Bosentan Tablets (Tracleer—Actelion)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
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The FDA recently approved the first oral drug for the treatment of pulmonary arterial hypertension (PAH). Bosentan is an endothelin-1 receptor antagonist developed by Actelion Pharmaceuticals. The drug will not be available in pharmacies, rather it will be dispensed via a direct distribution program by calling the company at 1-866-228-3546. Bosentan will be marketed under the tradename Tracleer.
Indications
Bosentan is indicated for the treatment of PAH in patients with WHO Class III or IV symptoms, to improve exercise ability and decrease the rate of clinical worsening.1
Dosage
The starting dose is 62.5 mg twice daily (morning and evening) for 4 weeks. The dose is then increased to 125 mg twice daily. It may be taken without regard to meals. Higher doses are not recommended due to potential for liver toxicity. Dose adjustment is not required in patients with renal impairment. It should be used with caution in patients with mild hepatic impairment and should be avoided in those with more severe impairment. If ALT or AST levels are confirmed to be elevated between 3 to 5 times upper limit of normal (ULN), the dose of bosentan should be reduced or discontinued. If ALT or AST levels are between 5 and 8 times the ULN, treatment should be stopped. Levels should be monitored every 2 weeks, and if the levels return to pretreatment levels, dose should be continued or reinstated. If ALT or AST is > 8 times ULN, treatment should be discontinued and not reintroduced.1
Bosentan is available as 62.5 mg and 125 mg tablets.
Potential Advantages
Bosentan is the first oral drug for the treatment of PAH. Clinical studies indicate that bosentan improves the 6-minute walk distance. A change from baseline of 27 ± 75 m and 70 ± 56 m was reported in 2 studies compared to -8 ± 96 m and -6 ± 121 m for placebo, respectively.1,2 In addition, bosentan produced improvements in cardiopulmonary hemodynamics such as cardiac index, pulmonary artery pressure, mean right arterial pressure, and pulmonary vascular resistance compared to placebo. Improvement in Borg dyspnea index and WHO functional class were also reported.2 The effects appear to be maintained for 20-28 weeks.
Potential Disadvantages
Bosentan is contraindicated in pregnancy, as the drug is likely to produce major birth defects. Contraception other than hormonal contraceptives (oral, injectable, or implantable) must be used during bosentan therapy since the drug may reduce the effectiveness of these methods of contraception. Bosentan is an inducer of cytochrome P450 isoenzyme 3A4 that metabolizes these drugs.1 Concomitant administration of cyclosporine or glyburide and bosentan is contraindicated. Dosage adjustment may be needed with simvastatin or other statins. Bosentan is also an inducer of CYP 2C9. Since bosentan is potentially hepatotoxic, liver aminotransferases should be measured at baseline and monthly thereafter. Bosentan also causes a dose-related decrease in hemoglobin and hematocrit. Hemoglobin levels should be monitored 1-3 months after initiation of therapy and every 3 months thereafter.1 In one study, mean reduction in hemoglobin was 0.9 g/dL detected in the first few weeks or therapy and stabilizing in 4-12 weeks.1 The mechanism for this effect is not known. Other side effects include headache and flushing. There are currently no published data on the effect of bosentan on survival.
Comments
Endothelin-1 is a potent peptide vasoconstrictor that has been implicated in different pulmonary diseases including pulmonary hypertension.5 Bosentan is an endothelin-1 receptor antagonist, which has been shown to improve cardiopulmonary parameters. The efficacy of bosentan was based on 2 placebo-controlled studies involving a total of 245 patients. These patients had symptomatic, severe (WHO classes III-IV), primary pulmonary hypertension or pulmonary hypertension due to scleroderma or other connective tissue diseases or autoimmune diseases. Bosentan was added to current therapy that included vasodilators, anticoagulants, diuretics, digoxin, or supplemental oxygen. Patients on epoprostenol (prostacyclin, Flolan) were not included in these studies. The primary end point was a 6-minute walking distance. Patients on bosentan in the BREATHE-1 (Bosentan Randomized Trial of Endothelin Receptor Antagonist THErapy) trial (n = 231) had a mean increase in 6-minute walk at 4 months from 326 ± 73 m to 353 ± 115 m compared to 344 ± 76 m to 336 ± 129 m for placebo. In a smaller study (n = 32), bosentan patients improved from 360 ± 86 m to 431 ± 66 m compared to 355 ± 82 m to 350 ± 147 m at 3 months. Secondary end points included cardiopulmonary hemodynamics. In addition, clinical worsening was not reported in patients given bosentan. Similar end points have also been reported for epoprostenol when added to conventional therapy. Improvements in median walking distances at 12 weeks for epoprostenol compared to conventional therapy alone were from 270 m to 316 m compared to 240 m to 192 m in one study (n = 111) and 315 m to 362 m vs. 220 to 204 m in another (n = 81).7,8 The results do not appear to be dramatically different although comparing across studies can be problematic.
Clinical Implications
PAH is a chronic life-threatening condition defined as abnormally high blood pressure in the pulmonary artery. This increase in pulmonary vascular resistance leads to right ventricular failure and death.3 In untreated patients, the survival rate is 40-50% at 2 years after the onset of symptoms with a median life expectancy of 2.8 years.6 PAH is a rare condition affecting about 100,000 people in the United States and Europe. It has been associated with exposure to fenfluramine, dexfenfluramine, cocaine, methamphetamine, other street drugs, and certain toxins.4 Epoprostenol is currently the most effective therapy for PAH and has been reported to improve survival,7 however, it requires constant, 24 hour a day, intravenous administration via a central catheter with its associated risks. An orally administered drug such as bosentan offers a significant advantage. How it compares to epoprostenol in efficacy is not known since there are currently no comparative studies between these drugs. Neither treatment is a cure for this difficult-to- manage disease.
References
1. Tracleer Product Information. Actelion Pharmaceuticals US, Inc. November 2001.
2. Channick RN, et al. Lancet. 2001;358:1119-1123.
3. Robin IJ. N Engl J Med. 1997;336:111-117.
4. Pulmonary Hypertension Association. 2001.
5. Hay DW. Clin Exp Pharmacol Physiol. 1999;26: 168-171.
6. D’Alonzo GE, et al. Ann Intern Med. 1991;115:343-349.
7. Barst RJ, et al. N Engl J Med. 1996;334(5):296-302.
8. Badesch DB, et al. Ann Intern Med. 2000;132(6): 425-434.
Dr. Elliott, Chair, Formulary Committee, Northern California Kaiser Permanente, Assistant Clinical Professor of Medicine, University of California-San Francisco; and Dr. Chan, Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA, are Associate Editors of Internal Medicine Alert.
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