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PharmaCare has Tracleer in-stock and is prepared to assist with the paperwork and phone calls necessary to initiate appropriate therapy through the Tracleer Assistance Program (TAP 1-866-279-0669).

For immediate patient pharmacy enrollment, please call 1-800-238-7828. Full product information is available by calling toll-free 1-800-238-7828 or by visiting tracleer.com

PRODUCT INFORMATION
Tracleer^TM (bosentan) tablets received FDA approval on November 20, 2001. Tracleer is the first of a new class of orally active, dual endothelin-receptor antagonists available for the treatment of Pulmonary Arterial Hypertension (PAH). Tracleer is indicated for the treatment of PAH patients in the World Health Organization (WHO) functional Class III or IV, a life-threatening condition that can severely impair the function of the heart and the lungs.

CLINICAL TRIALS
The indication of Tracleer is based on two Phase III, international, double-blind, placebo-controlled, prospective multi-center clinical trials that were conducted to evaluate the safety and efficacy of the drug. The primary endpoint of both studies was an improvement in exercise capacity(6-minute walk distance). The results from both trials showed that treatment with Tracleer resulted in a significant increase in exercise capacity. The improvement in distance walked was apparent with 1 month of treatment and was maintained for up to 7 months. Furthermore, there was a significant reduction in dyspnea immediately after the walk test (Borg dyspnea score) and significant improvement in WHO Functional Class in Tracleer-treated patients.

MECHANISM OF ACTION
Tracleer is a non-peptide, orally active, dual endothelin (ET) receptor antagonist that inhibits the activity of endothelin-1 (ET-1) by competitively binding to both ET_A and ET_B receptors. ET-1 plays an important role in the pathophysiology of PAH by inducing vasoconstriction of the pulmonary arteries and promoting proliferation of the vascular smooth muscle and profibrotic effects of the endothelium. Inhibition of the ET-1 leads to Tracleer's therapeutic effects of decreased pulmonary fibrosis and inflammation, decreased pulmonary vascular hypertrophy and right ventricular hypertrophy, and decreased pulmonary artery pressure (in animal models of the disease).

DOSAGE AND ADMINISTRATION

• In clinical studies the recommended starting dose of Tracleer is 62.5 mg PO BID for 4 weeks.
• The same studies suggest after 4 weeks the dose be increased to a target dose of 125 mg bid as a maintenance dose.
• Tracleer can be taken with or without food.

DRUG INTERACTION
Since the cytochrome P-450 isoenzymes, CYP3A4 and CYP2C9, and subsequent biliary clearance are responsible for the metabolism of Tracleer, plasma levels of Tracleer may change if combined with medications metabolized by the same isoenzymes. Ketoconazole and Cyclosporine have been shown to increase the concentration of Tracleer by inhibiting CYP3A4. Tracleer may also be responsible for the reduction in the efficacy of drugs metabolized by CYP3A4 or CYP2C9(i.e. statins and warfarin) since it induces CYP3A4 and CYP2C9 activity. Tracleer should not be combined with glyburide due to an increased risk of elevated aminotransferase levels.

ADVERSE REACTIONS
The most common drug-related adverse events (> = 3 % of patients treated with Tracleer) includes headache, edema, flushing, hypotension, dyspnea, nausea and vomiting, cough, abdominal pain, influenza, and dizziness. More serious adverse events include anemia and elevated liver enzyme levels (see Monitoring Parameters).

MONITORING PARAMETERS

• Tracleer carries a BOX WARNING for potential liver injury. Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly. If elevations in liver aminotransferase levels are seen, changes in monitoring and treatment must be initiated (see Dosage Adjustment and Monitoring), and if elevations are accompanied by clinical symptoms of liver injury (i.e. nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in billirubin >= 2 x ULN, treatment should be stopped.
• Tracleer carries a BOX WARNING for a CONTRAINDICATION for use in pregnancy. Pregnancy must be excluded before the start of treatment and prevented thereafter by use of reliable contraception. Hormonal contraceptives, including oral, injectable, and implantable contraceptives may not be reliable in the presence of Tracleer due to a potential drug interaction and thus should not be used as the sole contraceptive method. Follow-up urine or serum pregnancy test should be obtained monthly in women of childbearing potential.
• Hemoglobin (Hgb) levels should be monitored after 1 and 3 months of therapy and then every 3 months.

DOSAGE ADJUSTMENT AND MONITORING

CONTRAINDICATIONS
The use of Tracleer should be avoided in patients with ALT/AST >3 x ULN at baseline, patients with moderate to sever liver impairment, patients taking glyburide or cyclosporine A, and pregnant women.

AVAILABILITY

• Tracleer is available as 62.5 mg strength and 125 mg strength tablets.
• Tracleer should be stored between 20°C - 25°C (68°F - 77°F).

Physicians seeking to prescribe, or patients wanting to learn more about, Tracleer should contact the Tracleer Access Program (TAP) Monday through Friday (excluding holidays) from 8:00 a.m. to 8:00 p.m. Eastern Standard Time. The Patient Enrollment Forms are available by calling TAP, by faxing a request to 1- 866-279-0669, or by contacting an Actelion representative. PharmaCare is the nation's leading specialty pharmaceutical provider with over 11,000 contracted insurance plans, clinically-trained pharmacists and nationwide delivery to your office or patient's home at no additional charge. Choose PharmaCare as the Tracleer Pharmacy for your patients.

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