TOPROL XL (Page 5 of 6)

14.1 Angina Pectoris

By blocking catecholamine-induced increases in heart rate, in velocity and extent of myocardial contraction, and in blood pressure, metoprolol reduces the oxygen requirements of the heart at any given level of effort, thus making it useful in the long-term management of angina pectoris.

In controlled clinical trials, an immediate-release formulation of metoprolol has been shown to be an effective antianginal agent, reducing the number of angina attacks and increasing exercise tolerance. The dosage used in these studies ranged from 100 to 400 mg daily. TOPROL-XL, in dosages of 100 to 400 mg once daily, has been shown to possess beta-blockade similar to conventional metoprolol tablets administered two to four times daily.

14.2 Heart Failure

MERIT-HF was a double-blind, placebo-controlled study of TOPROL-XL conducted in 14 countries including the US. It randomized 3991 patients (1990 to TOPROL-XL) with ejection fraction ≤0.40 and NYHA Class II-IV heart failure attributable to ischemia, hypertension, or cardiomyopathy. The protocol excluded patients with contraindications to beta-blocker use, those expected to undergo heart surgery, and those within 28 days of myocardial infarction or unstable angina. The primary endpoints of the trial were (1) all-cause mortality plus all-cause hospitalization (time to first event) and (2) all-cause mortality. Patients were stabilized on optimal concomitant therapy for heart failure, including diuretics, ACE inhibitors, cardiac glycosides, and nitrates. At randomization, 41% of patients were NYHA Class II; 55% NYHA Class III; 65% of patients had heart failure attributed to ischemic heart disease; 44% had a history of hypertension; 25% had diabetes mellitus; 48% had a history of myocardial infarction. Among patients in the trial, 90% were on diuretics, 89% were on ACE inhibitors, 64% were on digitalis, 27% were on a lipid-lowering agent, 37% were on an oral anticoagulant, and the mean ejection fraction was 0.28. The mean duration of follow-up was one year. At the end of the study, the mean daily dose of TOPROL-XL was 159 mg.

The trial was terminated early for a statistically significant reduction in all-cause mortality (34%, nominal p= 0.00009). The risk of all-cause mortality plus all-cause hospitalization was reduced by 19% (p= 0.00012). The trial also showed improvements in heart failure-related mortality and heart failure-related hospitalizations, and NYHA functional class.

The table below shows the principal results for the overall study population. The figure below illustrates principal results for a wide variety of subgroup comparisons, including US vs. non-US populations (the latter of which was not pre-specified). The combined endpoints of all-cause mortality plus all-cause hospitalization and of mortality plus heart failure hospitalization showed consistent effects in the overall study population and the subgroups, including women and the US population. However, in the US subgroup (n=1071) and women (n=898), overall mortality and cardiovascular mortality appeared less affected. Analyses of female and US patients were carried out because they each represented about 25% 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.

Clinical Endpoints in the MERIT-HF Study
*
Time to first event
Comparison of treatment groups examines the number of hospitalizations (Wilcoxon test); relative risk and risk reduction are not applicable.

Clinical Endpoint

Number of Patients

Relative Risk (95% Cl)

Risk Reduction With TOPROL-XL

Nominal P-value

Placebo

n=2001

TOPROL-XL

n=1990

All-cause mortality plus all-caused hospitalization *

767

641

0.81(0.73- 0.90)

19%

0.00012

All-cause mortality

217

145

0.66(0.53- 0.81)

34%

0.00009

All-cause mortality plus heart failure hospitalization *

439

311

0.69(0.60- 0.80)

31%

0.0000008

Cardiovascular mortality

203

128

0.62(0.50- 0.78)

38%

0.000022

Sudden death

132

79

0.59(0.45- 0.78)

41%

0.0002

Death due to worsening heart failure

58

30

0.51(0.33- 0.79)

49%

0.0023

Hospitalizations due to worsening heart failure

451

317

N/A

N/A

0.0000076

Cardiovascular hospitalization

773

649

N/A

N/A

0.00028

Merit results graph
(click image for full-size original)

15 REFERENCES

1. Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K, Villar JC et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. 2008; 371:1839-47.

16 HOW SUPPLIED/STORAGE AND HANDLING

Tablets containing metoprolol succinate equivalent to the indicated weight of metoprolol tartrate, USP, are white, biconvex, film-coated, and scored.

Tablet

Shape

Engraving

25 mg

Oval

A/

β

Overbagged with 10 tablets per bag

NDC 55154-9608-0

50 mg

Round

A/

mo

Overbagged with 10 tablets per bag

NDC 55154-5026-0

100 mg

Round

A/

ms

Overbagged with 10 tablets per bag

NDC 55154-9609-0

Store at 25°C (77°F). Excursions permitted to 15-30°C (59- 86°F). (See USP Controlled Room Temperature.)

Repackaged by:

Cardinal Health

Zanesville, OH 43701

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