Metoprolol succinate

1 INDICATIONS AND USAGE Metoprolol succinate, is a 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. ( 1.1 ) • Angina Pectoris. ( 1.2 ) • Heart Failure, to reduce the risk of cardiovascular mortality and heart failure hospitalizations in patients with heart failure ( 1.3 ) 1.1 Hypertension Metoprolol succinate extended-release tablets are 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 are 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 are indicated to reduce the risk of cardiovascular mortality and heart-failure hospitalization in patients with heart failure.

2 DOSAGE AND ADMINISTRATION • Administer once daily. Titrate at weekly or longer intervals as needed and tolerated. ( 2 ) • Hypertension: Starting dose is 25 mg to 100 mg. ( 2.1 ) • Angina Pectoris: Starting dose is 100 mg. ( 2.2 ) • Heart Failure: Starting dose is 12.5 mg or 25 mg. ( 2.3 ) • Switching from immediate-release metoprolol to metoprolol succinate extended-release tablets: use the same total daily dose of metoprolol succinate extended-release tablets. ( 2 ) 2.1 Hypertension Adults: The usual initial dosage is 25 mg to 100 mg daily in a single dose. Adjust dosage at weekly (or longer) intervals until optimum blood pressure reduction is achieved. In general, the maximum effect of any given dosage level will be apparent after 1 week of therapy. Dosages above 400 mg per day have not been studied. Pediatric Hypertensive Patients ≥ 6 Years of age: The recommended starting dose of metoprolol succinate extended-release tablets are 1 mg/kg once daily, but the maximum initial dose should not exceed 50 mg once daily. Adjust dosage according to blood pressure response. Doses above 2 mg/kg (or in excess of 200 mg) once daily have not been studied in pediatric patients [see Use in SpecificPopulations ( 8.4 ) and Clinical Pharmacology ( 12.3 )]. Metoprolol succinate extended-release tablets have not been studied in pediatric patients < 6 years of age [see Use in Specific Populations ( 8.4 )] . 2.2 Angina Pectoris Individualize the dosage of metoprolol succinate extended-release tablets. The usual initial dosage is 100 mg daily, given in a single dose. Gradually increase the dosage at weekly intervals until optimum clinical response has been obtained or there is a pronounced slowing of the heart rate. Dosages above 400 mg per day have not been studied. If treatment is to be discontinued, reduce the dosage gradually over a period of 1 to 2 weeks [see Warnings and Precautions ( 5 )]. 2.3 Heart Failure Dosage must be individualized and closely monitored during up-titration. Prior to initiation of metoprolol succinate extended-release tablets, stabilize the dose of other heart failure drug therapy. The recommended starting dose of metoprolol succinate extended-release tablets are 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. Double the dose every two weeks to the highest dosage level tolerated by the patient or up to 200 mg of metoprolol succinate extended-release tablets. Initial difficulty with titration should not preclude later attempts to introduce metoprolol succinate extended-release tablets. If patients experience symptomatic bradycardia, reduce the dose of metoprolol succinate extended-release tablets. If transient worsening of heart failure occurs, consider treating with increased doses of diuretics, lowering the dose of metoprolol succinate extended-release tablets, or temporarily discontinuing it. The dose of metoprolol succinate extended-release tablets should not be increased until symptoms of worsening heart failure have been stabilized. 2.4 Administration Metoprolol succinate extended-release tablets are scored and can be divided; however, do not crush or chew the whole or half tablet.

3 DOSAGE FORMS AND STRENGTHS Metoprolol Succinate Extended-Release Tablets, USP are available containing 23.75 mg, 47.5 mg, 95 mg or 190 mg of metoprolol succinate, USP equivalent to 25 mg, 50 mg, 100 mg or 200 mg of metoprolol tartrate, USP, respectively. 25 mg tablets: White to off white, oval shape, biconvex film coated tablet with breakline on one side and debossed with 'A' and '3' on each side of breakline on other side. 50 mg tablets: White to off white, round shape, biconvex film coated tablet with breakline on one side and debossed with 'A50' on other side. 100 mg tablets: White to off white, round shape, biconvex film coated tablet with breakline on one side and debossed with 'A100' on other side. 200 mg tablets: White to off white, oval shape, biconvex film coated tablet with breakline on one side and debossed with 'A200' on other side. Metoprolol succinate extended-release tablets: 25 mg, 50 mg, 100 mg, and 200 mg. ( 3 )

4 CONTRAINDICATIONS Metoprolol succinate extended-release tablets are contraindicated in severe bradycardia, second- or third- degree heart block, cardiogenic shock, decompensated heart failure, sick sinus syndrome (unless a permanent pacemaker is in place), and in patients who are hypersensitive to any component of this product. • Known hypersensitivity to product components. ( 4 ) • Severe bradycardia: Greater than first degree heart block, or sick sinus syndrome without a pacemaker. ( 4 ) • Cardiogenic shock or decompensated heart failure. ( 4 )

