Biovail: Study Suggests Bedtime Dose of Cardizem LA Protects Angina Patients from Morning Risks

Business Wire, March 30, 2003

Business Editors, Health/Medical Writers

CHICAGO--(BUSINESS WIRE)--March 30, 2003

Presentation at American College of Cardiology Shows New

Formulation Doubles Morning Exercise Tolerance, a Key Angina

Measure

Nighttime dosing of a newly approved blood pressure medication may provide angina patients with added protection in the morning hours when painful and potentially life-threatening attacks are most likely to occur, according to a study presented today at the 52nd Annual Scientific Session of the American College of Cardiology.

Researchers reported that bedtime dosing of Cardizem(R) LA, a graded-release formulation of diltiazem, improved key angina measures more than 200 percent when compared to morning doses. The benefits of nighttime dosing were most pronounced between the hours of 7 AM and 11 AM, although enhanced benefits were seen throughout the day.

"Angina is a painful and often debilitating condition, as well as a significant warning sign of blockage in the coronary arteries that may lead to heart attack, stroke or sudden cardiac death," said Stephen P. Glasser, MD, lead study author and professor of epidemiology at the University of Minnesota, School of Public Health. "For this reason, it is important to administer treatment that is designed to provide optimal protection at a time when patients are most vulnerable."

Angina - or more formally angina pectoris - is a medical term for chest pain that arises when blood flow within the heart muscle is restricted. This restriction, known as ischemia, deprives the heart of adequate oxygen and is most often caused by excessive build up of fatty deposits on the coronary artery walls. Symptoms are most likely to occur when patients are physically active or under emotional stress because these states increase the heart's demand for oxygenated blood that can not make it through the partially blocked blood vessels.

Angina is also considered an important precursor of an impending cardiovascular event, such as heart attack, stroke or sudden cardiac death. Like angina, these life-threatening events are also most likely to occur in the morning hours. Research demonstrates a 50 percent increased risk of stroke and a 40 percent increased risk of heart attack between the hours of 6 AM and noon.

In the double-blind, three-week angina study, 311 patients with exercise induced ischemia and angina symptoms - confirmed by baseline treadmill stress tests - were randomized to placebo or four different treatment groups receiving daily Cardizem(R) LA doses of either 180 mg PM, 360mg PM, 360mg AM or 420mg PM. Stress tests were repeated at endpoint to evaluate changes in exercise tolerance or the amount of time a patient can exercise before angina symptoms occur. Testing was done at two different time periods - between the hours of 6 PM and 8 PM and 7 AM and 11AM. The time windows were selected to measure the effects of various dosing schedules at peak (when blood levels of medication are highest) and trough (when blood levels are lowest).

At peak, the morning and nighttime doses of Cardizem(R) LA demonstrated comparable efficacy. At trough, however, the true advantages of nighttime dosing emerged. For example, median duration of exercise (in seconds) at trough was 30.8 for the 180mg PM dose, 39 for the 360mg PM dose, 36 for the 420mg PM dose and only 19.5 for 360mg AM dose. Between the critical hours of 7 AM and 11 AM, nighttime dosing doubled exercise tolerance when compared to morning dosing. Specifically, morning exercise duration ranged from 41 to 49.5 for the various PM doses and was only 19.5 for the 360mg AM dose. Similar results favoring PM dosing were demonstrated for other key measures including time to onset of angina and time to onset of ischemia.

"The results underscore that, when dosed at night, Cardizem(R) LA provides enhanced 24-hour control and optimal morning protection when angina patients are at greatest risk," explains Glasser. "These results are not seen with any other diltiazem formulation."

Cardizem(R) LA was well tolerated. Adverse events were generally mild to moderate in nature and comparable to placebo at the highest dose studied in this trial (420mg). The most commonly reported adverse effects reported in the study were edema, dizziness and fatigue.

Biovail Pharmaceuticals, Inc. is the U.S. subsidiary of Biovail Corporation (NYSE,TSX: BVF), an international full service pharmaceutical company, engaged in the formulation, clinical testing, registration, manufacture, sale and promotion of pharmaceutical products utilizing advanced drug delivery technologies.

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