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metoprolol tartrate 100 mg tab (generic lopressor)

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Uses

Metoprolol is used for the management of hypertension, angina, acute myocardial infarction, and heart failure. The drug also has been used for supraventricular and ventricular tachyarrhythmias and prophylaxis of migraine headache.

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. While specific pharmacologic properties and other factors may appropriately influence the choice of a β-blocker in individual patients, evidence of clinically important differences among the agents in terms of overall efficacy and/or safety is limited. Patients who do not respond to or cannot tolerate one β-blocker may be successfully treated with a different agent.

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. 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 4 classes of antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics). Although β-blockers were previously considered a drug of choice for the initial management of hypertension, most current guidelines no longer recommend these drugs as first-line therapy because of the lack of established superiority over other recommended drug classes and at least one study demonstrating that they may be less effective than angiotensin II receptor antagonists in preventing cardiovascular death, myocardial infarction, or stroke. However, β-blockers may still be considered in hypertensive patients who have a compelling indication (e.g., prior myocardial infarction, 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. 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). Because many patients eventually will need drugs from 2 or more antihypertensive classes, experts generally state that the emphasis should be placed on achieving appropriate blood pressure control rather than on identifying a preferred drug to achieve that control.

Considerations in Initiating Antihypertensive Therapy

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.

While the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended antihypertensive drug therapy in all patients with systolic/diastolic blood pressure of 140/90 mm Hg or higher who fail to respond to lifestyle/behavioral modifications, other experts, including the panel members appointed to the Eighth Joint National Committee (JNC 8 expert panel) currently recommend a higher systolic blood pressure threshold for older individuals (e.g., the JNC 8 expert panel recommends a threshold of 150 mm Hg for patients 60 years of age or older).

In addition, there is some variation in the blood pressure thresholds and treatment goals recommended for patients with diabetes mellitus or chronic kidney disease. In the past, initial antihypertensive drug therapy was recommended for patients with diabetes mellitus or chronic kidney disease who had blood pressures of 130/80 mm Hg or higher; however, current hypertension management guidelines generally recommend the same blood pressure threshold of 140/90 mm Hg for initiating antihypertensive drug therapy in these individuals as for the general population of patients without these conditions, although a lower goal (e.g., less than 130/80 mm Hg) may still be considered.

Further study is needed to more clearly define optimum blood pressure goals in patients with hypertension; when determining appropriate blood pressure goals, individual risks and benefits should be considered in addition to the evidence from clinical studies.

Antihypertensive drug therapy generally should be initiated gradually and titrated at intervals of approximately 2-4 weeks to achieve the target blood pressure. The goal is to reduce blood pressure to levels below the threshold used for initiating drug therapy. Addition of a second drug should be initiated when use of monotherapy in adequate dosages fails to achieve goal blood pressure. Some experts state that initial antihypertensive therapy with a combination of drugs may be considered in patients with systolic/diastolic blood pressure greater than 20/10 mm Hg above goal blood pressure. 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). Initial combined therapy may be particularly useful in patients with markedly high baseline blood pressures and those with additional risk factors.

Initial Drug Therapy

For initial antihypertensive drug therapy, experts currently recommend a thiazide diuretic, calcium-channel blocker, ACE inhibitor, or angiotensin II receptor antagonist. β-Blockers generally are not preferred for initial monotherapy in patients with uncomplicated hypertension, but may be beneficial in patients with a compelling indication (e.g., ischemic heart disease, atrial tachyarrhythmias, history of myocardial infarction, heart failure) for their use.

Follow-up and Maintenance Therapy

Several strategies are recommended for the titration and combination of antihypertensive drugs; these strategies 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). If goal blood pressure is not achieved with initial monotherapy with one of the recommended antihypertensive drug classes, a second drug from one of the recommended drug classes may be added; if goal blood pressure is still not achieved with optimal dosages of 2 antihypertensive agents, a third drug from one of the recommended drug classes may be added. If more than 3 drugs are required, other antihypertensive drug classes, including β-blockers, may be considered. If the blood pressure goal cannot be achieved with the above recommended strategies, consultation with a hypertension specialist should be considered.

