AHFS Class:

• beta-Adrenergic Blocking Agents 24:20

Generic Name(s):

• Metoprolol Succinate

• Metoprolol Tartrate

• Metoprolol Tartrate and Hydrochlorothiazide

Metoprolol is a β₁-selective adrenergic blocking agent (β-blocker).109,147

Metoprolol is used for the management of hypertension,109,157,161,501,1200 angina,109,147,213,214,279 acute myocardial infarction (MI),109,527 and heart failure.147,165,170,173,175,176,179,199,215,216,524,800 The drug also has been used for supraventricular and ventricular tachyarrhythmias†300,301 and prophylaxis of migraine headache†.231

The choice of a β-adrenergic blocking agent (β-blocker) depends on numerous factors, including pharmacologic properties (e.g., relative β-selectivity, intrinsic sympathomimetic activity, membrane-stabilizing activity, lipophilicity), pharmacokinetics, intended use, and adverse effect profile, as well as the patient's coexisting disease states or conditions, response, and tolerance.233,267,268,269,270,271,272,273,274,275,276,277,278 While specific pharmacologic properties and other factors may appropriately influence the choice of a β-blocker in individual patients,1235 evidence of clinically important differences among the agents in terms of overall efficacy and/or safety is limited. 267,269,270,271,272,273,274,275,276,277,278 Patients who do not respond to or cannot tolerate one β-blocker may be successfully treated with a different agent.269,270,271,272,275,277,278

In the management of hypertension or chronic stable angina pectoris in patients with chronic obstructive pulmonary disease (COPD) or type 1 diabetes mellitus, many clinicians prefer to use low dosages of a β₁-selective adrenergic blocking agent (e.g., atenolol, metoprolol), rather than a nonselective agent (e.g., nadolol, pindolol, propranolol, timolol). However, selectivity of these agents is relative and dose dependent. Some clinicians also will recommend using a β₁-selective agent or an agent with intrinsic sympathomimetic activity (ISA) (e.g., pindolol), rather than a nonselective agent, for the management of hypertension or angina pectoris in patients with peripheral vascular disease, but there is no evidence that the choice of β-blocker substantially affects efficacy.

Hypertension

Metoprolol is used alone or in combination with other classes of antihypertensive agents in the management of hypertension.110,150,151,152,153,154,155,156,157,161,501,502,503,504,515,1200β-Blockers often are used concurrently with a diuretic because of their additive effects. β-Blockers also have been combined with vasodilators (e.g., hydralazine, minoxidil) to counteract the reflex tachycardia that occurs with vasodilators.

Metoprolol's efficacy in the management of hypertension is similar to that of other β-blockers; however, metoprolol may be preferred over a nonselective β-blocker, like propranolol, in hypertensive patients with certain concomitant disease states. Metoprolol may be associated with less risk of bronchospasm than propranolol in patients with bronchitis. Metoprolol's relative cardioselectivity may be advantageous in hypertensive patients with concomitant heart failure controlled by diuretics and cardiac glycosides; however, it remains to be established whether metoprolol is less likely to cause heart failure in these patients than is propranolol. In patients with catecholamine excess (e.g., pheochromocytoma, drug-induced hypoglycemia, or acute withdrawal of adrenergic blocking agents), metoprolol reportedly is less likely to produce impairment of peripheral circulation, heart failure, and hypertensive reactions than is propranolol. Because metoprolol may cause less inhibition of glycogenolysis than does propranolol, metoprolol may be preferred in patients with diabetes mellitus who are receiving insulin or oral antidiabetic agents (e.g., sulfonylurea drugs); however, additional study is required.

In contrast to many other antihypertensive agents, metoprolol lowers blood pressure equally well in the upright or supine position. The drug appears to be safe and effective in the management of hypertension in patients with renal damage. Although metoprolol is apparently more effective in reducing blood pressure in patients with normal or elevated plasma renin concentrations, the drug also lowers blood pressure in patients with low renin hypertension. Tolerance to the antihypertensive effect of metoprolol apparently does not occur during long-term administration.

Current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of drugs from 4 classes of antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics).501,502,503,504,1200 Most guidelines no longer recommend β-blockers as first-line therapy for hypertension because of the lack of established superiority over other recommended drug classes and evidence from at least one study demonstrating that β-blockers may be less effective than angiotensin II receptor antagonists in preventing cardiovascular death, MI, or stroke.242,501,503,504,515,1200 However, therapy with a β-blocker may still be considered in hypertensive patients who have a compelling indication (e.g., prior MI, ischemic heart disease, heart failure) for their use or as add-on therapy in those who do not respond adequately to the preferred drug classes.501,502,503,504,523,524,527,800,1200 (See Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors, under Uses: Hypertension.) Ultimately, choice of antihypertensive therapy should be individualized, considering the clinical characteristics of the patient (e.g., age, ethnicity/race, comorbid conditions, cardiovascular risk factors) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, costs).501,502,503,504,515,1200,1201

General Considerations for Initial and Maintenance Antihypertensive Therapy

Nonpharmacologic Therapy

Nonpharmacologic measures (i.e., lifestyle/behavioral modifications) that are effective in lowering blood pressure include weight reduction (for those who are overweight or obese), dietary changes to include foods such as fruits, vegetables, whole grains, and low-fat dairy products that are rich in potassium, calcium, magnesium, and fiber (i.e., adoption of the Dietary Approaches to Stop Hypertension [DASH] eating plan), sodium reduction, increased physical activity, and moderation of alcohol intake.1200 Such lifestyle/behavioral modifications, including smoking cessation, enhance antihypertensive drug efficacy and decrease cardiovascular risk and remain an indispensable part of the management of hypertension.502,504,1200 Lifestyle/behavioral modifications without antihypertensive drug therapy are recommended for individuals classified by a 2017 multidisciplinary hypertension guideline of the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations as having elevated blood pressure (systolic blood pressure 120-129 mm Hg and diastolic blood pressure less than 80 mm Hg) and in those with stage 1 hypertension (systolic blood pressure 130-139 mm Hg or diastolic blood pressure 80-89 mm Hg) who do not have preexisting cardiovascular disease or an estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk of 10% or greater.1200

Initiation of Drug Therapy

Drug therapy in the management of hypertension must be individualized and adjusted based on the degree of blood pressure elevation while also considering cardiovascular risk factors.161,162,229,230,235,257,502,1200,1201 Drug therapy generally is reserved for patients who respond inadequately to nondrug therapy (i.e., lifestyle modifications such as diet [including sodium restriction and adequate potassium and calcium intake], regular aerobic physical activity, moderation of alcohol consumption, and weight reduction) or in whom the degree of blood pressure elevation or coexisting risk factors requires more prompt or aggressive therapy; however, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.504,505,506,507,508,515,523,530,1200,1201,1207,1209

The 2017 ACC/AHA hypertension guideline and many experts currently state that the treatment of hypertension should be based not only on blood pressure values but also on patients' cardiovascular risk factors.502,1200,1219 For secondary prevention of recurrent cardiovascular disease events in adults with clinical cardiovascular disease or for primary prevention in adults with an estimated 10-year ASCVD risk of 10% or higher, the 2017 ACC/AHA hypertension guideline recommends initiation of antihypertensive drug therapy in conjunction with lifestyle/behavioral modifications at an average systolic blood pressure of 130 mm Hg or an average diastolic blood pressure of 80 mm Hg or higher.1200 For primary prevention of cardiovascular disease events in adults with a low (less than 10%) estimated 10-year risk of ASCVD, the 2017 ACC/AHA hypertension guideline recommends initiation of antihypertensive drug therapy in conjunction with lifestyle/behavioral modifications at a systolic blood pressure of 140 mm Hg or higher or a diastolic blood pressure of 90 mm Hg or higher.1200 After initiation of antihypertensive drug therapy, regardless of the ASCVD risk, the 2017 ACC/AHA hypertension guideline generally recommends a blood pressure goal of less than 130/80 mm Hg in all adults.1200 In addition, a systolic blood pressure goal of less than 130 mm Hg also is recommended for noninstitutionalized ambulatory patients 65 years of age or older with an average systolic blood pressure of at least 130 mm Hg.1200 While these blood pressure goals are lower than those recommended for most patients in previous guidelines, they are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of systolic blood pressure.1200,1202,1210

Most data indicate that patients with a higher cardiovascular risk will benefit the most from tighter blood pressure control; however, some experts state this treatment goal also may be beneficial in those at lower cardiovascular risk.1200 Other clinicians believe that the benefits of such blood pressure lowering do not outweigh the risks in those patients considered to be at lower risk of cardiovascular disease and that reclassifying individuals formerly considered to have prehypertension as having hypertension may potentially lead to use of drug therapy in such patients without consideration of cardiovascular risk.1201,1222,1223,1229 Previous hypertension guidelines, such as those from the JNC 8 expert panel, generally have recommended initiation of antihypertensive treatment in patients with a systolic blood pressure of at least 140 mm Hg or a diastolic blood pressure of at least 90 mm Hg, targeted a blood pressure goal of less than 140/90 mm Hg regardless of cardiovascular risk, and used higher systolic blood pressure thresholds and targets in geriatric patients.501 Some clinicians continue to support the target blood pressures recommended by the JNC 8 expert panel because of concerns that such recommendations in the 2017 ACC/AHA hypertension guideline are based on extrapolation of data from the high-risk population in the SPRINT study to a lower-risk population.1223,1224 Also, because more than 90% of patients in SPRINT were already receiving antihypertensive drugs at baseline, data are lacking on the effects of initiating drug therapy at a lower blood pressure threshold (130/80 mm Hg) in patients at high risk of cardiovascular disease.1223 The potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs should be considered when deciding a patient's treatment goal.1200,1220,1229

The 2017 ACC/AHA hypertension guideline recommends an ASCVD risk assessment for all adults with hypertension; however, experts state that it can be assumed that patients with hypertension and diabetes mellitus or chronic kidney disease (CKD) are at high risk for cardiovascular disease and that antihypertensive drug therapy should be initiated in these patients at a blood pressure of 130/80 mm Hg or higher.1200 ACC/AHA also recommends a blood pressure goal of less than 130/80 mm Hg in patients with hypertension and diabetes mellitus or CKD.1200 These recommendations are based on a systematic review of high-quality evidence from randomized controlled trials, meta-analyses, and post hoc analyses that have demonstrated substantial reductions in the risk of important clinical outcomes (e.g., cardiovascular events) regardless of comorbid conditions or age when systolic blood pressure is lowered to less than 130 mm Hg.1200,1213 However, some clinicians have questioned the generalizability of findings from some of the trials (e.g., SPRINT) used to support the 2017 ACC/AHA hypertension guideline.1224 For example, SPRINT included adults (mean age: 68 years) without diabetes mellitus who were at high risk of cardiovascular disease.1209,1210 While benefits of intensive blood pressure control were observed in this patient population, some clinicians have questioned whether these findings apply to younger patients who have a low risk of cardiovascular disease.1223 In patients with CKD in the SPRINT trial, intensive blood pressure management (achieving a mean systolic blood pressure of approximately 122 mm Hg compared with 136 mm Hg with standard treatment) provided a similar beneficial reduction in the composite cardiovascular disease primary outcome and all-cause mortality as in the full patient cohort.1200,1210 Because most patients with CKD die from cardiovascular complications, the findings of this study further support a lower blood pressure target of less than 130/80 mm Hg.1200 Data are lacking to determine the ideal blood pressure goal in patients with hypertension and diabetes mellitus; also, studies evaluating the benefits of intensive blood pressure control in patients with diabetes mellitus have provided conflicting results.521,1200,1213

