Last updated Nov. 28, 2022, by Teresa Carvalho, MS
Fact-checked by José Lopes, PhD
What is Tracleer for PH?
Tracleer (bosentan) is an oral endothelin receptor antagonist (ERA) that aims to improve the ability to exercise in people with pulmonary arterial hypertension (PAH). It also works to reduce disease progression in PAH patients.
The medication is manufactured by Janssen in the U.S., the European Union, and other countries.
Several generic versions of Tracleer have been approved.
How does Tracleer work?
Tracleer is a molecule that blocks the actions of endothelin-1 (ET-1), a protein that causes blood vessels to narrow. In healthy people, ET-1 helps maintain a balance between high and low blood pressure. However, people with PAH produce too much ET-1, with abnormally high levels of ET-1 in both the bloodstream and inside the lining of blood vessels (the endothelium).
ET-1 exerts its effects on blood vessels by binding to one of two endothelin receptors — ETA or ETB. Tracleer binds to these receptors to block ET-1 from stimulating blood vessel narrowing, which helps the vessels relax and increases blood flow to the lungs.
Who can take Tracleer?
Tracleer has been approved for the treatment of both adults and children with PAH.
In the U.S., the therapy was approved in 2001 to improve exercise ability and to decrease disease worsening in PAH patients who belong to class 3 and 4 of the World Health Organization (WHO) system of functional classification. These classes include patients with significant limitation of normal activities.
The therapy’s approval was expanded in 2009 to class 2 patients, who experience discomfort and shortness of breath when doing normal chores.
In 2017, the U.S. Food and Drug Administration (FDA) approved the therapy in children with idiopathic (no known cause) or congenital PAH, ages 3 and older. It was the first FDA-approved medication for children with PAH.
In Europe, the treatment was first approved by regulatory authorities in 2002. That was expanded in 2009 to PAH children, ages 2 and older.
Who should not take Tracleer?
Tracleer should not be used by women who are pregnant or plan to become pregnant, as it may harm the developing fetus. Women of childbearing age should use two effective contraceptive methods while on Tracleer, and for one month after stopping the treatment, unless they have an intrauterine device or tubal sterilization, in which case no other method is needed.
Patients taking the immunosuppressant cyclosporine A should not be given Tracleer, as the simultaneous use of both medications may increase concentrations of bosentan — the therapy’s active ingredient — in the blood. Treatment with glyburide, used for diabetes, also is contraindicated in people taking Tracleer as it increases the risk of elevated liver enzyme levels.
Those who develop hypersensitivity, or allergic reactions, to Tracleer’s active component (bosentan) or any of its ingredients also should avoid this therapy.
How is Tracleer administered?
Tracleer is available as oral tablets in the following strengths:
- 32 mg, for oral suspension. These tablets can be divided into four parts, are pale yellow to off-white in color, and bear the number 32.
- 62.5 mg. Round, biconvex, and orange-white in color, these tablets are debossed with 62.5.
- 125 mg. Tablets at this strength are oval, biconvex, and orange-white, and bear the number 125.
Dosing is based on age and weight. In patients older than 12, the recommended doses are:
- an initial dose of 62.5 mg, twice daily, for four weeks, for patients weighing more than 40 kg (88 pounds). This is followed by a maintenance dose of 125 mg twice a day.
- 62.5 mg, twice daily, for patients weighing less than 40 kg.
In children ages 12 or younger, Tracleer also is recommended to be taken twice daily. The following doses are recommended, based on weight:
- 16 mg, for patients starting at 4 kg (8.8 pounds) and up to 8 kg (17.6 pounds).
- 32 mg, for those with weights between 8 kg and 16 kg (35.2 pounds).
- 48 mg, starting at a weight of 16 kg and up to 24 kg (52.8 pounds).
- 64 mg, for patients weighing between 24 kg and 40 kg, or 88 pounds.
Tracleer can be taken with or without food. A minimal amount of water should be added to make a liquid medicine right before taking the medication.
Dispersible tablets that have been broken to adjust the dose may be stored at room temperature (20 C to 25 C, 68 F to 77 F) in the opened blister for up to seven days.
