Bosentan (Tracleer®)

Treatments for Pulmonary Hypertension

Issued by PHA’s Scientific Leadership Council. Information is based on the United States Food and Drug Administration drug labeling.
Last Updated February 2012

 

What is bosentan?

Bosentan is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH) in World Health Organization (WHO) Group 1 patients to improve exercise ability and decrease clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%) and PAH associated with congenital systemic-to-pulmonary shunts (18%).

Bosentan is an oral medication and was approved by the United States Food and Drug Administration (FDA) in 2001.

How does bosentan work?

Bosentan works by blocking the effects of a substance called endothelin, which is made by the body in increased amounts in patients with PAH. Endothelin causes blood vessels to narrow (constrict). It also causes overgrowth of the muscle in the walls of the blood vessels in the lungs. By blocking the action of endothelin, bosentan can lead to a reduction in the blood pressure in the lungs and to improvement in activity level and well being.

Short-term randomized studies demonstrate bosentan improves both exercise capacity and sense of well being. Long-term open label trials of the drug showed sustained benefit in exercise capacity.

One study demonstrated that bosentan improved hemodynamics and delayed time to clinical worsening in NYHA functional class II patients; however, six-minute walk distance was not significantly better.

In a small study of patients with congenital heart disease with Eisenmenger syndrome (right to left shunting), bosentan demonstrated improved 6 minute walk distance and hemodynamics such as pulmonary vascular resistance.

How is bosentan given?

Bosentan is a pill that is taken orally twice a day with or without food. The initial dose for most patients is 62.5 mg twice a day. If there are no problems or side effects after one month, the dose is increased to 125 mg twice a day, which is the FDA approved dose.

In patients over age 12 but with low body weight (less than 40 kg), the recommended dose is 62.5 mg twice daily.

How is bosentan supplied?

62.5 (round) and 125 (oval) mg, film-coated, biconvex, orange-white tablets.

How do patients obtain bosentan?

Bosentan must be prescribed by a physician and insurance approval must be obtained prior to starting therapy. Once approved by insurance, bosentan is then sent directly to patients by any of the following specialty pharmacies: Accredo Health Inc., Aetna Specialty Pharmacy, CVS Caremark, Cigna Tel-Drug, CuraScript, and Walgreens Specialty Pharmacy (Medmark). Bosentan can only be obtained through the Tracleer® Access Program (T.A.P.).

Will insurance pay for bosentan?

It is expected that most insurance plans will pay for bosentan prescriptions; however, plans with a set co-payment may result in substantial cost to the patient.

Medicaid and most state-run insurance plans will pay for bosentan. Medicare will also cover bosentan in most cases under the part D component of that program.

Actelion PAH Pathways® (866-288-3546) offers a variety of options to cover either partial or full drug costs for any patient with qualifying financial circumstances. Caring Voice Coalition (888-267-1440), an organization that provides grants to assist with drug cost for patients with chronic illnesses, may also provide coverage if the patient qualifies for such assistance.

What are the frequent side effects of bosentan?

Bosentan is generally well tolerated.

The most common side effects compared to placebo (sugar pill) are respiratory tract infections and anemia (low red blood cell count or hemoglobin); however, the decrease in hemoglobin is rarely severe enough to require transfusion.

The major potential side effect of bosentan is damage to the liver. in The development of abnormal liver function tests (LFTs), measured in blood samples to greater than 3 times the upper limit of normal is observed in about 10% of patients receiving this medication.

Fluid retention or swelling is a known side effect of ERAs. In the clinical trials with bosentan, fluid retention was observed slightly more commonly (1.7%) in patients taking bosentan compared to placebo. It is important to notify your doctor if you experience swelling. Treatment may be required including sodium and fluid restriction as well as a diuretic.

Decreases in sperm count have been observed in men taking bosentan.

How are side effects of bosentan monitored?

Because of the potential for damage to the liver, liver function tests must be obtained before initiating therapy and subsequently on a monthly basis as long as a patient is receiving bosentan.

Bosentan should be discontinued if the liver enzymes (hepatic aminotransferases) are accompanied by signs and symptoms of liver dysfunction or injury or by an increased total bilirubin to more than 2 times the upper limit of normal.

Because of the potential harm to the fetus, women of childbearing potential must also have a pregnancy test before initiating therapy and subsequently on a monthly basis as long as a patient is receiving bosentan.

Hematocrit (red blood cell count) should be checked at 1 and 3 months then monitored once every three months thereafter as long as a patient is receiving bosentan.

What are considerations for use of bosentan in special populations?

Use of bosentan is contraindicated in pregnancy. Bosentan has been shown to be harmful to the growing fetus in rats. Patients should not become pregnant while taking bosentan; therefore, two forms of contraception are recommended in order to be sure to prevent pregnancy. An exception to this recommendation would be for patients who have had a surgical sterilization procedure such as a tubal ligation or for women who use a Copper T380A or LNg 20 intrauterine device (IUD) as a form of contraception. In addition, a pregnancy test prior to the initiation and monthly thereafter while taking bosentan is advised. If a patient becomes pregnant while taking bosentan, she should immediately notify the prescribing physician. It is not known whether bosentan passes into breast milk; therefore, nursing mothers should not take bosentan.

Bosentan has been studied in children and appears to be safe. Nonetheless, the dose may need to be adjusted and should be discussed with the prescribing physician.

Bosentan is not recommended in patients with moderate to severe hepatic (liver) impairment. Use caution with mild liver impairment.

Dose adjustment for bosentan is not required for patients with renal (kidney) impairment.

Could a patient be allergic to bosentan?

This is possible, although such reports are rare.

What are important drug interactions with bosentan?

Bosentan is metabolized by an enzymatic pathway that may result in important drug interactions.

Bosentan may decrease the effectiveness of hormonal contraceptives given by any route. Hormonal contraceptives should not be used alone for the prevention of pregnancy during treatment with bosentan.

Bosentan should not be used with cyclosporine A or glyburide.

Ritonavir or ritonavir containing combination drugs require a special approach and dose adjustment if used with bosentan. Discontinue bosentan 36 hours prior to initiation of ritonavir. For patients already on ritonavir, initiate bosentan at 62.5 mg daily or every other day.

In patients receiving cholesterol lowering medications, cholesterol levels should be monitored carefully to determine if a dose adjustment is required for the cholesterol medication.

For patients taking rifampin and bosentan, drug levels may be altered. Liver function tests should also be carefully monitored.

Although not studied in humans, caution should be exercised if tacrolimus and bosentan are used together.

Bosentan levels may be increased with co-administration of ketoconazole.

While there are changes in drug levels with co-administration of sildenafil and bosentan, the differences do not appear to be clinically important.

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