Clinical studies reviewed for the 2017 ACC/AHA hypertension guideline have shown similar quantitative benefits from blood pressure lowering in hypertensive patients with or without diabetes mellitus.1213 In a randomized, controlled study (ACCORD-BP) that compared a higher (systolic blood pressure less than 140 mm Hg) versus lower (systolic blood pressure less than 120 mm Hg) blood pressure goal in patients with diabetes mellitus, there was no difference in the incidence of cardiovascular outcomes (e.g., composite outcome of cardiovascular death, nonfatal MI, and nonfatal stroke).521,1214 However, some experts state that this study was underpowered to detect a difference between the 2 treatment groups and that the factorial design of the study complicated interpretation of the results.1200,1216 Although SPRINT did not include patients with diabetes mellitus, patients in this study with prediabetes demonstrated a similar cardiovascular benefit from intensive treatment of blood pressure as normoglycemic patients.1200 A meta-analysis of data from ACCORD and SPRINT suggests that the findings of both studies are consistent and that patients with diabetes mellitus benefit from more intensive blood pressure control.1202,1217 These data support the 2017 ACC/AHA hypertension guideline recommendation of a blood pressure treatment goal of less than 130/80 mm Hg in patients with hypertension and diabetes mellitus.1200 Alternatively, the American Diabetes Association (ADA) recommends a blood pressure goal of less than 140/90 mm Hg in patients with diabetes mellitus.1214 The ADA states that a lower blood pressure goal (e.g., less than 130/80 mm Hg) may be appropriate for patients with a high risk of cardiovascular disease and diabetes mellitus if it can be achieved without undue treatment burden.1214

Further study is needed to more clearly define optimum blood pressure goals in patients with hypertension, particularly in high-risk groups (e.g., patients with diabetes mellitus, cardiovascular disease, or cerebrovascular disease; black patients); when determining appropriate blood pressure goals, individual risks and benefits should be considered in addition to the evidence from clinical studies.503,507,515,526,530,1200

Experts state that in patients with stage 1 hypertension (especially the elderly, those with a history of hypotension, or those who have experienced adverse drug effects), it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target blood pressure.1200 However, although some patients can begin treatment with a single antihypertensive agent, the 2017 ACC/AHA hypertension guideline recommends initiation of antihypertensive therapy with 2 drugs from different pharmacologic classes (either as separate agents or in a fixed-dose combination) in patients with stage 2 hypertension and an average blood pressure more than 20/10 mm Hg above their target blood pressure.1200 Such combined therapy may increase the likelihood of achieving goal blood pressure in a more timely fashion, but also may increase the risk of adverse effects (e.g., orthostatic hypotension) in some patients (e.g., elderly).235,257,1200 Drug regimens with complementary activity, where a second antihypertensive agent is used to block compensatory responses to the first agent or affect a different pressor mechanism, can result in additive blood pressure lowering and are preferred.1200 Drug combinations that have similar mechanisms of action or clinical effects (e.g., the combination of an ACE inhibitor and an angiotensin II receptor antagonist) generally should be avoided.1200 Many patients who begin therapy with a single antihypertensive agent will subsequently require at least 2 drugs from different pharmacologic classes to achieve their blood pressure goal.1200 Experts state that other patient-specific factors, such as age, concurrent medications, drug adherence, drug interactions, the overall treatment regimen, cost, and comorbidities, also should be considered when deciding on an antihypertensive drug regimen.1200 For any stage of hypertension, antihypertensive drug dosages should be adjusted and/or other agents substituted or added until goal blood pressure is achieved.1200 (See Follow-up and Maintenance Drug Therapy under Hypertension: General Considerations for Initial and Maintenance Antihypertensive Therapy, in Uses.)

Follow-up and Maintenance Drug Therapy

Several strategies are used for the titration and combination of antihypertensive drugs; these strategies, which are generally based on those used in randomized controlled studies, include maximizing the dosage of the first drug before adding a second drug, adding a second drug before achieving maximum dosage of the initial drug, or initiating therapy with 2 drugs simultaneously (either as separate preparations or as a fixed-dose combination).1200 Combined use of an ACE inhibitor and angiotensin II receptor antagonist should be avoided because of the potential risk of adverse renal effects.1200 After initiating a new or adjusted antihypertensive drug regimen, patients should have their blood pressure reevaluated monthly until adequate blood pressure control is achieved.1200 Effective blood pressure control can be achieved in most hypertensive patients, but many will ultimately require therapy with 2 or more antihypertensive drugs.239,1200 In addition to measuring blood pressure, clinicians should evaluate patients for orthostatic hypotension, adverse drug effects, adherence to drug therapy and lifestyle modifications, and the need for drug dosage adjustments.1200 Laboratory testing such as electrolytes and renal function status and other assessments of target organ damage also should be performed.1200

Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors

Drug therapy in patients with hypertension and underlying cardiovascular or other risk factors should be carefully individualized based on the underlying disease(s), concomitant drugs, tolerance to drug-induced adverse effects, and blood pressure goal.235,502,1200 (See Table 2 on Compelling Indications for Drug Classes based on Comorbid Conditions, under Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.)

Ischemic Heart Disease

The selection of an appropriate antihypertensive agent in patients with ischemic heart disease should be based on individual patient characteristics, and may include a β-blocker, with the addition of other drugs (e.g., ACE inhibitors, thiazide diuretics, calcium-channel blockers) as necessary to achieve blood pressure goals.523,525,1200 Because of the demonstrated mortality benefit of β-blockers following MI, these drugs should be administered in all patients who have survived an MI.133,253,523,527,1200 The 2017 ACC/AHA hypertension guideline states that β-blockers used for ischemic heart disease/angina that are also effective in lowering blood pressure include bisoprolol, carvedilol, metoprolol succinate, metoprolol tartrate, nadolol, propranolol, and timolol.1200

Heart Failure

While β-blockers as single therapies are not superior to other antihypertensive agents in the reduction of all cardiovascular outcomes,524 certain β-blockers (bisoprolol, carvedilol, extended-release metoprolol succinate) have been shown to be effective in reducing the incidence of heart failure and associated morbidity and mortality.252,524,1200 (See Uses: Heart Failure.)

Other Special Considerations for Antihypertensive Drug Therapy

Race

Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control.1200 In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blockers than to monotherapy with β-blockers, ACE inhibitors, or angiotensin II receptor antagonists.229,230,233,265,266,501,504,1200 However, such diminished response to a β-blocker is largely eliminated when the drug is administered concomitantly with a thiazide diuretic.504 In addition, some experts state that when use of β-blockers is indicated in hypertensive patients with underlying cardiovascular or other risk factors, these indications should be applied equally to black hypertensive patients.233

For information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.

Chronic Stable Angina

Metoprolol is used for the management of chronic stable angina pectoris. β-Blockers are recommended as the anti-ischemic drugs of choice in most patients with chronic stable angina; despite differences in cardioselectivity, intrinsic sympathomimetic activity, and other clinical factors, all β-blockers appear to be equally effective for this indication.1101 In placebo-controlled studies, metoprolol reduced the frequency of anginal attacks, reduced nitroglycerin consumption, and increased exercise tolerance.

Combination therapy with a β-blocker and a nitrate appears to be more effective than either drug alone because β-blockers attenuate the increased sympathetic tone and reflex tachycardia associated with nitrate therapy while nitrate therapy (e.g., nitroglycerin) counteracts the potential increase in left-ventricular wall tension associated with a decrease in heart rate.1101 Combined therapy with a β-blocker and a dihydropyridine calcium-channel blocker also may be useful because the tendency to develop tachycardia with the calcium-channel blocker is counteracted by the β-blocker.1101 However, caution should be exercised in the concomitant use of β-blockers and the nondihydropyridine calcium-channel blockers verapamil or diltiazem because of the potential for excessive fatigue, bradycardia, or atrioventricular (AV) block.1101 Concomitant use of metoprolol with cardiac glycosides may be beneficial in patients with angina pectoris, especially in those with cardiomegaly, because both drugs reduce myocardial oxygen consumption; however, the potential effect of combined therapy on AV conduction should be considered. (See Drug Interactions: Cardiovascular Drugs.)

Non-ST-Segment-Elevation Acute Coronary Syndromes

β-Blockers are used as part of the standard therapeutic measures for managing non-ST-segment-elevation acute coronary syndromes (NSTE ACS).1100 Patients with NSTE ACS have either unstable angina or non-ST-segment-elevation MI (NSTEMI); because these conditions are part of a continuum of acute myocardial ischemia and have indistinguishable clinical features upon presentation, the same initial treatment strategies are recommended.805,1100 The American Heart Association/American College of Cardiology (AHA/ACC) guideline for the management of patients with NSTE ACS recommends an early invasive strategy (angiographic evaluation with the intent to perform revascularization procedures such as percutaneous coronary intervention [PCI] with coronary artery stent implantation or coronary artery bypass grafting [CABG]) or an ischemia-guided strategy (initial medical management followed by cardiac catheterization and revascularization if indicated) in patients with definite or likely NSTE ACS; standard medical therapies for all patients should include a β-blocker, antiplatelet agents (aspirin and/or a P2Y12-receptor antagonist), anticoagulant agents (e.g., low-molecular weight or unfractionated heparin), nitrates (e.g., nitroglycerin), and analgesic agents regardless of the initial management approach.1100 The guideline states that oral β-blocker therapy should be initiated within the first 24 hours in patients who do not have manifestations of heart failure, evidence of a low-output state, increased risk of cardiogenic shock, or any other contraindications to β-blocker therapy; use of IV β-blockers is potentially harmful in patients with risk factors for cardiogenic shock.1100 Continued therapy with a β-blocker proven to reduce mortality (bisoprolol, carvedilol, or metoprolol succinate) is recommended in patients with stabilized heart failure and reduced systolic function.1100 (See Uses: Heart Failure, in Carvedilol 24:24.)

Acute Myocardial Infarction

Metoprolol tartrate is used orally and IV to reduce the risk of cardiovascular mortality in hemodynamically stable patients with definite or suspected acute MI. The term MI is used when there is evidence of myocardial necrosis in the setting of acute myocardial ischemia.807 ST-segment-elevation MI (STEMI) is distinguished from NSTEMI based on the presence or absence of ST-segment elevation on ECG.527,807,808,1100 Patients with STEMI typically have complete arterial occlusion; therefore, immediate reperfusion therapy (with primary PCI or thrombolytic agents) is the current standard of care for such patients.527,803,805,808 Because the clinical presentation of NSTEMI is similar to that of unstable angina, these conditions are considered together in current expert guidelines.1100 (See Uses: Non-ST-Segment Elevation Acute Coronary Syndromes.) During the early stage of a definite or suspected MI, metoprolol has been initiated with IV doses, followed by continued oral dosing; however, experts currently recommend that early IV use of β-blockers be limited to selected patients.527,603,1100

Because β-blockers can reduce myocardial oxygen demand during the first few hours of an acute MI by reducing heart rate, arterial blood pressure, and/or myocardial contractility, and also have been shown to reduce mortality, early IV therapy with these drugs was routinely recommended following acute MI.123,124,125,128,136,137,138,139,145,802,803,1100 Evidence supporting this recommendation was generally based on studies conducted prior to the reperfusion era demonstrating a reduction in mortality and other clinical benefits (i.e., reduced infarct size, incidence of ventricular arrhythmias, chest pain, and cardiac enzyme elevations) with early use of β-blockers during MI.158,803,804 In one double-blind, placebo-controlled study in patients with definite or suspected acute MI, therapy with metoprolol tartrate (initiated IV as soon as possible after arrival to the hospital and continued orally for 3 months) was associated with a 36% reduction in mortality.603 The mortality benefit of metoprolol was similar between patients who were treated early (no more than 8 hours from the onset of symptoms) and those who initiated treatment at a later time.603 Patients receiving metoprolol also had substantial reductions in ventricular fibrillation and chest pain.603 (See Uses: Acute Myocardial Infarction, in Atenolol 24:24.)

