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Metoprolol: Drug information

Metoprolol: Drug information
(For additional information see "Metoprolol: Patient drug information" and see "Metoprolol: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Ischemic heart disease:

Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction (MI) have occurred. When discontinuing chronically administered metoprolol, particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1 to 2 weeks and carefully monitor the patient. If angina markedly worsens or acute coronary insufficiency develops, reinstate metoprolol administration promptly, at least temporarily, and take other measures appropriate for the management of unstable angina. Warn patients against interruption or discontinuation of therapy without their health care provider's advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue metoprolol therapy abruptly, even in patients treated only for hypertension.

Brand Names: US
  • Kapspargo Sprinkle;
  • Lopressor;
  • Toprol XL
Brand Names: Canada
  • AA-Metoprolol SR;
  • AG-Metoprolol-L;
  • APO-Metoprolol;
  • APO-Metoprolol Type L;
  • DOM-Metoprolol-L;
  • JAMP-Metoprolol-L;
  • Lopresor SR [DSC];
  • Lopresor [DSC];
  • Metoprolol-L;
  • PMS-Metoprolol-L;
  • RIVA-Metoprolol-L;
  • Sandoz Metoprolol SR [DSC];
  • TEVA-Metoprolol
Pharmacologic Category
  • Antianginal Agent;
  • Antihypertensive;
  • Beta-Blocker, Beta-1 Selective
Dosing: Adult
Angina pectoris

Angina pectoris:

Note: For vasospastic angina, beta-blockers are not recommended; calcium channel blockers and nitrates are preferred. For nonvasospastic angina, guidelines recommend titrating dose to a resting heart rate of 55 to 60 beats per minute (Ref), while other experts recommend target of 60 to 70 beats per minute (Ref).

Immediate release (metoprolol tartrate): Oral: Initial: 50 mg twice daily; may increase dose at weekly intervals to desired effect; usual dosage range: 50 to 200 mg twice daily; maximum dose: 400 mg/day.

Extended release (metoprolol succinate): Oral: Initial: 100 mg once daily; may increase dose at weekly intervals to desired effect; maximum dose: 400 mg/day.

Note: For microvascular angina, some experts start with 50 mg/day (divided twice daily for the immediate-release formulation or once daily for the extended-release formulation) and increase to 100 to 200 mg/day as needed to control symptoms (Ref).

Atrial fibrillation/flutter

Atrial fibrillation/flutter (off-label use):

Note: Initiate cautiously in patients with concomitant heart failure at a dose that is appropriate for that indication. Avoid initiating or up-titrating therapy in patients with decompensated heart failure; for unstable patients, electrical cardioversion is preferred (Ref).

Acute ventricular rate control:

IV: 2.5 to 5 mg over 2 minutes; repeat dose every 5 minutes as needed; maximum total dose: 15 mg.

Maintenance of ventricular rate control:

Immediate release (metoprolol tartrate): Oral: Initial: 25 mg twice daily; increase dose gradually as tolerated to achieve ventricular rate control up to 100 mg twice daily (Ref).

Extended release (metoprolol succinate): Oral: Initial: 50 mg once daily; increase dose gradually as tolerated to achieve ventricular rate control up to 400 mg once daily (Ref).

Atrial fibrillation prevention after cardiac surgery:

Note: Initiate prior to surgery (preferentially at least 48 hours before) or postoperatively when hemodynamically stable. Continue therapy at least until the first postoperative visit in patients with no other indication for beta-blocker therapy (Ref).

Immediate release (metoprolol tartrate) : Oral: Initial: 25 to 50 mg twice daily; titrate based on daily evaluation of hemodynamic response to the maximally tolerated dose; maximum dose: 200 mg/day (Ref).

Extended release (metoprolol succinate): Oral: Initial: 50 mg once daily; titrate based on daily evaluation of hemodynamic response to the maximally tolerated dose; maximum dose: 200 mg/day (Ref).

Heart failure with reduced ejection fraction

Heart failure with reduced ejection fraction:

Note: Initiate only in stable, euvolemic patients. In hospitalized patients, volume status should be optimized and IV diuretics, IV vasodilators, and IV inotropic agents successfully discontinued prior to initiating therapy. Use caution when initiating in patients with NYHA class IV symptoms or recent heart failure exacerbation (particularly in those who required inotropes during their hospital course) (Ref).

Extended release (metoprolol succinate): Oral: Initial: 12.5 to 25 mg once daily; up-titrate gradually (eg, doubling the dose every ≥1 to 2 weeks) to a target dose of 200 mg once daily while monitoring for signs and symptoms of heart failure (Ref).

Hypertension, chronic

Hypertension, chronic (alternative agent):

Note: Not recommended in the absence of specific comorbidities (eg, ischemic heart disease, heart failure with reduced ejection fraction, arrhythmia) (Ref).