Thus, metoprolol can be used for the management of hypertension as initial monotherapy (not usually preferred, but may be used for a compelling indication) or as a component of a multiple-drug regimen. β-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.

Antihypertensive Therapy for Patients with Underlying Cardiovascular or 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. on Compelling Indications for Drug Classes based on Comorbid Conditions, in Antihypertensive Therapy for Patients with Underlying Cardiovascular and Other Risk Factors 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, but 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. Because of the demonstrated mortality benefit of β-blockers following myocardial infarction, these drugs should be administered in all patients who have survived a myocardial infarction.

Heart Failure

While β-blockers as single therapies are not superior to other antihypertensive agents in the reduction of all cardiovascular outcomes, 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.(See Uses: Heart Failure.)

Other Special Considerations for Antihypertensive Therapy

Race

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. However, such diminished response to a β-blocker is largely eliminated when the drug is administered concomitantly with a thiazide diuretic. 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.

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.

Angina

Chronic Stable Angina

Metoprolol is used for the management of chronic stable angina pectoris. In placebo-controlled studies, metoprolol reduced the frequency of anginal attacks, reduced nitroglycerin consumption, and increased the patients' exercise tolerance. The efficacy of metoprolol in the management of chronic stable angina appears to be similar to that of other β-blockers. Some authorities state that β-blockers are the anti-ischemic drugs of choice in geriatric patients with stable angina.

Combination therapy with a beta-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 volume and end-diastolic pressure and wall tension associated with a decrease in heart rate. Combined therapy with a β-blocker and a slow-release or long-acting dihydropyridine-derivative calcium-channel blocker also may be useful because the tendency to develop tachycardia with the calcium-channel blocker is counteracted by the β-blocker. 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 marked fatigue (with high-dose verapamil or diltiazem), extreme bradycardia, or atrioventricular (AV) block. 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.)

Unstable Angina/Non-ST-Segment Elevation Myocardial Infarction

A β-blocker is used as part of the standard therapeutic measures for managing unstable angina/non-ST-segment elevation myocardial infarction; these measures also include therapy with aspirin and/or clopidogrel, low-molecular weight or unfractionated heparin, and nitrates (e.g., nitroglycerin) followed by either conservative medical management or early aggressive management, such as angiographic evaluation and revascularization procedures (e.g., percutaneous coronary intervention [PCI], coronary artery bypass grafting [CABG], coronary artery stent implantation) as required. The American College of Cardiology (ACC) and the American Heart Association (AHA) recommend administration of an IV β-blocker followed by oral β-blocker therapy for patients with unstable angina at high risk of death or nonfatal myocardial infarction (i.e., patients with at least one of the following features: accelerating tempo of ischemic symptoms in preceding 48 hours; prolonged ongoing pain at rest; angina at rest with transient ST-segment changes exceeding 0.5 mV; new or presumed new bundle branch block; sustained ventricular tachycardia; hypotension, bradycardia, or tachycardia; age exceeding 75 years; elevated serum cardiac markers [e.g., troponin T or I concentrations exceeding 0.1 ng/mL]; new or worsening mitral regurgitation murmur; S3 gallop or new/worsening rales; or pulmonary edema likely resulting from ischemia) who do not have contraindications to these drugs; oral β-blocker therapy is recommended for lower-risk patients. β-Blockers without intrinsic sympathomimetic activity (e.g., metoprolol, atenolol, propranolol, esmolol) are preferable in the management of unstable angina.