Studies conducted after the widespread use of reperfusion therapy generally have demonstrated more attenuated benefits with early β-blocker therapy in patients with acute MI; while β-blockers may still confer benefits (e.g., reduction in the risk of reinfarction and ventricular arrhythmias), there is less certainty regarding the drugs' effects on mortality in patients receiving contemporary revascularization and pharmacologic therapies (antiplatelet agents, ACE inhibitors, and lipid-lowering therapies).527,801,802,804,1100 In addition, early use of β-blockers (particularly when administered IV) has been associated with an increased risk of cardiogenic shock.527,801,804,1100 In the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT), there was no difference in mortality or the combined end point of death, reinfarction, or cardiac arrest between patients receiving early metoprolol therapy (initiated IV for up to 3 doses and continued orally) and those receiving placebo.801 Although patients who received metoprolol had a lower risk of reinfarction and ventricular fibrillation, these benefits were accompanied by a substantially higher risk of cardiogenic shock, particularly within the first day of treatment.527,801 Based on the currently available evidence, the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline for the management of STEMI recommends oral β-blocker therapy in all patients who do not have manifestations of heart failure, evidence of a low-output state, increased risk of cardiogenic shock, or any other contraindications to β-blocker therapy.527 Such therapy should be initiated within the first 24 hours following acute MI and continued during and after hospitalization.527 Because of conflicting evidence of benefit and the potential for harm, the guidelines recommend limiting use of IV β-blockers to patients with refractory hypertension or ongoing ischemia.527

Although the efficacy of metoprolol tartrate following administration of the drug for longer than 3 months has not been conclusively established, the benefits of long-term β-blocker therapy for secondary prevention have been well established in numerous clinical studies.527,804,806,1101 Patients with MI complicated by heart failure, left ventricular dysfunction, or ventricular arrhythmias appear to derive the most benefit from long-term β-blocker therapy.527 Data from studies using other β-blockers suggest that treatment should be continued for at least 1-3 years if not indefinitely after infarction unless contraindicated. Several large, randomized studies have demonstrated that long-term therapy with a β-blocker can reduce the rates of reinfarction and mortality (e.g., sudden or nonsudden cardiac death) following acute MI.123,126,127,128,130,131,132,133,134,144 It is estimated that such therapy could result in a relative reduction in mortality of about 25% annually for years 1-3 after infarction, with high-risk patients exhibiting the greatest potential benefit;123,126,127,128,130,135,141,144 the benefit of continued therapy may persist for at least several years beyond this period, although less substantially.126,130,143,144 Therefore, metoprolol, like other β-blockers, can be used for secondary prevention following acute MI to reduce the risk of reinfarction and mortality.109,123,126,127,144,527 The AHA/ACCF secondary prevention guideline recommends β-blocker therapy in all patients with left ventricular systolic dysfunction (ejection fraction of 40% or less) and a prior MI; use of a β-blocker with proven mortality benefit (bisoprolol, carvedilol, or metoprolol succinate) is recommended.525,1101 (See Uses: Heart Failure, in Carvedilol 24:24.) Although the benefits of long-term β-blockade in post-MI patients with normal left ventricular function are less well established, the guideline recommends continued β-blocker therapy for at least 3 years in such patients.525 Further studies are needed to establish the optimal duration of β-blocker therapy for secondary prevention of MI.527,802,804

Supraventricular Arrhythmias

β-Blockers, including metoprolol, have been used to slow ventricular rate in patients with supraventricular tachycardia† (SVT).300,301,401 The American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) guideline for the management of adult patients with supraventricular tachycardia recommends the use of β-blockers in the treatment of various SVTs (e.g., atrial flutter, junctional tachycardia, focal atrial tachycardia, AV nodal reentrant tachycardia [AVNRT]); in general, an IV β-blocker is recommended for acute treatment, while an oral β-blocker is recommended for ongoing management of these arrhythmias.300,301 Vagal maneuvers and/or IV adenosine are considered first-line interventions for the acute treatment of SVT and should be attempted prior to other therapies when clinically indicated; if such measures are ineffective or not feasible, an IV β-blocker may be considered in hemodynamically stable patients.300 Although evidence of efficacy is limited, experts state that the overall safety of β-adrenergic blockers warrants their use in patients with SVT.300 Patients should be closely monitored for hypotension and bradycardia during administration of these drugs.300

Atrial Fibrillation and Flutter

β-Blockers, including metoprolol, have been used to slow rapid ventricular response in patients with atrial fibrillation† or atrial flutter†.300,301 IV β-blockers (e.g., esmolol, propranolol, metoprolol) are recommended as one of several drug therapy options for ventricular rate control in patients with nonpreexcited atrial fibrillation or flutter; an oral β-blocker may be used for ongoing rate control in such patients.300,301 Choice of a specific β-blocker should be individualized based on the patient's clinical condition.301

Atrial Tachycardia

IV β-blockers may be used for the acute treatment of patients with hemodynamically stable focal atrial tachycardia† (i.e., regular SVT arising from a localized atrial site), and an oral β-blocker may be used for ongoing management.300

While evidence is more limited, IV metoprolol also has been used in patients with multifocal atrial tachycardia† (rapid, irregular rhythm with at least 3 distinct P-wave morphologies) to control ventricular rate and convert to normal sinus rhythm.115,116,119,300 Multifocal atrial tachycardia is commonly associated with an underlying condition (e.g., pulmonary, coronary, or valvular heart disease) and is generally not responsive to antiarrhythmic drug therapy.300 Antiarrhythmic drug therapy usually is reserved for patients who do not respond to initial attempts at correcting or managing potential precipitating factors (e.g., exacerbation of COPD or congestive heart failure, electrolyte and/or ventilatory disturbances, infection, theophylline toxicity) or in whom a precipitating factor cannot be identified.115,119,122,300 Therapy with IV metoprolol has been associated with slowing of atrial116 and ventricular rates115,119 and conversion to sinus rhythm115,119 in many patients with this arrhythmia; therefore, some experts state that IV metoprolol may be useful for the acute treatment of patients with multifocal atrial tachycardia who do not have respiratory decompensation, sinus node dysfunction, or AV block.115,116,119,300 Metoprolol also may be useful orally for chronic suppression of symptomatic multifocal atrial tachycardia.115,116,300

Paroxysmal Supraventricular Tachycardia

IV β-blockers may be used for the acute treatment of hemodynamically stable patients with paroxysmal supraventricular tachycardia (PSVT), including AVNRT†, that is uncontrolled or unconverted by vagal maneuvers and adenosine; an oral β-blocker may be used for the ongoing management of such patients who are not candidates for, or prefer not to undergo, catheter ablation.300

Junctional Tachycardia

β-Blockers are considered one of several drug therapy options for the treatment of junctional tachycardia† (i.e., nonreentrant SVT originating from the AV junction), a rapid, occasionally irregular, narrow-complex tachycardia.300 While evidence is limited, there is some data indicating that β-blocking agents (specifically propranolol) are modestly effective in terminating and/or reducing the incidence of junctional tachycardia.300

Ventricular Arrhythmias

Ventricular Fibrillation

β-Blockers have been used in patients with cardiac arrest precipitated by ventricular fibrillation or pulseless ventricular tachycardia†.400 However, AHA states that routine administration of β-adrenergic blocking agents after cardiac arrest is potentially harmful (e.g., may worsen hemodynamic instability, exacerbate heart failure, or cause bradyarrhythmias) and is therefore not recommended.400

Polymorphic Ventricular Tachycardia

β-Blockers may be useful in the management of certain forms of polymorphic ventricular tachycardia† (e.g., associated with acute ischemia).401

Heart Failure

Metoprolol is used (usually in conjunction with other heart failure therapies) in the management of mild to moderately severe (New York Heart Association [NYHA] class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin.147,165,170,173,175,198,199,215,216,252,524,800 In clinical studies, metoprolol (as extended-release metoprolol succinate) increased survival and reduced the risk of hospitalization in patients with chronic heart failure.147,165,170,173,175,198,199,215,216,252,524,800 Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure.524,701,703,800 Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement and/or reduction in heart-failure related hospitalizations.524,800 Experts recommend that all asymptomatic patients with reduced left ventricular ejection fraction (LVEF) (ACCF/AHA stage B heart failure) receive therapy with an ACE inhibitor and a β-blocker to prevent symptomatic heart failure and to reduce morbidity and mortality.524,800 In patients with prior or current symptoms of heart failure and reduced LVEF (ACCF/AHA stage C heart failure), ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend inhibition of the renin-angiotensin-aldosterone (RAA) system with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality.800 While ACE inhibitors have been the preferred drugs for inhibition of the RAA system because of their established benefits in patients with heart failure and reduced ejection fraction, some evidence indicates that therapy with an ARNI may be more effective than ACE inhibitor therapy in reducing cardiovascular death and heart failure-related hospitalization in such patients.702,800 ACCF, AHA, and HFSA recommend that patients with chronic symptomatic heart failure with reduced LVEF (NYHA class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality.800

Because of favorable effects on survival and disease progression, therapy with a clinical trial-proven β-blocker (bisoprolol, carvedilol, extended-release metoprolol succinate) should be initiated as soon as the patient is diagnosed with heart failure and reduced LVEF.524 While bisoprolol, carvedilol, and extended-release metoprolol have been effective in reducing the risk of death in patients with chronic heart failure, these positive findings should not be considered indicative of a β-blocker class effect.524 Even when symptoms are mild or improve with other therapies, β-blocker therapy should not be delayed until symptoms return or the disease progresses.524 Despite concerns about β-blockade potentially masking some signs of hypoglycemia,109,147 patients with diabetes mellitus may be particularly likely to experience a reduction in morbidity and mortality with the use of β-blockers.163,174 If a patient cannot tolerate a β-blocker or if increasing the β-blocker dosage is ineffective, ivabradine should be considered an alternative or additional treatment option.701,709,710,800 Some evidence suggests that ivabradine is effective in reducing hospitalizations related to heart failure, but unlike β-blockers, ivabradine has not been shown to reduce cardiovascular mortality.707,708,710,711,712 (See Uses: Heart Failure, in Ivabradine 24:04.92.)