5 WARNINGS AND PRECAUTIONS • Abrupt cessation may exacerbate myocardial ischemia. ( 5.1 ) • Heart Failure: Worsening cardiac failure may occur. ( 5.2 ) • Bronchospastic Disease: Avoid beta-blockers. ( 5.3 ) • Concomitant use of glycosides, clonidine, diltiazem and verapamil with beta-blockers can increase the risk of bradycardia. ( 5.4 ) • Pheochromocytoma: Initiate therapy with an alpha-blocker. ( 5.5 ) • Major Surgery: Avoid initiation of high-dose extended-release metoprolol in patients undergoing non-cardiac surgery. Do not routinely withdraw chronic beta-blocker therapy prior to surgery. ( 5.6 , 6.1 ) • Hypoglycemia: May increase risk for hypoglycemia and mask early warning signs. ( 5.7 ) • Thyrotoxicosis: Abrupt withdrawal in patients with thyrotoxicosis might precipitate a thyroid storm. ( 5.8 ) • Peripheral Vascular Disease: Can aggravate symptoms of arterial insufficiency. ( 5.9 ) • Patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. ( 5.10 ) 5.1 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. When discontinuing chronically administered metoprolol succinate extended-release tablets, particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1 to 2 weeks and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, promptly reinstate metoprolol succinate extended-release tablets, and take measures appropriate for the management of unstable angina. Warn patients not to interrupt therapy without their physician’s advice. Because coronary artery disease is common and may be unrecognized, avoid abruptly discontinuing metoprolol succinate extended-release tablets in patients treated only for hypertension. 5.2 Heart Failure Worsening cardiac failure may occur during up-titration of metoprolol succinate extended-release tablets. If such symptoms occur, increase diuretics and restore clinical stability before advancing the dose of metoprolol succinate extended-release tablets [see Dosage and Administration ( 2 )]. It may be necessary to lower the dose of metoprolol succinate extended-release tablets or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of metoprolol succinate extended-release tablets. 5.3 Bronchospastic Disease Patients with bronchospastic diseases should, in general, not receive beta-blockers. Because of its relative beta 1 -cardio-selectivity, however, metoprolol succinate extended-release tablets may be used in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Because beta 1 -selectivity is not absolute, use the lowest possible dose of metoprolol succinate extended-release tablets. Bronchodilators, including beta 2 -agonists, should be readily available or administered concomitantly [see Dosage and Administration ( 2 )] . 5.4 Bradycardia Bradycardia, including sinus pause, heart block, and cardiac arrest have occurred with the use of metoprolol succinate extended-release tablets. Patients with first-degree atrioventricular block, sinus node dysfunction, conduction disorders (including Wolff-Parkinson-White) or on concomitant drugs that cause bradycardia [see Drug Interactions (7.3)], may be at increased risk. Monitor heart rate in patients receiving metoprolol succinate extended-release tablets. If severe bradycardia develops, reduce or stop metoprolol succinate extended-release tablets. 5.5 Pheochromocytoma If metoprolol succinate extended-release tablets are used in the setting of pheochromocytoma, it should be given in combination with an alpha-blocker, and only after the alpha-blocker has been initiated. Administration of beta-blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle. 5.6 Major Surgery Avoid initiation of a high-dose regimen of extended-release metoprolol in patients undergoing non-cardiac surgery, since such use in patients with cardiovascular risk factors has been associated with bradycardia, hypotension, stroke, and death. Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. 5.7 Hypoglycemia Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment. 5.8 Thyrotoxicosis Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may precipitate a thyroid storm. 5.9 Peripheral Vascular Disease Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. 5.10 Anaphylactic Reaction While taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge and may be unresponsive to the usual doses of epinephrine used to treat an allergic reaction.

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 [see Contraindications (4) ]. • Most common adverse reactions: tiredness, dizziness, depression, shortness of breath, bradycardia, hypotension, diarrhea, pruritus, rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-272-7901 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=1,990) to placebo (n=2,001), 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 Occurring 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 Succinate Extended-Release Tablets n=1,990 % of patients Placebo n=2,001 % 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 8,351 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, 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Metoprolol Succinate Extended-Release Tablets, USP 200 mg tablets: White to off white, oval shape, biconvex film coated tablet with breakline on one side and debossed with 'A200' on other side. NDC 72162-1859-1: 100 Tablets in a BOTTLE NDC 72162-1859-5: 500 Tablets in a BOTTLE NDC 72162-1859-0: 1000 Tablets in a BOTTLE Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504