Nondihydropyridine calcium-channel blockers may be used to control ongoing or recurring ischemia in patients who are unable to tolerate β-blockers, provided no contraindications to therapy exist. ACE inhibitors may be used in patients with unstable angina who have hypertension despite treatment with nitroglycerin and a β-blocker or in patients with unstable angina who have left ventricular dysfunction, heart failure, or diabetes mellitus.

For more information on current antiplatelet and anticoagulant therapy for unstable angina/non-ST-segment elevation myocardial infarction,

Acute Myocardial Infarction

Metoprolol tartrate is used orally and IV to reduce the risk of cardiovascular mortality in patients who have had a definite or suspected acute myocardial infarction and are hemodynamically stable. Treatment with IV metoprolol tartrate can be initiated as soon as the patient's clinical condition allows. Alternatively, treatment can begin within 3-10 days following acute myocardial infarction. In one double-blind, placebo-controlled study in patients with definite or suspected acute myocardial infarction, administration of metoprolol tartrate for up to 3 months (begun as soon as possible after arrival in the hospital following myocardial infarction) reduced mortality by 36% during this time period. Although the drug does not appear to prevent ventricular premature complexes or short bursts of ventricular tachycardia, it does appear to decrease the occurrence of ventricular fibrillation. Treatment during the early phase of definite or suspected acute myocardial infarction can be initiated with IV administration of the drug; subsequent maintenance therapy may be administered orally.

Because β-blockers can reduce myocardial oxygen demand during the first few hours of an acute myocardial infarction (by reducing heart rate, arterial blood pressure, and/or myocardial contractility) and may favorably influence myocardial blood flow, thus potentially limiting myocardial damage, and because of evidence of efficacy in reducing cardiovascular mortality, early (preferably within the first few hours) IV therapy with the drugs following acute myocardial infarction currently is recommended (unless contraindicated) for patients (including those receiving thrombolytic therapy or primary angioplasty) with reflex tachycardia and/or systolic hypertension (but without signs of heart failure); those with continuing or recurrent ischemic pain, tachyarrhythmias (e.g., atrial fibrillation with a rapid ventricular response), non-ST-elevation infarction, and/or cardiac enzyme elevations indicative of recurrent injury; and those with postinfarction angina. Unless contraindicated, early IV therapy with the drugs also can be considered in patients with moderate left ventricular failure (presence of bibasilar rales without evidence of low cardiac output), provided they can be monitored closely, and in other patients who can be treated within the first 12 hours after onset of chest pain. Although the presence of moderate-to-severe left ventricular failure early in the course of acute myocardial infarction should preclude the use of early IV β-blocker therapy, it is a strong indication for the use of oral therapy prior to hospital discharge.

Although the efficacy of metoprolol tartrate following administration of the drug for longer than 3 months has not been conclusively established, 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-adrenergic blocking agent can reduce the rates of reinfarction and mortality (e.g., sudden or nonsudden cardiac death) following an acute myocardial infarction. 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; benefit of continued therapy may persist for at least several years beyond this period, although less substantially. Therefore, metoprolol tartrate like other β-blockers, can be used for secondary prevention following acute myocardial infarction to reduce the risk of reinfarction and mortality. Some experts state that such secondary prevention generally is recommended for all patients considered at moderate to high risk following an acute myocardial infarction, unless contraindicated, and that therapy be initiated within the first few days after infarction (if not already initiated acutely) and continued indefinitely. Secondary prevention also can be considered for low-risk patients who do not have a clear contraindication, for survivors of non-ST-elevation myocardial infarction, and for patients with non-Q-wave myocardial infarction. In addition, although the usefulness and efficacy are less well established by evidence and opinion, secondary prevention with β-blockers also can be considered for patients with moderate-to-severe left ventricular failure or other relative contraindication to β-blocker therapy, provided they can be monitored closely.

Supraventricular Arrhythmias

β-Blockers, including metoprolol, have been used to slow ventricular rate in patients with supraventricular tachycardia (SVT). 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. 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. Although evidence of efficacy is limited, experts state that the overall safety of β-adrenergic blockers warrants their use in patients with SVT. Patients should be closely monitored for hypotension and bradycardia during administration of these drugs.