In individualizing the decision to use a β-blocker, clinicians should consider that clinical studies establishing the effects of these drugs on morbidity and mortality excluded patients who were hospitalized or had unstable symptoms and enrolled few patients with current or recent NYHA class IV symptoms.163,215,216 The efficacy of β-blockers in such patients is not known,163,216 and they may be at particular risk of deterioration following initiation of therapy with β-blockers.163

In a large, randomized, double-blind, placebo-controlled study (Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure [MERIT-HF]) in patients with mild to severe (NYHA class II-IV) heart failure and a left ventricular ejection fraction of 0.4 or less, therapy with metoprolol succinate (as extended-release tablets) 12.5-25 mg daily as the tartrate (initial dosage depending on NYHA class, with dosage increased over 8 weeks to a target daily dosage of 200 mg daily) in addition to optimal standard therapy (principally ACE inhibitors and diuretics) was associated with a reduction in all-cause mortality of 34% (mortality rates of 7.2 and 11% with metoprolol and placebo, respectively).147,199,216 The MERIT-HF trial was terminated early because of the favorable effects of metoprolol on overall mortality; the mean follow-up period was 1 year.147,216 Sudden deaths and deaths from worsening heart failure also were reduced with metoprolol therapy.147,216 In addition to improved survival, metoprolol therapy improved NYHA class, reduced hospitalizations due to worsening heart failure, and resulted in beneficial effects on patient well-being (as determined by quality-of-life measurements); the composite end point of overall mortality and hospitalization for any cause was reduced by 19%. 147,199 Metoprolol therapy appeared to be well tolerated, with 64% of patients achieving the target dosage of 200 mg daily and 87% tolerating a daily dosage of 100 mg; the mean daily dosage of metoprolol as the tartrate was 159 mg.147,216

The beneficial effects of β-blockers in the management of heart failure are thought to result principally from inhibition of the effects of the sympathetic nervous system.163 Although the specific effects on the heart and circulation that are responsible for progression of heart failure remain to be established, sympathetic activity can increase ventricular volumes and pressure secondary to peripheral vasoconstriction and by impairing sodium excretion by the kidneys.163 Other sympathetic effects (e.g., induction of cardiac hypertrophy, arrhythmogenic activity) also may be involved.163 Collective experience indicates that long-term therapy with β-blockers, like that with ACE inhibitors, can reduce heart failure symptoms and improve clinical status in patients with chronic heart failure and also can decrease the risk of death as well as the combined risk of death and hospitalization.175,199,215,216,524 These beneficial effects were demonstrated in patients already receiving an ACE inhibitor, suggesting that combined inhibition of the renin-angiotensin system and sympathetic nervous system can produce additive effects.163,524

β-Blockers should not be used in patients with acutely decompensated heart failure requiring IV inotropic therapy (see Cautions: Precautions and Contraindications) and those with substantial fluid retention requiring intensive diuresis. 185,524 In the absence of hemodynamic instability or contraindications, it has been recommended that patients with heart failure and a reduced ejection fraction who are hospitalized for a symptomatic exacerbation continue to receive maintenance treatment with standard oral therapy (e.g., β-blocker, ACE inhibitor).524 Withholding of, or reduction in, β-blocker therapy may be considered in patients hospitalized after recent initiation or increase in β-blocker therapy.524 Initiation of β-blocker therapy in hospitalized patients is recommended once the patient's condition is stabilized (i.e., after optimization of volume status and successful discontinuance of IV diuretics, vasodilators, and inotropic agents).524 Caution should be used when initiating β-blockers in patients who have required inotrope therapy during their hospitalization.524

Vascular Headache

Migraine

Metoprolol has been used for the prophylaxis of migraine headache†.231 When used prophylactically, metoprolol can prevent migraine or reduce the number of attacks in some patients.231 Results of comparative studies suggest that metoprolol may be comparable to propranolol for this indication.231 However, the US Headache Consortium states that the quality of evidence for metoprolol is not as compelling as it is for propranolol for this indication.231 Metoprolol is not recommended for the treatment of a migraine attack that has already started.231 For further information on management and classification of migraine headache, see Vascular Headaches: General Principles in Migraine Therapy, under Uses in Sumatriptan 28:32.28.

Administration

Metoprolol tartrate and metoprolol succinate are administered orally. Metoprolol tartrate also may be administered IV.300,301

Absorption of metoprolol tartrate may be enhanced by administration with food. The manufacturer recommends that metoprolol tartrate be administered with or immediately following meals.109 Although administration with meals is not required, metoprolol tartrate should be given in a standardized relation to meals to minimize variance in effect. Food does not appear to affect the bioavailability of metoprolol succinate extended-release tablets.147

Metoprolol tartrate may be administered daily as a single dose or in divided doses;109 metoprolol succinate extended-release tablets should be administered daily as a single dose. If a dose is missed, the patient should take only the next scheduled dose (i.e., the next dose should not be doubled). Metoprolol succinate extended-release tablets are scored and can be divided; however, the tablet or half tablet should be swallowed whole and should not be chewed or crushed.147

Dispensing and Administration Precautions

Because of similarity in spelling between Toprol-XL^® (a trade name for metoprolol succinate) and Topamax^® (the trade name for topiramate, an anticonvulsant and antimigraine agent), the potential exists for dispensing or prescribing errors involving these drugs.261,262,263,264 In addition, there is a potential for dispensing errors involving confusion between Toprol-XL^® and Tegretol^® or Tegretol^®-XR (trade names for carbamazepine, an anticonvulsant that also is used for relief of pain associated with trigeminal neuralgia, as well as for various psychiatric disorders).261,263 According to medication error reports, the overlapping tablet strengths between Toprol-XL^® and Topamax^® (25, 50, 100, and 200 mg) and between Toprol-XL^® and Tegretol^® or Tegretol^®-XR (100 and 200 mg) and the fact that these drugs were stored closely together in pharmacies also may have been contributing factors in causing these errors.261,262,263,264 Another contributing factor to dispensing errors associated with Toprol-XL^® and Topamax^® may be the use of mnemonic abbreviations in computerized listings incorporating the first 3 letters and dose strength (e.g., “TOP25”).262 Extra care should be exercised to ensure the accuracy of both oral and written prescriptions for these drugs.261,262,263,264 The manufacturers of Toprol-XL^® and Topamax^® also recommend that pharmacists assess various measures of avoiding dispensing errors and implement them as appropriate (e.g., by verifying all orders for these drugs by citing both the trade and generic names to prescribers, attaching reminders to pharmacy shelves, separating the drugs on pharmacy shelves, counseling patients).261,262 (See Cautions: Precautions and Contraindications.)

Extemporaneously Compounded Oral Liquid

An extemporaneously compounded oral liquid formulation of metoprolol tartrate containing 10 mg/mL has been prepared using the commercially available tablets and sweetened vehicles.99

Standardize 4 Safety

Standardized concentrations for an extemporaneously prepared oral liquid formulation of metoprolol have been established through Standardize 4 Safety (S4S), 100a national patient safety initiative to reduce medication errors, especially during transitions of care. 100Multidisciplinary expert panels were convened to determine recommended standard concentrations. Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 100 For additional information on S4S (including updates that may be available), see [Web].100

Dosage

Dosages of metoprolol tartrate and metoprolol succinate are expressed in terms of the tartrate. Since there is no consistent interpatient correlation between the dosage of metoprolol and therapeutic response, dosage must be individualized according to the response of the patient. Blood pressure should be measured near the end of a dosing interval to determine whether satisfactory control is being maintained throughout the day. When patients receiving metoprolol tartrate conventional tablets are switched to metoprolol succinate extended-release tablets, the same daily dosage should be used. If long-term metoprolol therapy is to be discontinued, dosage of the drug should be gradually reduced over a period of 1-2 weeks. (See Cautions: Precautions and Contraindications.)

Hypertension

Metoprolol Therapy

The manufacturers state that the usual initial adult oral dosage of metoprolol tartrate conventional tablets, given alone or in combination with a diuretic, is 100 mg daily given in single or divided doses.600 When administered as metoprolol succinate extended-release tablets, the manufacturers state that the recommended initial dosage in terms of metoprolol tartrate is 25-100 mg administered once daily.602 Some clinicians recommend an initial dosage of at least 50 mg 3 times daily as metoprolol tartrate conventional tablets, for better control. Dosage may be increased at weekly (or longer) intervals until optimum hypotensive effect is achieved.600,602 In general, the maximum effect of any given dosage will be apparent within 1 week. The manufacturers state that oral dosages in terms of metoprolol tartrate should not exceed 450 mg daily as conventional tablets or 400 mg daily as extended-release tablets; dosages of the respective formulations exceeding these have not been studied.600,602

Some experts state the usual dosage range is 100-200 mg daily, given in 2 divided doses daily as conventional tablets or 50-200 mg once daily given as extended-release tablets.1200

The fact that β₁-adrenergic blocking selectivity of metoprolol diminishes as dosage is increased should be considered.

Patients with severe hypertension may require more uniform plasma concentrations for adequate control and in some hypertensive patients, especially when lower dosages (e.g., 100 mg daily) are used, blood pressure increases slightly toward the end of the dosing interval with once- or twice-daily administration. If a satisfactory response is not maintained throughout the day, larger doses, more frequent administration, or use of extended-release tablets may achieve better control.

If metoprolol tartrate is used for the management of hypertension in children 1-17 years of age†, some experts have recommended an initial oral dosage of 1-2 mg/kg daily given in 2 divided doses.260 Such experts have suggested that dosage may be increased as necessary to a maximum dosage of 6 mg/kg (up to 200 mg) daily given in 2 divided doses.260 The manufacturer states that if extended-release metoprolol succinate is used for hypertension in children 6 years of age or older, an initial oral dosage of 1 mg/kg (up to 50 mg) daily in terms of metoprolol tartrate is recommended.602 The dosage should be adjusted according to blood pressure response.602 The safety and efficacy of dosages exceeding 2 mg/kg (or 200 mg) once daily have not been established in pediatric patients.602 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Metoprolol/Hydrochlorothiazide Fixed-combination Therapy

When combination therapy is required, the manufacturer recommends that commercially available preparations containing metoprolol tartrate in fixed combination with a thiazide diuretic should not be used initially. Dosage should first be adjusted by administering each drug separately. If it is determined that the optimum maintenance dosage corresponds to the ratio in the commercial combination preparation, the fixed combination may be used. Dosage regimens using fixed-combination preparations that exceed 50 mg of hydrochlorothiazide daily are not recommended.

Blood Pressure Monitoring and Treatment Goals

Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, calcium-channel blocker, thiazide diuretic) may be added; if target blood pressure is still not achieved with the use of 2 antihypertensive agents, a third drug may be added.1200,1216 (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with metoprolol, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1200,1216

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505,506,507,508,515,523,530,1201,1207,1209,1222 While previous hypertension guidelines have based target blood pressure goals on age and comorbidities,501,504,536 the 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guideline incorporates underlying cardiovascular risk into decision making regarding treatment and generally recommends the same target blood pressure (i.e., less than 130/80 mm Hg) for all adults.1200 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200,1220

For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.

Chronic Stable Angina

For the long-term management of angina pectoris, the initial adult dosage of metoprolol tartrate (conventional tablets)109 or metoprolol succinate (extended-release tablets)147 is 100 mg as the tartrate daily given in 2 divided doses109 or in a single dose,147 respectively. Dosage may be increased at weekly intervals until optimum control of angina is obtained or there is pronounced slowing of the heart rate. The usual maintenance dosage of metoprolol tartrate (conventional tablets) or metoprolol succinate (extended-release tablets) is 100-400 mg (expressed in terms of metoprolol tartrate) daily.147 Oral dosages exceeding 400 mg daily (given as metoprolol tartrate conventional tablets or as metoprolol succinate extended-release tablets)147 have not been studied. When discontinuance of metoprolol therapy is planned, dosage of the drug should be gradually reduced over a period of about 1-2 weeks. (See Cautions: Precautions and Contraindications.)

Acute Myocardial Infarction

Early Treatment

The manufacturer states that metoprolol therapy may be initiated as soon as possible after an acute myocardial infarction (MI) when the patient's hemodynamic condition has stabilized.603 During the early stage of a definite or suspected MI, the manufacturer recommends that treatment with metoprolol tartrate be initiated with the administration of three 5-mg rapid IV injections given at approximately 2-minute intervals as tolerated.603 Heart rate, blood pressure, and ECG should be monitored during IV administration, and the drug should be titrated to response.527,603 In patients who tolerate the full IV dose (15 mg), the manufacturer states that oral administration of metoprolol tartrate should be initiated 15 minutes after the last IV dose at a dosage of 50 mg every 6 hours for 48 hours. Thereafter, an oral maintenance dosage of 100 mg twice daily should be used. Patients who appear not to tolerate the usual total IV dose should initially receive an oral metoprolol tartrate dosage of 25 or 50 mg (depending on the degree of intolerance) every 6 hours beginning 15 minutes after the last IV dose or as soon as their clinical condition allows. In patients with severe intolerance, metoprolol should be discontinued.

