Metoprolol Tartrate

1 INDICATIONS AND USAGE Metoprolol tartrate tablet 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 ) • Myocardial Infarction, to reduce the risk of cardiovascular mortality when used in conjunction with intravenous metoprolol therapy in patients with definite or suspected acute myocardial infarction in hemodynamically stable patients. ( 1.3 ) 1.1 Hypertension Metoprolol tartrate tablets are indicated for the treatment of hypertension in adult patients, 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 tartrate tablets may be administered with other antihypertensive agents. 1.2 Angina Pectoris Metoprolol tartrate tablets are indicated in the long-term treatment of angina pectoris, to reduce angina attacks and to improve exercise tolerance. 1.3 Myocardial Infarction Metoprolol tartrate tablets are indicated in the treatment of hemodynamically stable patients with definite or suspected acute myocardial infarction to reduce cardiovascular mortality when used alone or in conjunction with intravenous metoprolol.

2 DOSAGE AND ADMINISTRATION • Administer once daily with food or after a meal. Titrate at weekly or longer intervals as needed and tolerated. ( 2 ) • Hypertension: Recommended starting dosage is 100 mg daily, in single or divided doses. ( 2.1 ) • Angina Pectoris: Recommended starting dosage is 100 mg daily, given as two divided doses. ( 2.2 ) • Myocardial Infarction: The starting dosage depends upon tolerance of intravenous metoprolol, see full prescribing information. ( 2.3 ) 2.1 Hypertension Individualize the dosage of metoprolol tartrate tablets. Metoprolol tartrate tablets should be taken with or immediately following meals. The usual initial dosage is 100 mg daily in single or divided doses. 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. The effective dosage range of metoprolol tartrate tablets is 100 mg to 450 mg per day. Dosages above 450 mg per day have not been studied. While once-daily dosing can maintain a reduction in blood pressure throughout the day, lower doses (especially 100 mg) may not maintain a full effect at the end of the 24-hour period. Larger or more frequent daily doses may be required. Measure blood pressure near the end of the dosing interval to determine whether satisfactory control is being maintained throughout the day. 2.2 Angina Pectoris The dosage of metoprolol tartrate tablets should be individualized. Metoprolol tartrate tablets should be taken with or immediately following meals. The usual initial dosage is 100 mg daily, given in two divided doses. Gradually increase the dosage at weekly intervals until optimum clinical response has been obtained or there is a pronounced slowing of the heart rate. The effective dosage range of metoprolol tartrate tablets is 100 to 400 mg per day. 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 (5.1)]. 2.3 Myocardial Infarction See prescribing information of intravenous metoprolol for dosage instructions for intravenous therapy. In patients who tolerate the full intravenous dose, initiate metoprolol tartrate tablets, 50 mg every 6 hours, 15 minutes after the last intravenous dose of metoprolol and continue for 48 hours. In the case of intolerance, reduce dose to 25 mg and administer for 48 hours. Titrate, based on tolerability, to a maintenance dosage of 100 mg twice daily. Continue therapy for at least 3 months. Although the efficacy of metoprolol tartrate beyond 3 months has not been conclusively established, data from studies with other beta-blockers suggest that treatment should be continued for 1 to 3 years.

3 DOSAGE FORMS AND STRENGTHS Metoprolol tartrate tablets, USP are supplied as: 25 mg tablets having functional scoring are white to off white film coated, round, biconvex tablet debossed with ‘L150’ on one side and breakline on other side. 50 mg tablets having functional scoring are pink, film coated, round, biconvex tablet debossed with ‘L151’ on one side and breakline on other side. 100 mg tablets having functional scoring are blue, film coated, round, biconvex tablet debossed with ‘L152’ on one side and breakline on other side. • Metoprolol tartrate tablets having functional scoring: 25 mg, 50 mg and 100 mg. ( 3 )