Atrial Fibrillation and Flutter

β-Blockers, including metoprolol, have been used to slow rapid ventricular response in patients with atrial fibrillation or atrial flutter. 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. Choice of a specific β-blocker should be individualized based on the patient's clinical condition.

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.

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.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. 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. Therapy with IV metoprolol has been associated with slowing of atrial and ventricular rates and conversion to sinus rhythm 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. Metoprolol also may be useful orally for chronic suppression of symptomatic multifocal atrial tachycardia.

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.

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. 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.

Ventricular Arrhythmias

Ventricular Fibrillation

β-Blockers have been used in patients with cardiac arrest precipitated by ventricular fibrillation or pulseless ventricular tachycardia. 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.

Polymorphic Ventricular Tachycardia

β-Blockers may be useful in the management of certain forms of polymorphic ventricular tachycardia (e.g., associated with acute ischemia). Although rare, this arrhythmia can be managed by aggressive attempts at reducing myocardial ischemia, including use of IV metoprolol, intra-aortic balloon pumping, and emergency percutaneous transluminal coronary angioplasty (PTCA)/coronary artery bypass graft (CABG) surgery.

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. In clinical studies, metoprolol (as extended-release metoprolol succinate) increased survival and reduced the risk of hospitalization in patients with chronic heart failure. 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. 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. Experts recommend that all asymptomatic patients with reduced left ventricular ejection fraction (LVEF) (American College of Cardiology Foundation [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. 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. 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. 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.

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. 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. Even when symptoms are mild or improve with other therapies, β-blocker therapy should not be delayed until symptoms return or the disease progresses. Despite concerns about β-blockade potentially masking some signs of hypoglycemia, patients with diabetes mellitus may be particularly likely to experience a reduction in morbidity and mortality with the use of β-blockers. 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. 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.

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. The efficacy of β-blockers in such patients is not known, and they may be at particular risk of deterioration following initiation of therapy with β-blockers.

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). 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. Sudden deaths and deaths from worsening heart failure also were reduced with metoprolol therapy. 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%. 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.

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. 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. Other sympathetic effects (e.g., induction of cardiac hypertrophy, arrhythmogenic activity) also may be involved. 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. 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.

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. 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). Withholding of, or reduction in, β-blocker therapy may be considered in patients hospitalized after recent initiation or increase in β-blocker therapy. 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). Caution should be used when initiating β-blockers in patients who have required inotrope therapy during their hospitalization.

Vascular Headache

Migraine

Metoprolol has been used for the prophylaxis of migraine headache. When used prophylactically, metoprolol can prevent migraine or reduce the number of attacks in some patients. Results of comparative studies suggest that metoprolol may be comparable to propranolol for this indication. 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. Metoprolol is not recommended for the treatment of a migraine attack that has already started. For further information on management and classification of migraine headache, .

Dosage and Administration

Administration

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

Absorption of metoprolol tartrate may be enhanced by administration with food. The manufacturer recommends that metoprolol tartrate be administered with or immediately following meals. 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.

Metoprolol tartrate may be administered daily as a single dose or in divided doses; 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.

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. 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). 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. 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''). Extra care should be exercised to ensure the accuracy of both oral and written prescriptions for these drugs. 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).(See Cautions: Precautions and Contraindications.)

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 panel members appointed to the Eighth Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8 expert panel) state that evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) should be used when available to determine target dosages of antihypertensive agents. Based on such information, an initial adult metoprolol dosage (expressed in terms of metoprolol tartrate) of 50 mg daily and a target dosage of 100-200 mg daily (given in 1 or 2 divided doses) are recommended.

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. 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. 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. 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.