The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline for the management of ST-segment-elevation MI (STEMI) recommends initiation of oral β-blocker therapy within the first 24 hours in patients who do not have manifestations of heart failure, evidence of a low-output state, increased risk of cardiogenic shock, or any other contraindications to β-blocker therapy.527 The recommended oral dosage of metoprolol tartrate is 25-50 mg every 6-12 hours; patients should be transitioned over the following 2-3 days to twice-daily dosing (using metoprolol tartrate) or daily dosing (using metoprolol succinate).527 Dosage should be titrated up to a total daily dose of 200 mg as tolerated.527 Because IV β-blockers can be potentially harmful in patients with risk factors for cardiogenic shock, these experts recommend that IV use be limited to patients who have refractory hypertension or have ongoing ischemia at the time of presentation.527 If IV therapy is employed, the recommended IV dosage of metoprolol tartrate is 5 mg every 5 minutes as tolerated up to 3 doses.527

Late Treatment and Long-term Secondary Prevention

In patients who have contraindications to metoprolol therapy during the early phase of definite or suspected acute MI, in patients who appear not to tolerate the full early treatment, or in patients in whom therapy is delayed for any other reason, the manufacturer recommends initiation of metoprolol therapy with an oral dosage of 100 mg twice daily as soon as their clinical condition allows.604 The manufacturer states that oral metoprolol therapy should be continued for at least 3 months;604 however, the optimal duration of β-blocker therapy following MI remains to be clearly established.527,802,804 Experts generally recommend that such therapy be continued long-term in post-MI patients with left ventricular systolic dysfunction, and for at least 3 years in those with normal left ventricular function.525,802,804,1101

Atrial Fibrillation

To slow rapid ventricular response in adults with atrial fibrillation†, metoprolol tartrate has been administered IV in doses of 2.5-5 mg administered over 2 minutes, up to a total of 3 doses.301 Once adequate control of heart rate or conversion to normal sinus rhythm has been achieved with parenteral metoprolol therapy, some experts suggest an oral metoprolol tartrate dosage of 25-100 mg twice daily or extended-release metoprolol succinate at a dosage of 50-400 mg once daily for long-term rate control in patients with atrial fibrillation.301

Other Supraventricular Arrhythmias

For the acute treatment of supraventricular tachycardia (SVT) (e.g., atrial flutter†, junctional tachycardia†, paroxysmal supraventricular tachycardia [PSVT]†, atrial tachycardia†) in adults, some experts recommend an initial IV metoprolol tartrate dose of 2.5-5 mg administered over 2 minutes; additional doses may be given every 10 minutes up to a maximum of 3 doses.300 The usual oral maintenance dosage for ongoing treatment of SVT is 200 mg twice daily (as metoprolol tartrate tablets) or 400 mg once daily (as metoprolol succinate extended-release tablets).300

Heart Failure

Prior to initiation of therapy with a β-blocker in patients with heart failure, the dosage of any concomitant heart failure therapy should be stabilized.147 Because of the potential for severe adverse effects (e.g., hypotension, bradycardia, fluid retention, worsening of heart failure),524 initiation of β-blocker therapy for heart failure and subsequent dosage adjustments should occur under close medical supervision.147,524

For the management of symptomatic heart failure, the manufacturer recommends an initial metoprolol succinate (extended-release tablets) dosage of 25 mg (expressed as the tartrate) once daily in adults with New York Heart Association (NYHA) class II heart failure; adults with more severe heart failure should receive an initial dosage of 12.5 mg once daily.147 The manufacturer recommends that the dosage be doubled every 2 weeks until a dosage of 200 mg once daily or the highest tolerated dosage is reached.147 Some experts recommend initiation of β-blocker therapy at a very low dosage (e.g., a metoprolol succinate dosage of 12.5-25 mg once daily [expressed as metoprolol tartrate] using the extended-release tablets) in patients with heart failure, with the dosage gradually titrated upward as tolerated (maximum dosage 200 mg once daily).524 If deterioration of heart failure (usually transient) becomes evident during titration of metoprolol therapy, the dosage of the concurrent diuretic should be increased147 and the dosage of metoprolol not escalated until symptoms of worsening heart failure (e.g., fluid retention) have stabilized; it may be necessary to decrease the dosage of metoprolol or temporarily discontinue the drug.147,524 Should patients with heart failure experience symptomatic bradycardia (e.g., dizziness) or second- or third-degree heart block, the dosage of metoprolol should be reduced.147,524 Initial difficulty in titrating metoprolol dosage should not preclude subsequent attempts to successfully titrate the dosage.147

It should be recognized that symptomatic improvement may not be evident for 2-3 months after initiating therapy with β-blockers.163,205 However, β-blocker therapy may reduce the risk of disease progression even if symptomatic improvement is not evident.524 In clinical trials, metoprolol dosages were not adjusted according to response but instead were increased as tolerated to a prespecified target dose.163,205 Once titrated to the target or highest tolerated dosage, therapy generally can be maintained at this level long term.163 In clinical trials, dosages usually were titrated up to 150-200 mg daily.163,170

Vascular Headaches

Migraine

Although dosages of metoprolol tartrate or metoprolol succinate for the prophylaxis of migraine† in adults have not been established, oral dosages of 50-300 mg daily have been used in clinical studies.231 The usual effective dosage of the drug in these studies was 200 mg daily.231

Metoprolol shares the toxic potentials of β-adrenergic blocking agents (β-blockers). Most adverse effects of metoprolol are mild and transient109,147 and occur more frequently at the onset of therapy than during prolonged treatment. The most frequent adverse effects are dizziness, tiredness, insomnia, and gastric upset.

Cardiovascular and Cerebrovascular Effects

The most common adverse cardiovascular effects of metoprolol are shortness of breath and bradycardia, occurring in about 3% of patients with hypertension or angina receiving metoprolol tartrate in clinical trials.109,147 Severe bradycardia should be treated with IM or IV administration of atropine sulfate.109,147 If there is an inadequate response to atropine, IV isoproterenol may be administered with caution.109,147 Cold extremities, arterial insufficiency (e.g., Raynaud's phenomenon), palpitations, congestive heart failure, peripheral edema, syncope, chest pain, or hypotension has been reported in about 1% of patients with hypertension or angina receiving metoprolol tartrate.109,147 Gangrene has been reported very rarely in patients with preexisting severe peripheral circulatory disorders receiving metoprolol tartrate.109 Claudication has been reported in patients with myocardial infarction (MI) receiving metoprolol tartrate, although a relationship to the drug is unclear.109 Raynaud's phenomenon may be treated by keeping the patient warm, stopping the drug, and, if necessary, administering a vasodilator. Adverse cardiovascular events occurring in greater than 1% of patients with heart failure receiving metoprolol succinate extended-release tablets but with a similar incidence (within 0.5%) in patients receiving placebo include MI, coronary artery disorder, cerebrovascular disorder, ventricular tachycardia, or aggravation of arrhythmia.147

If hypotension (systolic blood pressure of 90 mm Hg or less) occurs in patients with MI, metoprolol should be discontinued and appropriate cardiovascular monitoring and therapy instituted as necessary. (See Cautions: Precautions and Contraindications.) In patients without a prior history of heart failure, prolonged depression of the myocardium by metoprolol occasionally has resulted in heart failure. Intensification of AV block has occurred with other β-blockers and is a potential adverse effect of metoprolol.109,147 AV dissociation, AV conduction delays,281 complete heart block or cardiac arrest also may occur, especially in patients with preexisting heart block caused by digitalis or other factors.

During surgery, some patients who have received β-blockers may experience severe, protracted hypotension and, occasionally, difficulty in restarting and maintaining heart beat. The untoward effects of metoprolol may be reversed during surgery by IV administration of β-adrenergic agonists (e.g., isoproterenol, dopamine, dobutamine).

Nervous System Effects

Tiredness or dizziness has occurred in about 10% of patients with hypertension or angina receiving metoprolol tartrate in clinical trials;109,147 tiredness has been reported in about 1% of patients with MI receiving the drug.109 In addition, vertigo, sleep disturbances/insomnia, hallucinations, nightmares, headache, dizziness, visual disturbances, and confusion have been reported in patients with MI receiving the drug, although a causal relationship is unclear.109 Somnolence or increased dreaming also has been reported with metoprolol therapy; these effects may be alleviated by avoiding late-evening dosage. Rarely, impotence, nervousness, and general weakness have occurred. Depression has been reported in about 5% of patients receiving metoprolol tartrate for hypertension or angina.109,147 Reversible mental depression occurs less frequently with metoprolol than with propranolol but is a reason for withdrawal of the drugs, as it may progress to catatonia. An acute reversible syndrome characterized by disorientation to time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometric tests has been reported with other β-blockers and should be considered a potential adverse effect of metoprolol.109,147 Lethargy and, rarely, fullheadedness have occurred.

GI Effects

Diarrhea has occurred in about 5% of patients receiving metoprolol tartrate in clinical trials.109,147 Other GI symptoms such as nausea, gastric pain, constipation, flatulence, digestive tract disorders, heartburn, xerostomia, and hiccups also have been reported with oral metoprolol therapy. Nausea and abdominal pain have occurred in less than 1% of patients with MI receiving IV or oral metoprolol.109

Endocrine Effects

Unstable diabetes mellitus has been reported in patients with MI receiving metoprolol tartrate, although a relationship to the drug is unclear.109 Results of a large prospective cohort study of adults 45-64 years of age indicate that use of β-blockers in hypertensive patients is associated with increased risk (about 28%) of developing diabetes mellitus.191,192 In this study, the number of new cases of diabetes per 1000 person-years was 33.6 or 26.3 in patients receiving a β-blocker or no drug therapy, respectively.191 The association between the risk of developing diabetes mellitus and use of β-blockers reportedly was not confounded by weight gain, hyperinsulinemia, or differences in heart rate.191,192 It is not known if the risk of developing diabetes is affected by β-receptor selectivity.191 Further studies are needed to determine whether concomitant use of ACE inhibitors (which may improve insulin sensitivity) would abrogate β-blocker-induced adverse effects related to glucose intolerance.192 Therefore, until results of such studies are available, the proven benefits of β-blockers in reducing cardiovascular events in hypertensive patients must be weighed carefully against the possible risks of developing diabetes mellitus.191

Hypoglycemia,190 which may result in loss of consciousness, also may occur in nondiabetic patients receiving β-adrenergic blocking agents. Patients most at risk for the development of β-blocker-induced hypoglycemia are those undergoing dialysis, prolonged fasting, or severe exercise regimens.190

β-Blockers may mask signs and symptoms of hypoglycemia (e.g., palpitation, tachycardia, tremor) and potentiate insulin-induced hypoglycemia.190 Although it has been suggested that nonselective β-blockers are more likely to induce hypoglycemia than selective β-blockers, such an adverse effect also has been reported with selective β-blockers (e.g., atenolol).190 Selective β-blockers are less likely to mask symptoms of hypoglycemia or delay recovery from insulin-induced hypoglycemia than nonselective β-blockers; however, selective β-blockers can decrease insulin sensitivity by approximately 15-30%, which may result in increased insulin requirements.190

Other Adverse Effects

In spite of its relative β₁-blocking selectivity, β₂-adrenergic blockade leading to bronchoconstriction, dyspnea, and wheezing may occur with metoprolol dosages greater than 100 mg daily, particularly in patients with a history of asthma. Wheezing or dyspnea has been reported in about 1% of patients with hypertension or angina receiving metoprolol,109,147 and dyspnea of pulmonary origin has been reported in less than 1% of patients with MI receiving the drug.109 Rhinitis also has been reported in patients receiving metoprolol tartrate.109 In a large clinical trial, pneumonia was reported in greater than 1% of patients with heart failure receiving metoprolol succinate extended-release tablets but with a similar incidence (within 0.5%) in patients receiving placebo.147

Peyronie's disease,109,147 tinnitus,109,147 restless legs, a polymyalgia-like syndrome, musculoskeletal pain,109,147 decreased libido,109,147 blurred vision, dry mucous membranes, and sweating have occurred rarely in patients receiving metoprolol. Fatigue was reported in greater than 1% of patients with heart failure receiving metoprolol succinate extended-release tablets in a large clinical trial but with a similar incidence (within 0.5%) in patients receiving placebo.147

Pruritus,109,147 dry skin, worsening of psoriasis,109,147 and psoriasiform, maculopapular, and urticarial rash have occurred in some patients receiving metoprolol. Allergic reactions reported in patients receiving other β-blockers include erythematous rash, fever combined with aching and sore throat, laryngospasm, and respiratory distress.109,147 Reversible alopecia, agranulocytosis, thrombocytopenia, weight gain, arthritis, retroperitoneal fibrosis, and dry eyes have been reported rarely with metoprolol therapy.109,147 Discontinuance of the drug should be considered if any such reaction is not otherwise explicable.109,147 There have been some reported cases of increased antinuclear factor (ANF) levels during metoprolol therapy; however, other reports indicate decreased ANF levels, and no positive ANF findings have been associated with adverse effects of metoprolol involving the skin and eyes.