4 CONTRAINDICATIONS Metoprolol tartrate tablets are contraindicated in severe bradycardia, second-or third-degree heart block, cardiogenic shock, systolic blood pressure <100, 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 ) • Pheochromocytoma: Initiate therapy with an alpha blocker. ( 5.4 ) • 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. ( 5.5 , 6.1 ) • Diabetes: May mask symptoms of hypoglycemia. ( 5.6 ) • Thyrotoxicosis: Abrupt withdrawal in patients with thyrotoxicosis might precipitate a thyroid storm. ( 5.7 ) • Peripheral Vascular Disease: Can aggravate symptoms of arterial insufficiency. ( 5.9 ) 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 tartrate, 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 tartrate, 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 tartrate in patients treated only for hypertension. 5.2 Heart Failure Worsening cardiac failure may occur during up-titration of metoprolol tartrate. If such symptoms occur, increase diuretics and restore clinical stability before advancing the dose of metoprolol tartrate [see Dosage and Administration (2)]. It may be necessary to lower the dose of metoprolol tartrate or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of metoprolol tartrate. 5.3 Bronchospastic Disease Patients with bronchospastic disease, should in general, not receive beta-blockers, including metoprolol tartrate. Because of its relative beta 1 cardio-selectivity, however, metoprolol tartrate 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 tartrate. Bronchodilators, including beta 2 -agonists, should be readily available or administered concomitantly [see Dosage and Administration (2)]. 5.4 Pheochromocytoma If metoprolol tartrate is 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. 5.5 Major Surgery Avoid initiation of a high-dose regimen of beta-blocker therapy 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. 5.6 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. Beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. 5.7 Thyrotoxicosis Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may precipitate a thyroid storm. 5.8 Risk of Anaphylactic Reaction While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. 5.9 Peripheral Vascular Disease Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.

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 Alembic Pharmaceuticals Limited at 1-866-210-9797 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. Hypertension and Angina Most adverse effects have been mild and transient. Central Nervous System: Tiredness and dizziness have occurred in about 10% of patients. Depression has been reported in about 5 of 100 patients. Mental confusion and short-term memory loss have been reported. Headache, nightmares, and insomnia have also been reported. Cardiovascular: Shortness of breath and bradycardia have occurred in approximately 3% of patients. Cold extremities; arterial insufficiency, usually of the Raynaud type; palpitations; heart failure exacerbations; peripheral edema; and hypotension have been reported in about 1% of patients. Gangrene in patients with pre-existing severe peripheral circulatory disorders has also been reported [see Contraindications (4) and Warnings and Precautions (5.2)]. Respiratory: Wheezing (bronchospasm) and dyspnea have been reported in about 1% of patients [see Warnings and Precautions (5.3)]. Rhinitis has also been reported. Gastrointestinal: Diarrhea has occurred in about 5% of patients. Nausea, dry mouth, gastric pain, constipation, flatulence, and heartburn have been reported in about 1% of patients. Vomiting was a common occurrence. Hypersensitive Reactions: Pruritus or rash have occurred in about 5% of patients. Photosensitivity and worsening of psoriasis has been reported. Miscellaneous: Peyronie’s disease, musculoskeletal pain, blurred vision, and tinnitus has been reported. Myocardial Infarction In general, the adverse reactions observed in trials with metoprolol in MI are consistent with the hypertension and angina experience. In a randomized comparison of metoprolol tartrate and placebo in the setting of acute MI the following adverse reactions were reported: Metoprolol Tartrate Placebo Hypotension (systolic BP < 90 mm Hg) 27.4% 23.2% Bradycardia (heart rate < 40 beats/min) 15.9% 6.7% Second- or third-degree heart block 4.7% 4.7% First-degree heart block (P-R ≥ 0.26 sec) 5.3% 1.9% Heart failure 27.5% 29.6% 6.2 Post-Marketing Experience The following adverse reactions have been identified during post approval use of metoprolol tartrate. 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. 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, slightly clouded sensorium, and decreased performance on neuropsychometrics. Cardiovascular: Intensification of AV block [see Contraindications (4)]. Hematologic: Agranulocytosis, nonthrombocytopenic purpura and thrombocytopenic purpura. Hypersensitive Reactions: Fever combined with aching and sore throat, laryngospasm and respiratory distress. Laboratory Findings: Increase in blood triglycerides, elevated transaminase and decrease in High Density Lipoprotein (HDL)

16 HOW SUPPLIED/STORAGE AND HANDLING Metformin hydrochloride extended-release tablets USP, 500 mg are oval white tablets, with "OE" debossed on one side and "584" debossed on the other side. NDC 71335-3159-1: 30 Tablets in a BOTTLE NDC 71335-3159-2: 100 Tablets in a BOTTLE NDC 71335-3159-3: 60 Tablets in a BOTTLE NDC 71335-3159-4: 90 Tablets in a BOTTLE NDC 71335-3159-5: 180 Tablets in a BOTTLE Store at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Dispense in light-resistant containers. Repackaged/Relabeled by: Bryant Ranch Prepack Burbank, CA 91504