Immediate release (metoprolol tartrate): Oral: Initial: 50 mg twice daily; titrate at weekly (or longer) intervals as needed based on patient response; maximum dose: 400 mg/day; usual dosage range: 100 to 200 mg/day in 2 divided doses (Ref).

Extended release (metoprolol succinate): Oral: Initial: 25 to 100 mg once daily; titrate at weekly (or longer) intervals as needed based on patient response; maximum dose: 400 mg/day; usual dosage range: 50 to 200 mg once daily (Ref).

Migraine, prevention

Migraine, prevention (off-label use):

Note: An adequate trial for assessment of effect is considered to be at least 2 to 3 months at a therapeutic dose (Ref).

Immediate release (metoprolol tartrate) : Oral: Initial: 25 mg twice daily; titrate slowly (eg, every 1 to 2 weeks) based on patient response and tolerability up to 200 mg/day in divided doses (Ref).

Myocardial infarction, early treatment and secondary prevention

Myocardial infarction, early treatment and secondary prevention:

Note: An oral beta-blocker is recommended within the first 24 hours for most patients. Patients who did not receive a beta-blocker within 24 hours of myocardial infarction should be reevaluated for secondary prevention at a later date. The optimal duration of therapy is unknown; treat for a minimum of 3 years (Ref).

IV:

Note: Small doses of IV metoprolol at the time of presentation may be considered for ST-elevation myocardial infarction (STEMI) patients with hypertension or ongoing ischemia if no contraindications exist.

Initial: 5 mg; repeat dose every 5 minutes for up to 3 doses as needed based on heart rate and blood pressure; maximum total dose: 15 mg; begin oral therapy 15 to 30 minutes after the last IV dose (Ref).

Oral:

Immediate release (metoprolol tartrate): Initial: 25 to 50 mg every 6 to 12 hours in the acute setting; may consider a lower starting dose of 12.5 mg every 6 to 12 hours when there is concern for adverse effects; for outpatients, transition to twice-daily dosing of metoprolol tartrate (immediate release) or to daily metoprolol succinate (extended release); titrate dose based on heart rate and blood pressure as tolerated up to a maximum dose of 200 mg/day (Ref).

Extended release (metoprolol succinate): Initial: 25 to 50 mg once daily; titrate dose based on heart rate and blood pressure as tolerated up to 200 mg once daily (Ref).

Supraventricular tachycardia

Supraventricular tachycardia (eg, atrioventricular nodal reentrant tachycardia, atrioventricular reentrant tachycardia, focal atrial tachycardia, multifocal atrial tachycardia) (off-label use):

Note: Consider for hemodynamically stable patients if vagal maneuvers and/or adenosine are unsuccessful. Do not use in patients with preexcitation associated with an accessory pathway, as this can lead to ventricular arrhythmias (Ref).

Acute treatment:

IV: 2.5 to 5 mg over 2 minutes; repeat dose every 5 minutes as needed; maximum total dose: 15 mg. Note: Initiate cautiously in patients with concomitant heart failure. Avoid in patients with decompensated heart failure (electrical cardioversion preferred) (Ref).

Maintenance therapy:

Immediate release (metoprolol tartrate): Oral: Initial: 25 mg twice daily; maximum dose: 400 mg/day (Ref).

Extended release (metoprolol succinate): Oral: Initial: 50 mg once daily; maximum dose: 400 mg/day (Ref).

Thyrotoxicosis

Thyrotoxicosis (off-label use):

Note: For control of cardiovascular effects until euthyroidism established (Ref).

Immediate release (metoprolol tartrate): Oral: 25 to 50 mg every 8 to 12 hours; may also consider administering an equivalent dose of the once-daily ER formulation (metoprolol succinate) (Ref).

Ventricular arrhythmias

Ventricular arrhythmias (off-label use):

Sustained ventricular tachycardia, incessant ventricular tachycardia, or electric storm (hemodynamically stable):

Note: Beta-blockers are generally administered in addition to an antiarrhythmic drug (eg, amiodarone) for these indications. A beta-blocker is also used to reduce shocks in patients who receive an implantable cardioverter defibrillator for these indications (Ref); propranolol may be the preferred beta-blocker in these situations (Ref).

Acute ventricular tachycardia:

IV: 5 mg every 5 minutes up to 3 doses (Ref).

Prevention of ventricular arrhythmias :

Immediate release (metoprolol tartrate): Oral: Initial: 12.5 to 25 mg twice daily; increase as needed based on patient response; maximum dose: 200 mg/day in 2 or 3 divided doses (Ref).

Extended release (metoprolol succinate): Oral: 25 to 100 mg 1 to 2 times daily (Ref).

Nonsustained ventricular tachycardia or ventricular premature beats, symptomatic:

Immediate release (metoprolol tartrate): Oral: 50 to 200 mg/day in 2 or 3 divided doses (Ref).

Extended release (metoprolol succinate): Oral: 25 to 100 mg 1 to 2 times daily (Ref).

