Last updated: October 29, 2014

Trade Names: Tracleer

Drug Class: Endothelin receptor antagonist

Preparations: Tablets: 62.5 and 125 mg

Dose: Initially 62.5 mg twice daily for a month; if tolerated, increase to 125 mg twice daily in adults weighing >40 kg.

Indications: (Only available through Tracleer Access Program, a restricted distribution program)
Pulmonary arterial hypertension; off label use for severe digital ulcers with Raynaud’s

Mechanism of Action: Blocks endothelin A and B receptors and prevents vasoconstriction

Contraindications: Hypersensitivity, pregnancy, use of glyburide or cyclosporine

Precautions: Because of teratogenicity and risk of liver impairment, prescribing is restricted through REMS program to registered prescribers. Avoid with hepatic impairment. Obtain baseline LFTs and monitor. Exclude pregnancy. Use 2 methods of reliable contraception.

Monitoring: Monitor LFTs at least monthly. Stop bosentan if transaminases have increased and there are any symptoms of clinical hepatic injury (fatigue, jaundice, nausea, increased bilirubin>2x upper limit of normal). Decrease dose to 62.5 mg twice daily  or interrupt therapy and monitor carefully (at least every 2 weeks) if a modest (3 to 5  times) increase in transaminases and no clinical symptoms of liver injury. Stop drug if transaminases are markedly elevated (five times or greater). Perform a monthly pregnancy test. Monitor hemoglobin monthly for 3 months, then every 3 months.

Pregnancy Risk: X. Teratogenic; contraindicated in pregnancy

Adverse Effects
Common: GI side effects, headache, anemia, edema, increased transaminases, decreased sperm count
Less common: Fatigue, flushing, liver injury, rash

Drug Interactions
Increased bosentan levels: Ritonavir, ketoconazole, cyclosporine and likely other CYP3A inhibitors; CYP2C9 inhibitors including fluconazole and amiodarone.
Increased hepatotoxicity: Glyburide
Decreased levels of other drugs: Bosentan decreases levels of cyclosporine, and because it induces CYP2C9 and CYP3A, it may decrease levels of a range of other drugs including hormonal contraceptives.

Patient Instructions: Do not become pregnant. Report nausea, vomiting, and orange-yellow discoloration of eyes, skin, or urine.

Comments: Bosentan is only prescribed by physicians expert in the management of pulmonary hypertension, generally cardiologists or pulmonologists with a special interest in pulmonary hypertension. Access to the drug is limited and obtained through the Tracleer access program. In subset analysis of a clinical trial, stabilization of 6-minute walk distance occurred in patients with scleroderma with pulmonary hypertension treated with bosentan. Bosentan may decrease formation of new digital ulcers in scleroderma but did not appear to speed healing.

Clinical Pharmacology: Bioavailability, 50%, half-life, 5 hours, hepatic metabolism by CYP3A and CYP2C9

Cost: $$$$$

Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896–903.PMID:11907289
Dhillon S. Bosentan: a review of its use in the management of digital ulcers associated with systemic sclerosis. Drugs. 2009;69:2005-24. PMID:19747014

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