 3- to 4-fold higher than with bosentan alone. The mechanism of this interaction is most likely inhibition of transport protein-mediated uptake of bosentan into hepatocytes by cyclosporine. The blood concentrations of cyclosporine A (a CYP3A4 substrate) decreased by approximately 50%. This is most likely due to induction of CYP3A4 by bosentan.