Metoprolol Succinate: Package Insert and Label Information (Page 3 of 4)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have been conducted to evaluate the carcinogenic potential of metoprolol tartrate. In 2-year studies in rats at three oral dosage levels of up to 800 mg/kg/day (41 times, on a mg/m 2 basis, the daily dose of 200 mg for a 60-kg patient), there was no increase in the development of spontaneously occurring benign or malignant neoplasms of any type. The only histologic changes that appeared to be drug related were an increased incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg/day (18 times, on a mg/m 2 basis, the daily dose of 200 mg for a 60-kg patient), benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (benign plus malignant) lung tumors, nor in the overall incidence of tumors or malignant tumors. This 21-month study was repeated in CD-1 mice, and no statistically or biologically significant differences were observed between treated and control mice of either sex for any type of tumor.

All genotoxicity tests performed on metoprolol tartrate (a dominant lethal study in mice, chromosome studies in somatic cells, a Salmonella /mammalian-microsome mutagenicity test, and a nucleus anomaly test in somatic interphase nuclei) and metoprolol succinate (a Salmonella /mammalian-microsome mutagenicity test) were negative.

No evidence of impaired fertility due to metoprolol tartrate was observed in a study performed in rats at doses up to 22 times, on a mg/m 2 basis, the daily dose of 200 mg in a 60-kg patient.

14 CLINICAL STUDIES

In five controlled studies in normal healthy subjects, the same daily doses of metoprolol succinate extended-release tablets and immediate-release metoprolol were compared in terms of the extent and duration of beta 1 -blockade produced. Both formulations were given in a dose range equivalent to 100 to 400 mg of immediate-release metoprolol per day. In these studies, metoprolol succinate extended-release tablets were administered once a day and immediate-release metoprolol was administered once to four times a day. A sixth controlled study compared the beta 1 -blocking effects of a 50 mg daily dose of the two formulations. In each study, beta 1 -blockade was expressed as the percent change from baseline in exercise heart rate following standardized submaximal exercise tolerance tests at steady state. Metoprolol succinate extended-release tablets administered once a day, and immediate-release metoprolol administered once to four times a day, provided comparable total beta 1 -blockade over 24 hours (area under the beta 1 -blockade versus time curve) in the dose range 100 to 400 mg. At a dosage of 50 mg once daily, metoprolol succinate extended-release tablets produced significantly higher total beta 1 -blockade over 24 hours than immediate-release metoprolol. For metoprolol succinate extended-release tablets, the percent reduction in exercise heart rate was relatively stable throughout the entire dosage interval and the level of beta 1 -blockade increased with increasing doses from 50 to 300 mg daily. The effects at peak/trough (i.e., at 24-hours post-dosing) were: 14/9, 16/10, 24/14, 27/22 and 27/20% reduction in exercise heart rate for doses of 50, 100, 200, 300 and 400 mg metoprolol succinate extended-release tablets once a day, respectively. In contrast to metoprolol succinate extended-release tablets, immediate-release metoprolol given at a dose of 50 to 100 mg once a day produced a significantly larger peak effect on exercise tachycardia, but the effect was not evident at 24 hours. To match the peak to trough ratio obtained with metoprolol succinate extended-release tablets over the dosing range of 200 to 400 mg, a t.i.d. to q.i.d. divided dosing regimen was required for immediate-release metoprolol. A controlled cross-over study in heart failure patients compared the plasma concentrations and beta 1 -blocking effects of 50 mg immediate-release metoprolol administered t.i.d., 100 mg and 200 mg metoprolol succinate extended-release tablets once daily. A 50 mg dose of immediate-release metoprolol t.i.d. produced a peak plasma level of metoprolol similar to the peak level observed with 200 mg of metoprolol succinate extended-release tablets. A 200 mg dose of metoprolol succinate extended-release tablets produced a larger effect on suppression of exercise-induced and Holter-monitored heart rate over 24 hours compared to 50 mg t.i.d. of immediate-release metoprolol.

In a double-blind study, 1,092 patients with mild-to-moderate hypertension were randomized to once daily metoprolol succinate extended-release tablets (25, 100, or 400 mg), PLENDIL ® (felodipine extended-release tablets), the combination, or placebo. After 9 weeks, metoprolol succinate extended-release tablets alone decreased sitting blood pressure by 6 to 8/4 to 7 mmHg (placebo-corrected change from baseline) at 24 hours post-dose. The combination of metoprolol succinate extended-release tablets with PLENDIL has greater effects on blood pressure.

