Metoprolol Succinate - Metoprolol Succinate tablet, Extended Release

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 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.
  )
  
• Angina Pectoris. (
  
  
  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.
  )
  
• Heart Failure, to reduce the risk of cardiovascular mortality and heart failure hospitalizations in patients with heart failure. (
  
  
  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 film coated oval shape tablets, scored on two sides, debossed with “Y” and “H” on one side and debossed with “164” on the other side.

50 mg tablets: White film coated oval shape tablets, scored on two sides, debossed with “Y” and “H” on one side and debossed with“165” on the other side.

100 mg tablets: White film coated oval shape tablets, scored on one side and debossed with “Y” and “H”, debossed with “163” on the other side.

200 mg tablets: White film coated oval shape tablets, scored on one side and debossed with “Y” and “H”, debossed with “161” on the other side.

• Hepatic Impairment: Consider initiating metoprolol succinate extended-release tablets therapy at low doses and gradually increase dosage to optimize therapy, while monitoring closely for adverse events. (
  
  
  8.6 Hepatic Impairment

  No studies have been performed with metoprolol succinate extended-release tablets in patients with hepatic impairment. Because metoprolol succinate extended-release tablets are metabolized by the liver, metoprolol blood levels are likely to increase substantially with poor hepatic function. Therefore, initiate therapy at doses lower than those recommended for a given indication; and increase doses gradually in patients with impaired hepatic function.
  )
  

• Abrupt cessation may exacerbate myocardial ischemia. (
  
  
  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.
  )
  
• Heart Failure: Worsening cardiac failure may occur. (
  
  
  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 ]

  . 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.
  )
  
• Bronchospastic Disease: Avoid beta-blockers. (
  
  
  5.3 Bronchospastic Disease

  Patients with bronchospastic diseases should, in general, not receive beta-blockers. Because of its relative beta₁-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 beta₁-selectivity is not absolute, use the lowest possible dose of metoprolol succinate extended-release tablets. Bronchodilators, including beta₂-agonists, should be readily available or administered concomitantly

  [see Dosage and Administration ]

  .
  )
  
• Concomitant use of glycosides, clonidine, and diltiazem and verapamil with beta-blockers can increase the risk of bradycardia. (
  
  
  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 ]

  , 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.
  )
  
• Pheochromocytoma: Initiate therapy with an alpha-blocker. (
  
  
  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.
  )
  
• 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 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.
  ,
  
  
  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 were 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.
  )
  
• Hypoglycemia: May increase risk for hypoglycemia and mask early warning signs. (
  
  
  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.
  )
  
• Thyrotoxicosis: Abrupt withdrawal in patients with thyrotoxicosis might precipitate a thyroid storm. (
  
  
  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.
  )
  
• Peripheral Vascular Disease: Can aggravate symptoms of arterial insufficiency. (
  
  
  5.9 Peripheral Vascular Disease

  Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.
  )
  
• Patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. (
  
  
  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 WARNINGS AND PRECAUTIONS

  • Abrupt cessation may exacerbate myocardial ischemia.
  • Heart Failure: Worsening cardiac failure may occur.
  • Bronchospastic Disease: Avoid beta-blockers.
  • Concomitant use of glycosides, clonidine, and diltiazem and verapamil with beta-blockers can increase the risk of bradycardia.
  • Pheochromocytoma: Initiate therapy with an alpha-blocker.
  • 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.
  • Hypoglycemia: May increase risk for hypoglycemia and mask early warning signs.
  • Thyrotoxicosis: Abrupt withdrawal in patients with thyrotoxicosis might precipitate a thyroid storm.
  • Peripheral Vascular Disease: Can aggravate symptoms of arterial insufficiency.
  • Patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

  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 ]

  . 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 beta₁-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 beta₁-selectivity is not absolute, use the lowest possible dose of metoprolol succinate extended-release tablets. Bronchodilators, including beta₂-agonists, should be readily available or administered concomitantly

  [see Dosage and Administration ]

  .

  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 ]

  , 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.

  )].
  
  
• Worsening heart failure
  
  
  [see Warnings and Precautions (
  
  

  5 WARNINGS AND PRECAUTIONS

  • Abrupt cessation may exacerbate myocardial ischemia.
  • Heart Failure: Worsening cardiac failure may occur.
  • Bronchospastic Disease: Avoid beta-blockers.
  • Concomitant use of glycosides, clonidine, and diltiazem and verapamil with beta-blockers can increase the risk of bradycardia.
  • Pheochromocytoma: Initiate therapy with an alpha-blocker.
  • 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.
  • Hypoglycemia: May increase risk for hypoglycemia and mask early warning signs.
  • Thyrotoxicosis: Abrupt withdrawal in patients with thyrotoxicosis might precipitate a thyroid storm.
  • Peripheral Vascular Disease: Can aggravate symptoms of arterial insufficiency.
  • Patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

  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 ]

  . 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 beta₁-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 beta₁-selectivity is not absolute, use the lowest possible dose of metoprolol succinate extended-release tablets. Bronchodilators, including beta₂-agonists, should be readily available or administered concomitantly

  [see Dosage and Administration ]

  .

  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 ]

  , 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.

  )]
  
  
  .
  
• Worsening AV block
  
  
  [see Contraindications (
  
  

  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.
  • Severe bradycardia: Greater than first degree heart block, or sick sinus syndrome without a pacemaker.
  • Cardiogenic shock or decompensated heart failure.

  )]
  
  
  .