Potential hematologic effects of β-blockers include eosinophilia, agranulocytosis, and nonthrombocytopenic and thrombocytopenic purpura.109,147

Other β-blockers may cause elevated BUN and serum creatinine concentrations in patients with severe heart disease, presumably because of decreased renal blood flow. Hepatitis, jaundice, or nonspecific hepatic dysfunction has been reported during postmarketing experience in patients receiving metoprolol.109,147 Subclinical hepatitis of unknown etiology occurred in one patient receiving metoprolol therapy for 6 months. Isolated instances of elevated serum transaminase, alkaline phosphatase, and lactate dehydrogenase concentrations also have been reported during postmarketing experience with metoprolol therapy.109,147 Metoprolol may increase serum uric acid concentration.

Precautions and Contraindications

Metoprolol shares the toxic potentials of β-blockers, and the usual precautions of these agents should be observed. When metoprolol is used as a fixed-combination preparation that includes hydrochlorothiazide, the cautions, precautions, and contraindications associated with thiazide diuretics must be considered in addition to those associated with metoprolol.159

In patients with heart failure, sympathetic stimulation is vital for the support of circulatory function.109,147,159,163,205 Metoprolol should be used with caution in patients with inadequate myocardial function, since heart failure may be precipitated by blockade of β-adrenergic stimulation when metoprolol therapy is administered. Exercise tolerance may decrease in patients with left ventricular dysfunction. In addition, in patients with latent cardiac insufficiency, prolonged β-adrenergic blockade may lead to cardiac failure. Although β-blockers should be avoided in patients with overt or decompensated heart failure, metoprolol may be administered cautiously to patients with well-compensated heart failure (e.g., those controlled with ACE inhibitors, diuretics, and/or cardiac glycosides). Patients receiving metoprolol therapy should be instructed to consult their physician at the first sign or symptom of impending cardiac failure (e.g., weight gain, increasing shortness of breath) and should be adequately treated (e.g., with a cardiac glycoside and/or diuretic) and observed closely; if cardiac failure continues, metoprolol should be discontinued, gradually if possible.147 Metoprolol should be administered with caution in patients with sinus node dysfunction, since the drug can depress SA node automaticity.

Abrupt withdrawal of β-blocker therapy may exacerbate angina symptoms or precipitate MI in patients with coronary artery disease. Therefore, patients receiving metoprolol (especially those with ischemic heart disease) should be warned not to interrupt or discontinue therapy without consulting their physician. When discontinuance of metoprolol therapy is planned, particularly in patients with ischemic heart disease, dosage of the drug should be gradually reduced over a period of about 1-2 weeks. When metoprolol therapy is discontinued, patients should be monitored carefully and advised to temporarily limit their physical activity. If exacerbation of angina occurs or acute coronary insufficiency develops after metoprolol therapy is interrupted, metoprolol therapy should be reinstituted promptly, at least temporarily, and appropriate measures for the management of unstable angina pectoris should be initiated. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue metoprolol therapy abruptly, even in patients receiving the drug for conditions other than angina.

In patients with MI, hemodynamic status should be carefully monitored during metoprolol therapy. If heart rate decreases to less than 40 beats/minute in patients receiving the drug, particularly if associated with evidence of decreased cardiac output, the manufacturer recommends that IV atropine be administered; if the bradycardia is refractory to atropine, the manufacturer recommends that metoprolol be discontinued and that cautious administration of isoproterenol or use of a cardiac pacemaker be considered. If heart block occurs in patients with MI during metoprolol therapy, the manufacturer recommends that the drug be discontinued and IV atropine be administered; if the heart block is refractory to atropine, the manufacturer recommends that cautious administration of isoproterenol or use of a cardiac pacemaker be considered. If hypotension (systolic blood pressure of 90 mm Hg or less) occurs in patients with MI, the manufacturer recommends that metoprolol be discontinued and the hemodynamic status of the patient and the extent of myocardial damage be carefully assessed. Invasive monitoring of central venous, pulmonary capillary wedge, and arterial pressures may be necessary; appropriate therapy with IV fluids and other treatment modalities should be instituted. If hypotension is associated with severe bradycardia or heart block, treatment should be directed at reversing these effects.

Metoprolol should be used with caution in patients undergoing major surgery involving general anesthesia, and the anesthetic used should be one that does not cause myocardial depression. (See Drug Interactions: Other Drugs.) The necessity of withdrawing β-adrenergic blocking therapy prior to major surgery is controversial. Metoprolol may impair the ability of the heart to respond to reflex β-adrenergic stimuli and may increase the risks associated with general anesthesia such as severe hypotension and maintenance of heart beat. As with other β-blockers, the effects of metoprolol can be reversed by administration of β-agonists (e.g., dobutamine, isoproterenol). If metoprolol is continued during major or dental surgery, the anesthesiologist or dentist should be informed that the patient is receiving the drug.

Since β-blockers may inhibit bronchodilation produced by endogenous catecholamines, the drugs generally should not be used in patients with bronchospastic disease;281 however, because of its relative β₁-selective adrenergic blocking activity, metoprolol may be used with caution in patients with bronchospastic disease who do not respond to or cannot tolerate other hypotensive agents. In such patients, the lowest effective dosage of metoprolol should be used in addition to maximal therapy with a β₂-adrenergic agonist (e.g., terbutaline); in addition, it would be prudent to initially administer metoprolol in lower dosage given in 3 divided doses daily to avoid the higher plasma concentrations of the drug associated with twice-daily dosing. Patients receiving metoprolol should contact their physician if any difficulty in breathing occurs. Bronchoconstriction is readily reversed with β₂-adrenergic agonists.

Although the oculomucocutaneous syndrome associated with practolol use has not occurred with metoprolol, some patients have experienced dry eyes and decreased tear production, minimal injection of conjunctivae and/or eyelids, punctate keratitis, keratoconjunctivitis or corneal ulceration; therefore, patients receiving metoprolol should be observed carefully for potential ocular adverse effects.

Signs of hyperthyroidism (e.g., tachycardia) may be masked by metoprolol, and patients having or suspected of developing thyrotoxicosis should be monitored carefully because abrupt withdrawal of β-adrenergic blockade might precipitate thyroid storm. In addition, it is recommended that metoprolol be used with caution in patients with diabetes mellitus (especially those with labile diabetes) since the drug also may mask signs and symptoms of hypoglycemia (e.g., tachycardia, palpitation, blood pressure changes, tremor, feelings of anxiety, but not sweating) and may potentiate insulin-induced hypoglycemia.(see Cautions: Endocrine Effects.) However, many clinicians state that patients with diabetes mellitus may be particularly likely to experience a reduction in morbidity and mortality with the use of β-blockers.163

The manufacturer states that metoprolol should be used with caution in patients with impaired hepatic function.109,147,159

Because of similarity in spelling between Toprol-XL^® (metoprolol succinate) and Topamax^® (the trade name for topiramate, an anticonvulsant and antimigraine agent), the potential exists for dispensing or prescribing errors involving these drugs.261,262,263,264 In addition, there is a potential for dispensing errors involving confusion between Toprol-XL^® and Tegretol^® or Tegretol^®-XR (trade names for carbamazepine, an anticonvulsant that also is used for relief of pain associated with trigeminal neuralgia, as well as for various psychiatric disorders).261,263 These medication errors have been associated with serious adverse events sometimes requiring hospitalization as a result of either lack of the intended medication (e.g., seizure recurrence, return of hallucinations, suicide attempt, hypertension recurrence) or exposure to the wrong drug (e.g., bradycardia in a patient erroneously receiving metoprolol).261,262,263,264 Therefore, extra care should be exercised to ensure the accuracy of both oral and written prescriptions for these drugs. (See Dispensing and Administration Precautions, in Dosage and Administration: Administration.)261,262,263,264 Patients should be advised to carefully check their medications and to bring any questions or concerns to the attention of the dispensing pharmacist.264 Dispensing errors involving Toprol-XL^® (metoprolol succinate) and Topamax^® (topiramate) or Tegretol^® or Tegretol^®-XR (carbamazepine) should be reported to the manufacturers, the USP/ISMP (Institute for Safe Medication Practices) Medication Errors Reporting Program by phone (800-233-7767), or directly to the FDA MedWatch program by phone (800-FDA-1088), fax (800-FDA-0178), or internet ([Web]).261,262,263,264

Metoprolol should be used with caution, if at all, in patients with AV conduction defects. The drug should be used with extreme caution in patients with substantial cardiomegaly. Metoprolol is contraindicated in patients with hypertension or angina who have sinus bradycardia, heart block greater than first degree, cardiogenic shock, overt or decompensated cardiac failure,109,147,159,163,205 severe peripheral, arterial circulatory disorders,109 pheochromocytoma (unless administered after initiating treatment with an alpha-adrenergic blocking agent),109 or sick sinus syndrome (unless a permanent pacemaker is in place).147 The drug is contraindicated in patients with acute MI who have a heart rate less than 45-60 beats/minute, heart block greater than first degree, systolic blood pressure less than 100 mm Hg, or moderate to severe cardiac failure.109 Metoprolol also is contraindicated in patients with a known history of hypersensitivity to metoprolol or any component of the formulations147 and in patients with a known history of hypersensitivity to other β-blockers.109

Pediatric Precautions

Although safety and efficacy of metoprolol tartrate remain to be fully established in children,109,147 some experts have recommended pediatric dosages for hypertension based on currently limited clinical experience.