In controlled clinical studies, an immediate-release dosage form of metoprolol was an effective antihypertensive agent when used alone or as concomitant therapy with thiazide-type diuretics at dosages of 100 to 450 mg daily. Metoprolol succinate extended-release tablets, in dosages of 100 to 400 mg once daily, produces similar β 1 -blockade as conventional metoprolol tablets administered two to four times daily. In addition, metoprolol succinate extended-release tablets administered at a dose of 50 mg once daily lowered blood pressure 24-hours post-dosing in placebo-controlled studies. In controlled, comparative, clinical studies, immediate-release metoprolol appeared comparable as an antihypertensive agent to propranolol, methyldopa, and thiazide-type diuretics, and affected both supine and standing blood pressure. Because of variable plasma levels attained with a given dose and lack of a consistent relationship of antihypertensive activity to drug plasma concentration, selection of proper dosage requires individual titration.

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. Metoprolol succinate extended-release tablets, in dosages of 100 to 400 mg once daily, have 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 metoprolol succinate extended-release tablets conducted in 14 countries including the US. It randomized 3,991 patients (1,990 to metoprolol succinate extended-release tablets) 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 metoprolol succinate extended-release tablets 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=1,071) 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

C li n i cal Endpoint

N umber of Patients

R elative Risk

(95% Cl)

R i sk Reduction With Metoprolol Succinate Extended-Release Tablets

N ominal P-value

P l acebo

n=2,001

Metoprolol Succinate Extended-Release Tablets

n=1,990

All-cause mortality plus all-caused hospitalization 1

767

641

0.81(0.73 to 0.90)

19%

0.00012

All-cause mortality

217

145

0.66(0.53 to 0.81)

34%

0.00009

All-cause mortality plus heart failure hospitalization 1

439

311

0.69(0.60 to 0.80)

31%

0.0000008

Cardiovascular mortality

203

128

0.62(0.50 to 0.78)

38%

0.000022

Sudden death

132

79

0.59(0.45 to 0.78)

41%

0.0002

Death due to worsening heart

failure

58

30

0.51(0.33 to 0.79)

49%

0.0023

Hospitalizations due to worsening heart failure 2

451

317

N/A

N/A

0.0000076

Cardiovascular hospitalization 2

773

649

N/A

N/A

0.00028

1. Time to first event

2. Comparison of treatment groups examines the number of hospitalizations (Wilcoxon test); relative risk and risk reduction are not applicable.

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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

Metoprolol Succinate Extended-Release Tablets USP, 100 mg are white film coated oval shape tablets, scored on one side and debossed with “Y” and “H”, debossed with “163” on the other side.

They are supplied in bottles of 100, 500 and 1,000 tablets.

Bottles of 100 tablets with child-resistant closure, NDC 70436-166-01

Bottles of 500 tablets, NDC 70436-166-02

Bottles of 1,000 tablets, NDC 70436-166-03

Metoprolol Succinate Extended-Release Tablets USP, 200 mg are white film coated oval shape tablets, scored on one side and debossed with “Y” and “H”, debossed with “161” on the other side.

They are supplied in bottles of 100, 500 and 1,000 tablets.

Bottles of 100 tablets with child-resistant closure, NDC 70436-167-01

Bottles of 500 tablets, NDC 70436-167-02

Bottles of 1,000 tablets, NDC 70436-167-03

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

As with all medications, keep out of the reach of children.

17 PATIENT COUNSELING INFORMATION

Advise patients to take metoprolol succinate extended-release tablets regularly and continuously, as directed, preferably with or immediately following meals. If a dose is missed, the patient should take only the next scheduled dose (without doubling it). Patients should not interrupt or discontinue metoprolol succinate extended-release tablets without consulting the physician.

Advise patients (1) to avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient’s response to therapy with metoprolol succinate extended-release tablets has been determined; (2) to contact the physician if any difficulty in breathing occurs; (3) to inform the physician or dentist before any type of surgery that he or she is taking metoprolol succinate extended-release tablets.

Heart failure patients should be advised to consult their physician if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath.

PLENDIL is a trademark of the AstraZeneca group of companies.

Manufactured by:

Yichang Humanwell Oral Solid Dosage Plant

Yichang, Hubei, China 443112

Distributed by:

Slate Run Pharmaceuticals, LLC

Columbus, Ohio 43215

Rev. 01/2021

PRINCIPAL DISPLAY PANEL — 100 mg Tablet Bottle Label

NDC 70436-166-01

Metoprolol Succinate Extended-Release Tablets, USP

100 mg, 100 Tablets

100mg-100ct
(click image for full-size original)

NDC 70436-166-02

Metoprolol Succinate Extended-Release Tablets, USP

100 mg, 500 Tablets

100mg-500ct
(click image for full-size original)

NDC 70436-166-03

Metoprolol Succinate Extended-Release Tablets, USP

100 mg, 1000 Tablets

100mg-1000ct
(click image for full-size original)

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