FDA Approves AstraZeneca's Toprol-XL -- Metoprolol Succinate -- for Heart Failure; Approval Based on Landmark Clinical Trial.

Business Editors/Health & Medical Writers

WAYNE, Pa.--(BW HealthWire)--Feb. 6, 2001

AstraZeneca (NYSE:AZN) today announced that the U.S. Food and Drug Administration (FDA) has approved Toprol-XL(R) (metoprolol succinate) extended-release tablets for the treatment of stable, symptomatic (NYHA(1) Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. In a landmark clinical trial, Toprol-XL has been shown to decrease the rate of mortality plus hospitalization, largely through a reduction in cardiovascular mortality and hospitalization for heart failure. The new heart failure indication is in addition to the use of Toprol-XL in treating hypertension and angina pectoris.

The approval for heart failure was based on results of the Metoprolol CR/XL (Controlled Release) Randomized Intervention Trial in Heart Failure (MERIT-HF), the largest heart failure trial ever completed (3,991 patients: 1,990 in Toprol-XL treatment arm) evaluating the efficacy of a beta-blocker. The trial was terminated earlier than expected by the Independent Safety Committee due to a significant reduction in mortality in patients treated with Toprol-XL as compared to placebo. In MERIT-HF, the use of Toprol-XL in combination with ACE inhibitors, diuretics and digitalis resulted in an all-cause mortality of 7.3 percent compared to 10.8 percent in the placebo group. This is a risk reduction of 34 percent. The risk of all-cause mortality plus all-cause hospitalization was reduced by 19 percent (placebo: 38 percent; Toprol-XL: 32 percent).

In MERIT-HF, the risk of cardiovascular mortality was reduced by 38 percent (placebo: 10.1 percent; Toprol-XL: 6.4 percent), and the risk of death from worsening heart failure was reduced by 49 percent (placebo: 2.9 percent; Toprol-XL: 1.5 percent). All mortality risk reductions were statistically significant. The data on all-cause mortality plus all-cause hospitalization and the data on all-cause mortality plus heart failure hospitalization showed consistent effects in the overall study population and subgroups, including women and the U.S. population. However, in the U.S. subgroup (n=1071) and women (n=898), overall mortality and cardiovascular mortality appeared less affected. Analyses of female and U.S. patients were carried out because they each represented about 25 percent of the overall population. Nonetheless, subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects.

MERIT-HF included patients across a spectrum of heart failure severity with the majority of patients in NYHA(1) Class II (41 percent) and Class III (55 percent). The study found that the addition of Toprol-XL to standard therapy showed benefit in patients in NYHA(1) classes II and III. The trial also showed improvements in heart failure-related mortality and heart failure-related hospitalizations, and NYHA functional class.

"The approval of Toprol-XL for heart failure is an important step in treating heart failure patients," said Arthur Feldman, M.D., professor of medicine at the University of Pittsburgh School of Medicine. "The MERIT-HF findings showed that beta-blockade had a marked benefit on survival in heart failure patients. Reduced mortality and hospitalizations are significant because heart failure patients usually require frequent hospital stays to stabilize their disease."

About TOPROL-XL

Toprol-XL is the most widely prescribed branded beta-blocker in the U.S. It is currently available in 50, 100 and 200 mg dividable tablets. A new 25 mg scored tablet will be available at launch. The recommended starting dose of Toprol-XL in heart failure is 25 mg once-daily for two weeks in patients with NYHA class II heart failure and 12.5 mg once-daily in patients with more severe heart failure. If this dosage is tolerated, it may be doubled every two weeks to the highest dosage level tolerated by the patient or up to 200 mg.

Toprol-XL is contraindicated in severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure and sick sinus syndrome (unless a permanent pacemaker is in place). Patients taking Toprol-XL should avoid abrupt cessation of therapy. Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. The dosage should be reduced gradually over a one-to two-week period while monitoring patients. For full prescribing information for Toprol-XL including boxed warning, call 1-800-236-9933 or visit www.astrazeneca-us.com.

In MERIT-HF comparing Toprol-XL to placebo in daily doses up to 200 mg once daily, 10.3 percent of Toprol-XL patients discontinued due to adverse events verses 12.2 percent of placebo patients. The most frequent adverse events that occurred at an incidence of equal to or more than one percent and greater than placebo by more than 0.5 percent were dizziness/vertigo (1.8 percent vs. 1.0 percent placebo), bradycardia (1.5 percent vs. 0.4 percent placebo) and accident and/or injury (1.4 percent vs. 0.8 percent placebo).

There is a risk of worsening cardiac failure during up-titration of the dose of Toprol-XL. Patients need to consult their physicians if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath.

About Congestive Heart Failure

Congestive heart failure is a condition in which the heart fails to pump blood normally. As a result, functions of many organs in the body are disturbed and symptoms such as fatigue and breathlessness develop. The most frequent underlying causes of heart failure are previous heart attack and high blood pressure. The incidence of heart failure continues to increase, due to an aging population.

In the U.S., approximately four-to-five million people have heart failure, with 550,000 new cases occurring each year. Heart failure results in almost one million hospitalizations each year and is the most common hospital discharge diagnosis in patients 65 years and older. It is the only major cardiovascular disorder that is increasing in incidence and prevalence. The impact of Toprol-XL on these statistics has not been determined.

About AstraZeneca

AstraZeneca (NYSE:AZN) is a major international healthcare business engaged in the research, development, manufacture and marketing of ethical (prescription) pharmaceuticals and the supply of healthcare services. It is one of the top five pharmaceutical companies in the world with healthcare sales of $15 billion and leading positions in sales of cardiovascular, gastrointestinal, oncology, anesthesia (including pain management), central nervous system (CNS) and respiratory products. In the United States, AstraZeneca is a $7.4 billion healthcare business with more than 10,000 employees.

Editors' Notes:

(1) Classification of heart failure is commonly based on the New York Heart Association (NYHA) classification of heart failure. There are four functional classes in the NYHA scheme:

-- Class I: No limitation: ordinary physical exercise does not cause undue
fatigue, dyspnea, or palpitations

-- Class II: Slight limitation of physical activity: comfortable at rest but
ordinary activity results in fatigue, palpitations or dyspnea (shortness of
breath, particularly after exercise and when lying down)

-- Class III: Marked limitation of physical activity: comfortable at rest but
less than ordinary activity results in symptoms

-- Class IV: Unable to carry out any physical activity without discomfort
(symptoms of heart failure are present even at rest with increased discomfort
with any physical activity)

For full prescribing information for Toprol-XL including boxed warning, media inquiries only, please contact Michele Pelkowski at 1-800-942-0424, ext. 4055, or visit www.astrazeneca-us.com.