TRACLEER THERAPY FOR PRIMARY PULMONARY HYPERTENSION (PPH)

Tracleer / Bosentan is the first of a new drug class, an endothelin receptor antagonist used to treat patients with pulmonary hypertension.The U.S. Food and Drug Administration (FDA) has announced to approval of TracleerT - the first oral medication for improving the exercise ability and decreasing clinical worsening of patients with the rare disorder of pulmonary hypertension. Tracleer (Bosentan) is a revolutionary advancement in the treatment of pulmonary hypertension (PH) and primary pulmonary hypertension (PPH).

Tracleer is the first tablet approved by the FDA for treatment for pulmonary hypertension. According to the FDA, Tracleer effectively blocks the action of endothelin, a substance made by the body. Endothelin narrows blood vessels and elevates blood pressure. The FDA states that "although endothelin is present in healthy people, high concentrations of the hormone have been found in the plasma and lungs of patients with [pulmonary hypertension] suggesting it is capable of causing the disease." According to the FDA, the use of Tracleer by persons with pulmonary hypertension may present two significant risks-liver toxicity and Tracleer's potential damage to a fetus.

TRACLEER (bosentan) belongs to a class of highly substituted pyrimidine derivatives, with no chiral centers. It is designated chemically as 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2]-bipyrimidin-4-yl]-benzenesulfonamide monohydrate. 

Tracleer (bosentan) is an orally active dual endothelin receptor antagonist (ERA). Tracleer works by blocking the binding of endothelin (ET) to both of its receptors ETA and ETB, thereby preventing the deleterious effects of ET. ET is produced and secreted by the endothelium, a single layer of cells covering the inner surface of blood vessels. ET not only regulates blood flow by causing blood vessels to narrow (vasoconstriction), but also causes other deleterious effects, such as stiffening blood vessels (fibrosis), changing their shape (remodeling) and size (hypertrophy), and predisposing them to inflammation. As a dual ERA, blocking both ET receptors, ETA and ETB, Tracleer has a unique potential compared to selective agents currently in development, which only block receptor type ETA. Tracleer represents the first approved drug of a new pharmaceutical class which blocks the detrimental effects of ET in disease situations, where its concentration is elevated.

TRACLEER - FDA TALK PAPER - NOV. 2001

FDA APPROVES FIRST ORAL MEDICATION FOR PULMONARY ARTERIAL HYPERTENSION

FDA today announced the approval of Tracleer (bosentan) tablets to improve the exercise ability of patients with a rare but fatal lung disorder called pulmonary arterial hypertension.Pulmonary arterial hypertension (PAH) is defined as abnormally high blood pressure in the arteries between the heart and lungs. PAH significantly reduces the ability of patients to exert themselves physically without becoming short of breath. PAH significantly shortens the life span of patients because it leads to heart failure.

Tracleer blocks the action of endothelin, a substance made by the body. Endothelin narrows blood vessels and elevates blood pressure. Although endothelin is present in healthy people, high concentrations of the hormone have been found in the plasma and lungs of patients with PAH suggesting it is capable of causing the disease.The use of Tracleer requires attention to two significant risks: liver toxicity and the drug's potential to damage a fetus. In order to ensure careful attention to monitoring for these risks, Tracleer will be available only through a direct distribution program from the drug's manufacturer, Actelion Pharmaceuticals US, Inc., of South San Francisco, Calif. It will not be available in commercial pharmacies.

These safety issues are highlighted in a black box warning in the drug's labeling for health professionals and explained in a brochure for patients. This information is known as a Medication Guide and must be distributed each time Tracleer is dispensed.Specifically, the black box information warns that liver enzyme levels must be measured before initiation of treatment with Tracleer and monthly thereafter to avoid liver injury. To date, the elevation of liver enzymes caused by Tracleer has been resolved without causing permanent liver damage.

Because of its potential to cause birth defects, Tracleer must not be prescribed to pregnant women. Female patients of childbearing potential must therefore take measures to prevent pregnancy, and monthly pregnancy testing will be required. Oral, injected and implanted contraceptives may not be reliably effective, because Tracleer may alter their metabolism in a way that reduces the effectiveness of hormonal contraceptives, so these methods must be supplemented by other methods or barrier methods must be used. Therefore, it is important for patients to consult with a gynecologist or other physician knowledgeable about contraceptives.

The FDA with the help of the Cardiovascular and Renal Drugs Advisory Committee determined that Tracleer is an effective treatment based on the results of two randomized, placebo-controlled clinical trials involving a total of 245 patients. In both studies, Tracleer or placebo was given in addition to any other medications currently prescribed. In both studies, treatment with Tracleer resulted in a significant increase compared to placebo in the 6-minute walking distance of patients receiving Tracleer, an additional 35 meters in one study and 54 meters in another. The improvement in walking distance was apparent after one month and fully developed by about two months of treatment. Significant improvement was maintained for up to seven months of Tracleer treatment.