The safety and efficacy of extended-release metoprolol succinate in pediatric patients has been evaluated in a placebo-controlled study in hypertensive patients 6-16 years of age.602,605 In this study, patients received extended-release metoprolol succinate 0.2, 1, or 2 mg/kg orally once daily (dosage expressed in terms of metoprolol tartrate) or placebo and were followed for 4 weeks.602,605 Although the primary efficacy end point (dose response for reduction in systolic blood pressure) was not met, several prespecified secondary end points were achieved.602,605 Compared with placebo, extended-release metoprolol succinate substantially reduced systolic blood pressure at the 1- and 2-mg/kg once-daily dosages, reduced diastolic blood pressure at the 2-mg/kg once-daily dosage, and demonstrated a dose-response relationship for reductions in diastolic blood pressure.602,605 No substantial differences in safety relative to adults were observed.602 Safety and efficacy of metoprolol succinate has not been established in children younger than 6 years of age.602

For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Geriatric Precautions

Clinical trials of conventional metoprolol tartrate or extended-release metoprolol succinate tablets for hypertension did not include sufficient numbers of patients 65 years and older to determine whether they respond differently than younger adults.147 While clinical experience generally has not revealed age-related differences in response to the drug, care should be taken in dosage selection of metoprolol.147 Safety and efficacy of conventional metoprolol tartrate tablets are similar in geriatric adults with MI and younger adults.109 However, since the possibility of greater sensitivity of some older patients cannot be ruled out, initial dosage should be selected carefully in these patients.109 Safety and efficacy of extended-release metoprolol succinate are similar in geriatric adults with heart failure and in younger adults. 147 Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, the manufacturer suggests that patients in this age group receive initial dosages of the drug in the lower end of the usual range.147

Mutagenicity and Carcinogenicity

There has been no evidence of mutagenic potential in tests performed to date with metoprolol.109,147 No evidence of metoprolol tartrate-induced mutagenicity was observed in dominant lethal tests in mice, chromosome tests in somatic cells, Salmonella mammalian microsome tests, or nucleus anomaly tests in somatic interphase nuclei.109,147 No evidence of mutagenicity was observed in the Salmonella mammalian microsome test using metoprolol succinate.147 In chronic toxicity studies, benign lung tumors (small adenomas) occurred more frequently in female Swiss albino mice receiving oral dosages of metoprolol tartrate up to 750 mg/kg daily (representing 18 times the daily dosage of 200 mg in a 60-kg patient on a mg/m²basis) for 21 months than in untreated control animals, although there was no increase in malignant lung tumors or total (benign plus malignant) lung tumors.109,147 In CD-1 mice, however, no differences were observed between treated and control mice of either gender for any tumor.109,147 In a 2-year study in rats, there was no evidence of increased development of spontaneously occurring benign or malignant neoplasms at dosages of metoprolol tartrate up to 800 mg/kg daily.109,147 However, in these rats, histologic changes included an increased incidence of mild focal accumulation of foamy macrophages in alveolar spaces and slight increases of biliary hyperplasia.109,147

Pregnancy, Fertility, and Lactation

Pregnancy

Distribution studies in mice have shown that the fetus is exposed to metoprolol when the drug is administered during pregnancy.109,147 Although there are no adequate and controlled studies to date in humans, metoprolol has been shown to increase postimplantation loss and to decrease neonatal survival in rats when given at metoprolol succinate dosages (expressed as the tartrate) up to 22 times a daily dosage of 200 mg in a 60-kg patient (on a mg/m² basis)147 or metoprolol tartrate dosages up to 55.5 times the maximum recommended human dosage of 450 mg daily.109,147 Metoprolol should be used during pregnancy only when clearly needed.109,147

Fertility

Reproduction studies in rats using metoprolol succinate dosages (expressed as the tartrate) up to 22 times a daily dosage of 200 mg in a 60-kg patient (on a mg/m² basis)147 or metoprolol tartrate dosages up to 55.5 times the maximum recommended human dosage of 450 mg have not revealed evidence of impaired fertility.109 Metoprolol has rarely caused Peyronie's disease in human males.109,147

Lactation

Since metoprolol is distributed into milk, the drug should be used with caution in nursing women.109,147 The extent to which metoprolol distributes into milk has not been clearly established, but the amount of drug a nursing infant would ingest (less than 1 mg/L of milk consumed daily)109,147 is believed to be too small to be clinically important;101,102 however, if a woman receiving metoprolol breastfeeds, the infant should be monitored for potential systemic effects of the drug.102

Cardiovascular Drugs

When metoprolol is administered with diuretics or other hypotensive drugs, the hypotensive effect of metoprolol may be increased. This effect is usually used to therapeutic advantage, but careful adjustment of dosage is necessary when these drugs are used concomitantly. An additive effect may be obtained when metoprolol is given to patients receiving catecholamine-depleting drugs, such as reserpine and monoamine oxidase inhibitors, resulting in hypotension and/or bradycardia. The β₁-adrenergic stimulating effects of sympathomimetic agents are antagonized by usual doses of metoprolol.

Concomitant use of β-adrenergic blocking agents (β-blockers) and certain other cardiovascular drugs (e.g., cardiac glycosides, nondihydropyridine calcium-channel blocking agents) can have additive negative effects on SA or AV nodal conduction. Caution should be exercised in the concomitant administration of β-blockers and other cardiovascular drugs (e.g., nondihydropyridine calcium-channel blocking agents).147 Slowing or complete suppression of SA node activity with development of slow ventricular rates (e.g., 30-40 bpm), often misdiagnosed as complete AV block, has been reported in patients receiving the nondihydropyridine calcium-channel blocking agent mibefradil (no longer commercially available in the US), principally in geriatric patients and in association with concomitant β-blocker therapy.

Because β-blockers may exacerbate rebound hypertension that may occur following discontinuance of clonidine therapy, β-blockers should be discontinued several days before gradual withdrawal of clonidine when clonidine therapy is to be discontinued in patients receiving a β-blocker and clonidine concurrently.147 If clonidine therapy is to be replaced by a β-blocker, administration of the β-blocker should be delayed for several days after clonidine therapy has been discontinued.147

Verapamil may substantially increase the oral bioavailability of metoprolol, a lipophilic drug.103,104,105,106,107,108 Area under the plasma metoprolol concentration-time curve has increased up to 300% following initiation of verapamil therapy.105,106 Verapamil appears to increase oral bioavailability of metoprolol by decreasing its hepatic clearance, although the exact mechanism(s) has not been elucidated.105,106 A similar pharmacokinetic interaction does not appear to occur when atenolol, a hydrophilic drug, and verapamil are used concomitantly.103,104,105,106,107,108 Concomitant use of verapamil and metoprolol should be avoided if possible and another β-blocker with which verapamil does not interact pharmacokinetically (e.g., atenolol) preferably used when combined therapy is required.105,106 If verapamil and metoprolol are used concomitantly, dosage of metoprolol should be adjusted carefully and the patient monitored closely.106

Drugs Affecting Hepatic Microsomal Enzymes

Metabolism of certain β-blockers (e.g., metoprolol, timolol) is mediated by the cytochrome (CYP) P-450 isoenzyme 2D6 (CYP2D6), and concurrent use of metoprolol with drugs that inhibit CYP2D6 (e.g., bupropion, cimetidine, diphenhydramine, fluoxetine, hydroxychloroquine, paroxetine, propafenone, quinidine, ritonavir, terbinafine, thioridazine) may increase plasma metoprolol concentrations, resulting in decreased cardioselectivity of the drug.147,200,201,202,208,210,211 Pending further experience with combination therapy with paroxetine and metoprolol, caution should be exercised when paroxetine and metoprolol are used concomitantly.209,211,212 In healthy individuals with an extensive metabolizer phenotype, coadministration of quinidine (100 mg) and metoprolol conventional tablets (200 mg) doubled the half life of metoprolol and tripled the plasma concentration of the S -enantiomer.147 In a limited number of patients with cardiovascular disease, concurrent administration of propafenone (150 mg 3 times daily) with metoprolol conventional tablets (50 mg 3 times daily) resulted in a twofold to fivefold increase in the steady-state plasma concentration of metoprolol.147

Other Drugs

Use of myocardial depressant general anesthetics (e.g., diethyl ether) in patients receiving a β-blocker, such as metoprolol, leads to a risk of hypotension and heart failure.

Administration of a β-blocker with a vasodilator, such as hydralazine, in patients with uremia could cause pulmonary hypertension secondary to β-adrenergic blockade of the pulmonary vasculature and to the increased cardiac output caused by the vasodilator.

Acute Toxicity

Pathogenesis

The acute lethal dose of metoprolol in humans is not known. The oral LD₅₀ of the drug is 1158-2460 and 3090-4670 mg/kg in mice and rats, respectively.

Manifestations

Limited information is available on acute metoprolol toxicity;109,147 several cases of overdosage with metoprolol tartrate or metoprolol succinate have been reported, some resulting in death. A 19-year-old man who ingested 10 g of metoprolol tartrate (160 mg/kg) was conscious with peripheral cyanosis, weak heart sounds, and no measurable blood pressure. Treatment consisted of gastric lavage, IV infusion of Ringer's injection, IV administration of sodium bicarbonate to correct acidosis, furosemide to relieve fluid retention, and glucagon and metaraminol to restore blood pressure. Within 12 hours after admission to the hospital, the patient exhibited no signs of cardiac depression. In general, overdosage of metoprolol may be expected to produce effects that are mainly extensions of pharmacologic effects, including symptomatic bradycardia, hypotension, bronchospasm, and acute cardiac failure;109 impaired conduction, decreased cardiac contractility, heart block, shock, and cardiac arrest also may occur.281 Other manifestations associated with overdosage of metoprolol succinate as extended-release tablets include atrioventricular block, cardiogenic shock, cardiac arrest, impairment of consciousness, nausea, vomiting, and cyanosis.147

Treatment

In acute metoprolol overdose, the stomach should be emptied immediately by gastric lavage.109,147 Supportive and symptomatic treatment should be initiated. For symptomatic bradycardia, IV atropine sulfate may be given; if bradycardia persists, IV isoproterenol hydrochloride may be administered cautiously.109,147 A vasopressor (e.g., dopamine, norepinephrine) may be given for severe hypotension;109,147 IV glucagon may be useful if hypotension is refractory to vasopressors.281 A β-adrenergic agonist (e.g., isoproterenol) and/or a theophylline derivative may be given for bronchospasm.109,147 For heart failure, a cardiac glycoside, diuretic, and oxygen should be used; IV glucagon also may be useful.

Pharmacology

At low doses, metoprolol is a selective inhibitor of β₁-adrenergic receptors. Like propranolol, metoprolol inhibits response to adrenergic stimuli by competitively blocking β₁-adrenergic receptors within the myocardium. Unlike propranolol, however, metoprolol blocks β₂-adrenergic receptors within bronchial and vascular smooth muscle only in high doses.

Through its myocardial β₁-adrenergic blocking action, metoprolol decreases resting heart rate and reflex orthostatic tachycardia, inhibits exercise-induced increases in heart rate, decreases myocardial contractility, and decreases cardiac output at rest and during exercise without a compensatory increase in peripheral resistance. The drug increases systolic ejection time and cardiac volume; stroke volume is unchanged. Metoprolol also decreases conduction velocity through the sinoatrial (SA) and atrioventricular (AV) nodes and decreases myocardial automaticity via β₁-adrenergic blockade. The drug has no intrinsic sympathomimetic activity and little or no membrane-stabilizing effect on the heart; membrane-stabilizing effects occur only at plasma concentrations much higher than those required for β-adrenergic blocking action.

The precise mechanism of metoprolol's hypotensive action has not been determined. It has been postulated that β-adrenergic blocking agents (β-blockers) reduce blood pressure by blocking peripheral (especially cardiac) adrenergic receptors (decreasing cardiac output), by decreasing sympathetic outflow from the CNS, and/or by suppressing renin release. Results of several studies suggest a reduction in peripheral resistance by inhibition of release of norepinephrine as a basis for metoprolol's hypotensive effect, but this requires further study. Like propranolol, metoprolol decreases blood pressure in both supine and standing positions.

In patients with normal or high concentrations of circulating renin, low doses of metoprolol are associated with a fall in plasma renin concentrations, possibly due, at least partly, to acute peripheral β₁-adrenergic blockade. Metoprolol also substantially reduces furosemide-induced renin release. Metoprolol and propranolol produce similar decreases in plasma renin activity (PRA) in patients with high PRA. The importance of these effects in decreasing blood pressure in hypertensive patients requires further investigation.

A small increase in serum potassium has been observed during metoprolol therapy and may be related to β₂-adrenergic blockade and reduced PRA and plasma aldosterone concentration.

The exact mechanism of action of metoprolol in patients with suspected or definite myocardial infarction (MI) has not been determined. In patients with MI, metoprolol reduces heart rate, systolic blood pressure, and cardiac output, but stroke volume, diastolic blood pressure, and pulmonary artery end diastolic pressure remain unchanged; the drug also appears to decrease the occurrence of ventricular fibrillation in these patients.

