Metoprolol: uses, appearance and warnings

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.

25 mg tablets: White to off-white, oval shaped, film coated scored tablets, debossed with I and 25 on either side of the score on one side and score on the other side free from physical defects. 50 mg tablets: White to off-white, round shaped, film coated scored tablets, debossed with I on one side of the score and debossed with 50 on the other side free from physical defects. 100 mg tablets: White to off-white, round shaped, film coated scored tablets, debossed with I one side of the score and debossed with 100 on the other side free from physical defects. 200 mg tablets: White to off-white, oval shaped, film coated scored tablets, debossed with I on one side of the score and 200 on the other side free from physical defects. Metoprolol succinate extended-release tablets: 25 mg, 50 mg, 100 mg and 200 mg. ( 3 )

Metoprolol succinate extended-release tablets containing metoprolol succinate equivalent to the indicated weight of metoprolol tartrate, USP are available as follows: Metoprolol succinate extended-release tablets USP, 25 mg White to off-white, oval shaped, film coated scored tablets, debossed with I and 25 on either side of the score on one side and score on the other side free from physical defects. Bottles of 30 NDC 62207-130-54 Bottles of 1000 NDC 62207-130-49 Metoprolol succinate extended-release tablets USP, 50 mg White to off-white, round shaped, film coated scored tablets, debossed with I on one side of the score and debossed with 50 on the other side free from physical defects. Bottles of 30 NDC 62207-133-54 Bottles of 1000 NDC 62207-133-49 Metoprolol succinate extended-release tablets USP, 100 mg White to off-white, round shaped, film coated scored tablets, debossed with I one side of the score and debossed with 100 on the other side free from physical defects. Bottles of 30 NDC 62207-131-54 Bottles of 1000 NDC 62207-131-49 Metoprolol succinate extended-release tablets USP, 200 mg White to off-white, oval shaped, film coated scored tablets, debossed with I on one side of the score and 200 on the other side free from physical defects. Bottles of 30 NDC 62207-132-54 Bottles of 1000 NDC 62207-132-49 Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature].

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 )

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, and 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.

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 Granules Pharmaceuticals Inc., at 1-877-770-3183 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. …

Catecholamine-depleting drugs may have an additive effect when given with beta-blocking agents. ( 7.1 ) CYP2D6 Inhibitors are likely to increase metoprolol concentration. ( 7.2 ) Beta-blockers including metoprolol, may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. ( 7.3 ) 7.1 Catecholamine Depleting Drugs Catecholamine depleting drugs (e.g., reserpine, monoamine oxidase (MAO) inhibitors) may have an additive effect when given with beta-blocking agents. Observe patients treated with metoprolol succinate extended-release tablets plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension. 7.2 CYP2D6 Inhibitors Drugs that are strong inhibitors of CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone were shown to double metoprolol concentrations. …