Some experts recommend a lower usual dosage range of 50-100 mg daily, given in 1 or 2 divided doses daily as conventional tablets or once daily as extended-release tablets. The rationale for this reduced dosage is that it usually is preferable to add another antihypertensive agent to the regimen than to continue increasing metoprolol tartrate dosage since the patient may not tolerate such continued increases.

In general, antihypertensive drug therapy should be initiated at a dosage lower than the target dosage to minimize the risk of adverse effects; dosage should then be titrated upward until the effective dosage is achieved. Blood pressure should be monitored regularly during therapy and, if necessary, dosage of the antihypertensive drug adjusted accordingly. In patients who experience intolerable adverse effects with metoprolol, dosage reduction should be considered; if adverse effects worsen or fail to resolve, it may be necessary to discontinue the β-adrenergic blocking agent (β-blocker) and initiate another class of antihypertensive agent. Target dosages of antihypertensive agents generally can be achieved within 2-4 weeks, but it may take up to several months.

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, some experts recommend a usual initial oral dosage of 1-2 mg/kg daily given in 2 divided doses. Dosage may be increased as necessary to a maximum dosage of 6 mg/kg (up to 200 mg) daily given in 2 divided doses. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, .

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

Careful monitoring of blood pressure during initial titration or subsequent upward adjustment in dosage of metoprolol tartrate and metoprolol succinate is recommended.

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure; specific target levels of blood pressure should be individualized based on consideration of multiple factors, including patient age and comorbidities, and the currently available evidence from clinical studies.(See Hypertension: Considerations in Initiating Antihypertensive Therapy, in Uses.)

For additional information on initiating and adjusting metoprolol tartrate or metoprolol succinate dosage in the management of hypertension, .

Angina

For the long-term management of angina pectoris, the initial adult dosage of metoprolol tartrate (conventional tablets) or metoprolol succinate (extended-release tablets) is 100 mg as the tartrate daily given in 2 divided doses or in a single dose, 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. Oral dosages exceeding 400 mg daily (given as metoprolol tartrate conventional tablets or as metoprolol succinate extended-release tablets) 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.)

In patients with unstable angina/non-ST-segment elevation myocardial infarction at high-risk for ischemic events, the American College of Cardiology (ACC) and the American Heart Association (AHA) suggest that therapy be initiated with an IV loading dose of a β-blocker (in patients who tolerate IV therapy) followed by conversion to an oral regimen. Metoprolol tartrate may be given IV in 5-mg increments over 1-2 minutes; the dose may be repeated every 5 minutes for a total IV dose of 15 mg. Patients who tolerate the total IV dosage may be switched to oral therapy 15 minutes after the last IV dose. Patients receiving IV β-blockers should have frequent monitoring of heart rate and blood pressure, ECG monitoring, and auscultation for rales and bronchospasm. The ACC and AHA recommend an oral metoprolol tartrate dosage of 25-50 mg every 6 hours for 48 hours; thereafter, patients should be maintained on 100 mg twice daily. The target resting heart rate with β-blocker therapy in patients with unstable angina is 50-60 bpm in the absence of dose-limiting adverse effects.

Acute Myocardial Infarction

Early Treatment

To reduce the risk of cardiovascular mortality during the early phase of definite or suspected acute myocardial infarction, treatment with metoprolol tartrate should be initiated with administration of 2.5- to 5-mg rapid IV injections given at approximately 2- to 5-minute intervals up to a total of 15 mg over 10-15 minutes. Heart rate, blood pressure, and ECG should be monitored, and IV metoprolol therapy should be halted when therapeutic efficacy is achieved (e.g., slowing of ventricular rate in atrial fibrillation) or if systolic blood pressure or heart rate declines to 100 mm Hg or 50 bpm, respectively.

In patients who tolerate the usual total IV dose (15 mg), 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.