In the management of angina pectoris, the mechanism of action of metoprolol is thought to be blockade of catecholamine-induced increases in heart rate, velocity and extent of myocardial contraction, and blood pressure, which results in a net decrease in myocardial oxygen consumption. In some studies, metoprolol (given as extended-release tablets) has improved left ventricular ejection fraction and has been shown to delay increases in left ventricular end-systolic and end-diastolic volumes after 6 months of therapy.147

Usual doses of metoprolol increase airway resistance and decrease ventilatory capacity in asthmatic patients but, because of its relatively selective β₁-adrenergic blocking activity, to a lesser degree than does an equivalent β₁-adrenergic receptor blocking dose of propranolol. Unlike propranolol, low dosages (up to 100 mg daily) of metoprolol tartrate do not appreciably inhibit isoproterenol-induced bronchodilation. Because of its relative β₁-adrenergic blocking selectivity, metoprolol causes little inhibition of glycogenolysis in skeletal and cardiac muscles. Metoprolol inhibits the increase in plasma glycerol caused by exercise. Metoprolol may cause less inhibition of insulin release than does propranolol and may therefore result in better glucose tolerance than does propranolol in patients with diabetes mellitus; however, results of studies of this effect are conflicting. Metoprolol does not appear to reduce free fatty acid concentrations in healthy individuals. Fasting triglyceride concentrations have been increased in some patients, while in others no consistent changes have occurred. Metoprolol may increase the peripheral platelet count by interfering with β-adrenergic receptors involved in platelet level regulation in the spleen.

Pharmacokinetics

Absorption

Metoprolol tartrate is rapidly and almost completely absorbed from the GI tract; absorption of a single oral dose of 20-100 mg is complete in 2.5-3 hours. After an oral dose, about 50% of the drug administered as conventional tablets appears to undergo first-pass metabolism in the liver. Bioavailability of orally administered metoprolol tartrate increases with increased doses, indicating a possible saturable disposition process of low capacity such as tissue binding in the liver. Steady-state oral bioavailability of extended-release tablets of metoprolol succinate given once daily at dosages equivalent to 50-400 mg of metoprolol tartrate is about 77% of that of conventional tablets at corresponding dosages given once daily or in divided doses.147,148 Food does not appear to affect bioavailability of metoprolol succinate extended-release tablets.147 Following a single oral dose as conventional tablets, metoprolol appears in the plasma within 10 minutes and peak plasma concentrations are reached in about 90 minutes. When metoprolol tartrate conventional tablets are administered with food rather than on an empty stomach, peak plasma concentrations are higher and the extent of absorption of the drug is increased. Following oral administration of metoprolol succinate as extended-release tablets, peak plasma metoprolol concentrations are about 25-50% of those attained after administration of metoprolol tartrate conventional tablets given once daily or in divided doses. However, in patients with heart failure, peak plasma concentrations attained after administration of metoprolol succinate as extended-release tablets (200 mg [expressed as the tartrate] once daily) are similar to those attained with conventional metoprolol tartrate tablets (50 mg 3 times daily).147,198 Time to peak concentration is longer with extended-release tablets,147,148 with peak plasma concentrations being reached in about 7 hours following administration of such tablets.148

Plasma concentrations attained 1 hour after an oral dose are linearly related to metoprolol tartrate doses ranging from 50-400 mg as conventional tablets. After an oral dose of metoprolol tartrate, plasma concentrations attained are quite variable among individuals (particularly in geriatric patients) and apparently do not correlate with hypotensive effects. However, oral doses ranging from 50-400 mg appear to cause dose-dependent reductions in systolic blood pressure and exercise-induced heart rate. In addition, a linear relationship between plasma concentration of the drug and reduction in exercise-induced heart rate appears to exist. In healthy adults, plasma metoprolol concentrations of 8-144 ng/mL are associated with an 8-23% reduction in exercised-induced tachycardia; plasma concentration-effect curves reach a plateau at about 53.5-80 ng/mL, and higher metoprolol plasma concentrations produce little additional β₁-adrenergic blocking effects.147 The relative β₁ selectivity of the drug diminishes at higher plasma metoprolol concentrations while β₂-blocking effects increase at higher plasma metoprolol concentrations.147 Such effects diminish at higher plasma metoprolol concentrations while β₂-adrenergic blocking effects increase at higher plasma metoprolol concentrations.147

Following oral administration of dosages equivalent to 100-400 mg of metoprolol tartrate given once daily as metoprolol succinate extended-release tablets in healthy individuals, steady-state β-adrenergic blocking effects (as measured by blockade of exercise-induced increases in heart rate) over a 24-hour period were similar to those following administration of metoprolol tartrate conventional tablets given 1-4 times daily.147,148 However, β-adrenergic blocking effects over a 24-hour period were higher following oral administration of metoprolol succinate extended-release tablets given once daily in a dosage equivalent to 50 mg of metoprolol tartrate compared with those following administration of the same dosage given as metoprolol tartrate conventional tablets.147,148 Following oral administration of metoprolol succinate as extended-release tablets, reduction in exercise-induced heart rate is stable throughout the entire dosing interval, and oral doses (equivalent to the tartrate) ranging from 50-400 mg appear to cause dose-dependent reductions in exercise-induced heart rate while a larger peak effect on exercise-induced tachycardia occurs following administration of 50-100 mg once daily as conventional tablets; this effect is not observed 24 hours after dosing.147 To achieve a similar effect to that attained with metoprolol succinate extended-release tablets, a total daily dosage of 200-400 mg is given in 3 or 4 divided doses if administered as conventional metoprolol tartrate tablets.147 In a randomized, crossover trial in patients with heart failure who had prior chronic therapy with metoprolol, the reduction in the average or exercise-induced heart rate over 24 hours was greater during short-term therapy with metoprolol succinate 200 mg (expressed as the tartrate) daily as extended-release tablets than with metoprolol tartrate 50 mg 3 times daily as conventional tablets. 147,198 The manufacturer of Toprol XL^® states that the relationship between plasma metoprolol concentrations and reduction in exercise-induced heart rate is independent of the pharmaceutical formulation.147 In patients with angina pectoris, a relationship between metoprolol tartrate dose and exercise capacity and reductions in left ventricular ischemia appears to exist for oral doses ranging from 50-400 mg. Following oral administration of multiple doses of metoprolol tartrate (50-80 mg 3 times daily), peak plasma concentrations range from 20-340 ng/mL.

In hypertensive patients, a reduction in systolic blood pressure during exercise has been reported within 15 minutes after a single oral dose of 50-80 mg of metoprolol tartrate and the effect persisted for 6 hours. Dosages of 150-450 mg daily cause a dose-dependent decrease in systolic blood pressure which averages 20 mm Hg; the effect is usually maximal within 1 week in healthy or hypertensive patients at rest and during exercise. The same dosage causes a less rapid but appreciable reduction in diastolic blood pressure which averages 10-15 mm Hg. Metoprolol succinate extended-release tablets given once daily at dosages equivalent to 100-400 mg of metoprolol tartrate produce similar hypotensive effects as conventional metoprolol tartrate tablets at similar dosages given 2-4 times daily; the hypotensive effect of extended-release tablets may persist for 24 hours.147 Duration of the β-adrenergic blocking effect (as measured by blockade of exercise-induced increases in heart rate) is dose related, increasing with increasing doses. With chronic therapy, hypotensive effects may persist for up to 4 weeks after withdrawal of the drug, possibly as a result of tissue-bound drug.

Plasma metoprolol concentrations attained after IV administration of the drug are approximately 2 times those attained following oral administration. Following IV infusion of metoprolol over 10 minutes in healthy individuals, maximum β-adrenergic blocking activity occurred at 20 minutes. In healthy individuals, a maximum reduction in exercise-induced heart rate of approximately 10 and 15% occurs following IV administration of a single 5- and 15-mg metoprolol dose, respectively; the effect on exercise-induced heart rate decreased linearly with time at the same rate for both doses and persisted for approximately 5 and 8 hours for the 5- and 15-mg doses, respectively.

Distribution

Metoprolol is widely distributed into body tissues. The concentration of the drug is greater in the heart, liver, lungs, and saliva than in the plasma. Metoprolol is 11-12% bound to serum proteins, apparently only to albumin. Following therapeutic doses, metoprolol concentrations in erythrocytes are about 20% greater than those in plasma, but the drug is available for elimination from these two sites at the same rate. Metoprolol crosses the placenta, and maternal and fetal blood concentrations are about equal. The drug crosses the blood-brain barrier; the concentration of metoprolol in CSF is about 78% of the simultaneous concentration in plasma. Metoprolol is distributed into milk in a concentration about 3-4 times that of maternal plasma concentrations,101,102 but the actual amount distributed into milk appears to be very small.

Elimination

Elimination of metoprolol appears to follow first-order kinetics and occurs mainly in the liver; the time required for the process apparently is independent of dose and duration of therapy. In healthy individuals and hypertensive patients, the elimination half-life of both unchanged drug and metabolites is about 3-4 hours. In poor hydroxylators of the drug, the elimination half-life is prolonged to about 7.6 hours. There is more interindividual variation in elimination half-lives in geriatric patients than in young healthy individuals. The half-life of metoprolol does not increase appreciably with impaired renal function.

Metoprolol is metabolized by the cytochrome P-450 (CYP) microsomal enzyme system, predominantly by the 2D6 isoenzyme (CYP2D6).147 When administered orally, metoprolol exhibits stereoselective metabolism that is dependent on oxidation phenotype.147 The CYP2D6 isoenzyme is absent in about 8% of Caucasians (poor metabolizers) and about 2% of most other populations.147 Since CYP2D6 can be inhibited by other drugs, concomitant use of such drugs with metoprolol in poor metabolizers will lead to increases in plasma metoprolol concentrations and a decrease in the β₁-selectivity of the drug.147 Metoprolol does not inhibit or enhance its own metabolism. Three main metabolites of the drug are formed by oxidative deamination, O -dealkylation with subsequent oxidation, and aliphatic hydroxylation; these metabolites account for 85% of the total urinary excretion of metabolites. The metabolites apparently do not have appreciable pharmacologic activity. The rate of hydroxylation, resulting in α-hydroxymetoprolol, is genetically determined and is subject to considerable interindividual variation. Poor hydroxylators of metoprolol have increased areas under the plasma concentration-time curves (AUCs), prolonged elimination half-lives (about 7.6 hours), higher urinary concentrations of unchanged drug, and negligible urinary concentrations of α-hydroxymetoprolol compared with extensive hydroxylators. β-Adrenergic blockade of exercise-induced tachycardia persists for at least 24 hours after administration of a single 200-mg oral dose of metoprolol tartrate in poor hydroxylators.

Metoprolol and its metabolites are excreted in urine mainly via glomerular filtration, although tubular secretion and reabsorption may be involved. About 95% of a single oral dose is excreted in urine within 72 hours. Less than 5% and approximately 10% of a metoprolol dose is excreted unchanged in urine following oral and IV administration of the drug, respectively.

Chemistry and Stability

Chemistry

Metoprolol is a β₁-selective adrenergic blocking agent.281 Metoprolol is commercially available as the tartrate salt in oral tablets and parenteral injection and as the succinate salt in oral extended-release tablets containing controlled-release coated pellets. Metoprolol tartrate is commercially available as a racemic mixture. Metoprolol tartrate occurs as a white, crystalline powder with a bitter taste and is very soluble in water and freely soluble in alcohol. The drug has a pK_a of 9.68. Metoprolol succinate occurs as a white, crystalline powder and is freely soluble in water and sparingly soluble in alcohol.147

Stability

Commercially available preparations of metoprolol tartrate should be protected from light. Metoprolol tartrate tablets should be protected from moisture and stored in tight, light-resistant containers at 25°C but may be exposed to temperatures ranging from 15-30°C.109 Metoprolol tartrate injection should be stored at a temperature of 25°C but may be exposed to temperatures ranging from 15-30°C;109,109 freezing of the injection should be avoided.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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