Metoprolol Succinate

1 INDICATIONS & USAGE Metoprolol succinate extended-release tablets, metoprolol succinate, beta-adrenergic blocker indicated for the treatment of: • Hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions.() • Angina Pectoris. () • Heart Failure, to reduce the risk of cardiovascular mortality and heart failure hospitalizations in patients with heart failure() 1.1 Hypertension Metoprolol succinate extended-release tablets is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including metoprolol. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. Metoprolol succinate extended-release tablets may be administered with other antihypertensive agents. 1.2 Angina Pectoris Metoprolol succinate extended-release tablets is indicated in the long-term treatment of angina pectoris, to reduce angina attacks and to improve exercise tolerance. 1.3 Heart Failure Metoprolol succinate extended-release tablets is indicated to reduce the risk of cardiovascular mortality and heart-failure hospitalization in patients with heart failure.

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in labeling: • Worsening angina or myocardial infarction [ see Warnings and Precautions (5) ] • Worsening heart failure [ see Warnings and Precautions (5) ] • Worsening AV block [ Error! Hyperlink reference not valid. ] Most common adverse reactions: tiredness, dizziness, depression, shortness of breath, bradycardia, hypotension, diarrhea, pruritus, rash. ( ) To report SUSPECTED ADVERSE REACTIONS, contact Oryza Pharmaceuticals, Inc. at 1-866-637-4281 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Hypertension and Angina: Most adverse reactions have been mild and transient. The most common (>2%) adverse reactions are tiredness, dizziness, depression, diarrhea, shortness of breath, bradycardia, and rash. Heart Failure: In the MERIT-HF study comparing metoprolol succinate extended-release tablets in daily doses up to 200 mg (mean dose 159 mg once- daily; n=1990) to placebo (n=2001), 10.3% of metoprolol succinate extended-release tablets patients discontinued for adverse reactions vs. 12.2% of placebo patients. The table below lists adverse reactions in the MERIT-HF study that occurred at an incidence of ≥ 1% in the metoprolol succinate extended-release tablets group and greater than placebo by more than 0.5%, regardless of the assessment of causality. Adverse Reactions Occuring in the MERIT-HF Study at an Incidence ≥ 1% in the Metoprolol Succinate Extended-Release Tablets Group and Greater Than Placebo by More Than 0.5% Metoprolol succinateextended-release tablets n=1990 % of patients Placebo n=2001 % of patients Dizziness/vertigo 1.8 1.0 Bradycardia 1.5 0.4 Post-operative Adverse Events: In a randomized, double-blind, placebo-controlled trial of 8351 patients with or at risk for atherosclerotic disease undergoing non-vascular surgery and who were not taking beta–blocker therapy, metoprolol succinate extended-release tablets 100 mg was started 2 to 4 hours prior to surgery then continued for 30 days at 200 mg per day. Metoprolol succinate extended-release tablets use was associated with a higher incidence of bradycardia (6.6% vs. 2.4%; HR, 2.74; 95% CI 2.19, 3.43), hypotension (15% vs.9.7%; HR 1.55; 95% CI 1.37, 1.74), stroke (1.0% vs. 0.5%; HR 2.17; 95% CI 1.26, 3.74) and death (3.1% vs. 2.3%; HR 1.33; 95% CI 1.03, 1.74) compared to placebo. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of metoprolol succinate extended-release tablets or immediate-release metoprolol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular: Cold extremities, arterial insufficiency (usually of the Raynaud type), palpitations, peripheral edema, syncope, chest pain and hypotension. Respiratory: Wheezing (bronchospasm), dyspnea. Central Nervous System: Confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety/nervousness, hallucinations, paresthesia. Gastrointestinal: Nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, vomiting. Hypersensitive Reactions: Pruritus. Miscellaneous: Musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, tinnitus, reversible alopecia, agranulocytosis, dry eyes, worsening of psoriasis, Peyronie’s disease, sweating, photosensitivity, taste disturbance. Potential Adverse Reactions: In addition, there are adverse reactions not listed above that have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to metoprolol succinate extended-release tablets. Central Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, clouded sensorium, and decreased performance on neuropsychometrics. Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura. Hypersensitive Reactions: Laryngospasm, respiratory distress.