Tracleer in clinical trials
Regulatory approval for patients with WHO functional class 3 and 4 was based on the results of two clinical trials called BREATHE-1 and Study 351.
BREATHE-1 trial and Study 351
BREATHE-1 compared two doses of Tracleer (125 mg and 250 mg, both twice daily) with a placebo. Study 351 compared 125 mg twice daily doses with a placebo.
In both trials, patients treated with Tracleer had a significant increase in exercise ability assessed by the 6-minute walking test, which measures the distance a patient is able to walk over six minutes. Participants who had received a 62.5 mg dose twice daily dose had an improvement in walk distance at one month of treatment that was maintained for up to seven months.
The Tracleer-treated patients also had a significant improvement in WHO functional class, as well as a reduction in shortness of breath during walk tests and the rate of clinical worsening. Notably, clinical worsening was measured as the sum of death, hospitalizations for PAH, therapy discontinuation, and need for the PH medication epoprostenol.
Study 351 also showed that treatment with Tracleer led to a significant reduction in pulmonary artery pressure, pulmonary vascular resistance — the internal resistance to blood flow within pulmonary arteries — and mean right arterial pressure, or the blood pressure in the upper-right chamber of the heart.
Tracleer was approved by the FDA for class 2 patients based on the results of the EARLY Phase 3 clinical trial (NCT00091715), completed in 2011. Participants in that trial were randomly assigned to receive Tracleer at 62.5 mg twice daily for four weeks, followed by 125 mg twice daily, or a placebo for six months.
Results showed that, when compared with study start values, treatment reduced pulmonary vascular resistance and increased exercise capacity. No such benefits were reported in the placebo group.
The FUTURE trials
A series of multi-center Phase 3 studies, called FUTURE-1 (NCT00319267), FUTURE-2 (NCT00319020), and FUTURE-3 (NCT01338415), tested the safety and tolerability of Tracleer in children.
FUTURE-1 included 36 children who received 2 mg/kg of Tracleer twice a day for four weeks, followed by 4 mg/kg twice a day for eight weeks. Results showed that a dose of 2 mg/kg twice a day achieved an acceptable risk/benefit profile.
FUTURE-2 and FUTURE-3 generally confirmed the long-term safety of Tracleer in this patient population, comparable to that seen in adults, and further supported 2 mg per kg, given twice daily, as the recommended dosing regimen in PAH children.
Common side effects of Tracleer
The most common side effects associated with Tracleer include:
- respiratory tract infections
- anemia, or low red blood cells counts
Tracleer carries a boxed warning that it can increase the risk of liver damage. The treatment is only prescribed by healthcare providers who are enrolled in the Bosentan Risk Evaluation and Mitigation Strategy (REMS) program. Levels of liver enzymes should be determined before starting the treatment and every month thereafter. Tracleer treatment should be discontinued if patients have increased levels of liver enzymes alongside symptoms of liver damage.
Tracleer can cause fluid retention and swelling, specially in ankles and legs. Patients are advised to talk with their healthcare provider if they have swelling of the ankles and legs with or without weight gain, or if they experience trouble with breathing.
Pulmonary veno-occlusive disease
In people with pulmonary veno-occlusive disease (PVOD) — a subtype of pulmonary hypertension characterized by the narrowing of veins — with signs of pulmonary edema, or buildup of fluid, a PVOD diagnosis should be considered and Tracleer treatment should be discontinued.
Decreased sperm counts
Preclinical studies showed that Tracleer, like other ERAs, may affect the production of sperm. In fact, lower sperm counts have been reported in patients on Tracleer.
Decreased red blood cell count
Tracleer may decrease levels of red blood cells and also of a protein in these cells called hemoglobin, which transports oxygen throughout the body. In post-marketing reports, this has led to blood transfusions. As such, healthcare providers are recommended to check hemoglobin levels one and three months after treatment start, and every three months thereafter. If a marked reduction in hemoglobin levels occurs, patients should be further examined to determine the underlying cause.
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