Late Treatment

To reduce the risk of cardiovascular mortality in patients who have contraindications to metoprolol therapy during the early phase of definite or suspected acute myocardial infarction, in patients who appear not to tolerate the full early treatment, or in patients in whom therapy is delayed for any other reason, metoprolol therapy should be initiated with an oral dosage of 100 mg twice daily as soon as their clinical condition allows. Oral metoprolol therapy should be continued for at least 3 months. The optimum duration of metoprolol therapy remains to be clearly established; some experts recommend continuing therapy indefinitely when contraindications to β-blocker therapy do not exist.

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. 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.

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. 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).

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. Because of the potential for severe adverse effects (e.g., hypotension, bradycardia, fluid retention, worsening of heart failure), initiation of β-blocker therapy for heart failure and subsequent dosage adjustments should occur under close medical supervision.

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. 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. 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). If deterioration of heart failure (usually transient) becomes evident during titration of metoprolol therapy, the dosage of the concurrent diuretic should be increased 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. 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. Initial difficulty in titrating metoprolol dosage should not preclude subsequent attempts to successfully titrate the dosage.

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

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. The usual effective dosage of the drug in these studies was 200 mg daily.

Cautions

Metoprolol shares the toxic potentials of β-adrenergic blocking agents (β-blockers). Most adverse effects of metoprolol are mild and transient 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. Severe bradycardia should be treated with IM or IV administration of atropine sulfate. If there is an inadequate response to atropine, IV isoproterenol may be administered with caution. 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. Gangrene has been reported very rarely in patients with preexisting severe peripheral circulatory disorders receiving metoprolol tartrate. Claudication has been reported in patients with myocardial infarction receiving metoprolol tartrate, although a relationship to the drug is unclear. 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 myocardial infarction, coronary artery disorder, cerebrovascular disorder, ventricular tachycardia, or aggravation of arrhythmia.

If hypotension (systolic blood pressure of 90 mm Hg or less) occurs in patients with myocardial infarction, 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. AV dissociation, AV conduction delays, 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; tiredness has been reported in about 1% of patients with myocardial infarction receiving the drug. In addition, vertigo, sleep disturbances/insomnia, hallucinations, nightmares, headache, dizziness, visual disturbances, and confusion have been reported in patients with myocardial infarction receiving the drug, although a causal relationship is unclear. 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. 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. Lethargy and, rarely, fullheadedness have occurred.

GI Effects

Diarrhea has occurred in about 5% of patients receiving metoprolol tartrate in clinical trials. 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 myocardial infarction receiving IV or oral metoprolol.

Endocrine Effects

Unstable diabetes mellitus has been reported in patients with myocardial infarction receiving metoprolol tartrate, although a relationship to the drug is unclear. 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. 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. 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. It is not known if the risk of developing diabetes is affected by β-receptor selectivity. 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. 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.

Hypoglycemia, 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.

β-Blockers may mask signs and symptoms of hypoglycemia (e.g., palpitation, tachycardia, tremor) and potentiate insulin-induced hypoglycemia. 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). 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.

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, and dyspnea of pulmonary origin has been reported in less than 1% of patients with myocardial infarction receiving the drug. Rhinitis also has been reported in patients receiving metoprolol tartrate. 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.

Peyronie's disease, tinnitus, restless legs, a polymyalgia-like syndrome, musculoskeletal pain, decreased libido, 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.

Pruritus, dry skin, worsening of psoriasis, 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. Reversible alopecia, agranulocytosis, thrombocytopenia, weight gain, arthritis, retroperitoneal fibrosis, and dry eyes have been reported rarely with metoprolol therapy. Discontinuance of the drug should be considered if any such reaction is not otherwise explicable. 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.

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. 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. 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.

In patients with heart failure, sympathetic stimulation is vital for the support of circulatory function. 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. 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 myocardial infarction 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 myocardial infarction, 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 myocardial infarction 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 myocardial infarction, 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; 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.

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

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. 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). 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). 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.) Patients should be advised to carefully check their medications and to bring any questions or concerns to the attention of the dispensing pharmacist. 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 (http://www.fda.gov/Safety/MedWatch).

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, severe peripheral, arterial circulatory disorders, pheochromocytoma (unless administered after initiating treatment with an alpha-adrenergic blocking agent), or sick sinus syndrome (unless a permanent pacemaker is in place). The drug is contraindicated in patients with acute myocardial infarction 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. Metoprolol also is contraindicated in patients with a known history of hypersensitivity to metoprolol or any component of the formulations and in patients with a known history of hypersensitivity to other β-blockers.

Pediatric Precautions

Although safety and efficacy remain to be fully established in children, some experts have recommended pediatric dosages for hypertension based on currently limited clinical experience. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, .

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. While clinical experience generally has not revealed age-related differences in response to the drug, care should be taken in dosage selection of metoprolol. Safety and efficacy of conventional metoprolol tartrate tablets are similar in geriatric adults with myocardial infarction and younger adults. However, since the possibility of greater sensitivity of some older patients cannot be ruled out, initial dosage should be selected carefully in these patients. Safety and efficacy of extended-release metoprolol succinate are similar in geriatric adults with heart failure and in younger adults. 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.

Mutagenicity and Carcinogenicity

There has been no evidence of mutagenic potential in tests performed to date with metoprolol. 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. No evidence of mutagenicity was observed in the Salmonella mammalian microsome test using metoprolol succinate. 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/mbasis) for 21 months than in untreated control animals, although there was no increase in malignant lung tumors or total (benign plus malignant) lung tumors. In CD-1 mice, however, no differences were observed between treated and control mice of either gender for any tumor. 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. 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.

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. 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/m basis) or metoprolol tartrate dosages up to 55.5 times the maximum recommended human dosage of 450 mg daily. Metoprolol should be used during pregnancy only when clearly needed.

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/m basis) or metoprolol tartrate dosages up to 55.5 times the maximum recommended human dosage of 450 mg have not revealed evidence of impaired fertility. Metoprolol has rarely caused Peyronie's disease in human males.

Lactation

Since metoprolol is distributed into milk, the drug should be used with caution in nursing women. 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) is believed to be too small to be clinically important; however, if a woman receiving metoprolol breastfeeds, the infant should be monitored for potential systemic effects of the drug.

Drug Interactions

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). 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. 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.

Verapamil may substantially increase the oral bioavailability of metoprolol, a lipophilic drug. Area under the plasma metoprolol concentration-time curve has increased up to 300% following initiation of verapamil therapy. Verapamil appears to increase oral bioavailability of metoprolol by decreasing its hepatic clearance, although the exact mechanism(s) has not been elucidated. A similar pharmacokinetic interaction does not appear to occur when atenolol, a hydrophilic drug, and verapamil are used concomitantly. 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. If verapamil and metoprolol are used concomitantly, dosage of metoprolol should be adjusted carefully and the patient monitored closely.

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. Pending further experience with combination therapy with paroxetine and metoprolol, caution should be exercised when paroxetine and metoprolol are used concomitantly. 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. 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.

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.

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. Food does not appear to affect bioavailability of metoprolol succinate extended-release tablets. 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). Time to peak concentration is longer with extended-release tablets, with peak plasma concentrations being reached in about 7 hours following administration of such tablets.

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. The relative β1 selectivity of the drug diminishes at higher plasma metoprolol concentrations while β2-blocking effects increase at higher plasma metoprolol concentrations. Such effects diminish at higher plasma metoprolol concentrations while β2-adrenergic blocking effects increase at higher plasma metoprolol concentrations.

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. 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. 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. 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. 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. 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. 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. 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, 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). When administered orally, metoprolol exhibits stereoselective metabolism that is dependent on oxidation phenotype. The CYP2D6 isoenzyme is absent in about 8% of Caucasians (poor metabolizers) and about 2% of most other populations. 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. 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.

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