Switching dosage forms:

Switching from immediate release (metoprolol tartrate) to extended release (metoprolol succinate): The same total daily dose of metoprolol should be used. Metoprolol tartrate is typically administered in 2 to 3 divided daily doses and metoprolol succinate is administered once daily.

Switching between oral and intravenous dosage forms: In most cases, equivalent beta-blocking effect is achieved when a 2.5:1 (Oral:IV) ratio is used. However, in one bioavailability study of healthy volunteers (N=5), the range of Oral:IV conversion ratios was approximately 2:1 to 5:1 (Ref). Therefore, patient variability may exist and a specific ratio may not apply to all patients, especially if comorbid conditions are present. The estimated equivalent IV total daily dose should be divided into 4 equal doses. For example, if a patient is receiving a chronic oral dose of metoprolol tartrate 25 mg twice daily (total daily dose of 50 mg), this could translate to a range of 2.5 mg IV every 6 hours (based on a 5:1 ratio) to 5 mg IV every 6 hours (based on a 2.5:1 ratio). Recognizing that patients receiving larger chronic oral doses should not automatically be converted to a large IV dose, consideration should be given to further reducing the initial IV dose and basing subsequent doses on the clinical response (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Altered kidney function: Mild to severe impairment: No dosage adjustment necessary (Ref).

Hemodialysis, intermittent (thrice weekly): Dialyzable (metabolites): No dosage adjustment necessary (Ref).

Peritoneal dialysis: No dosage adjustment necessary (Ref).

CRRT: No dosage adjustment necessary (Ref).

PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).

Dosing: Hepatic Impairment: Adult

There are no specific dosage adjustments provided in the manufacturer's labeling. Consider initiating with reduced doses and gradual dosage titration due to extensive hepatic metabolism.

Dosing: Pediatric

(For additional information see "Metoprolol: Pediatric drug information")

Note: Dose should be individualized based on patient response.

Heart failure

Heart failure (dilated cardiomyopathy): Limited data available: Children and Adolescents: Oral: Immediate release (metoprolol tartrate): Initial: 0.1 to 0.2 mg/kg/dose twice daily, may increase slowly (usually every 2 weeks) as needed up to 1 mg/kg/day; maximum daily dose: 2 mg/kg/day or 200 mg/day, whichever is less (Ref). Dosing based on a multicenter, open-label trial in 15 pediatric patients (age range: 2.5 to 15 years, mean: 8.6 ± 1.3 years) with dilated cardiomyopathy with heart failure that failed to show improvement in left ventricular function on conventional therapy; after 23 months of metoprolol, significant increases in ejection fraction (mean: 41.1%) and fractional shortening (mean: 23.3%) were observed; the reported mean maximum daily dose was 1.1 ± 0.1 mg/kg/day (range: 0.5 to 2.3 mg/kg/day) (Ref).

Hypertension

Hypertension: Note: Guidelines do not recommend beta-blockers as initial therapy in pediatric patients; beta-blockers should be reserved for use in patients who have contraindications to preferred agents or after ≥2 preferred agents have failed in patients with hypertension and chronic kidney disease, proteinuria, or diabetes mellitus (Ref).

Immediate-release tablets (metoprolol tartrate): Children and Adolescents ≤17 years: Oral: Initial: 0.5 to 1 mg/kg/dose (maximum initial dose: 25 mg/dose) twice daily; adjust dose based on patient response; maximum daily dose: 6 mg/kg/day or 200 mg/day, whichever is less (Ref)

Extended-release sprinkle capsules or tablets (metoprolol succinate): Children ≥6 years and Adolescents: Oral: Initial: 1 mg/kg/dose once daily (maximum initial dose: 50 mg/dose); adjust dose based on patient response; maximum daily dose: 2 mg/kg/day or 200 mg/day, whichever is less; higher doses have not been studied.

Syncope, vagal

Syncope, vagal: Limited data available: Children ≥7 years and Adolescents:

Tilt-table test: IV: 0.1 to 0.2 mg/kg; maximum dose: 10 mg/dose (Ref).

Chronic treatment: Oral: Immediate release (metoprolol tartrate): 0.5 to 1 mg/kg/dose two times daily; maximum daily dose: 6 mg/kg/day (Ref). Dosing based on two studies: In one study, oral metoprolol was initiated at doses of 0.8 to 2.8 mg/kg/day in 15 patients (8 to 20 years of age) after showing response to tilt-table testing. During follow up, a total of 6 patients discontinued therapy due to recurrent syncope or adverse events including irritability/moodiness, severe depression, and severe nausea (dose ranged in this group from 1.6 to 2.8 mg/kg/day) (Ref); in another study, oral doses of 1 to 2 mg/kg/day, rounded to the nearest 25 mg/day and divided into 2 doses daily were used in 19 patients (7 to 18 years of age) with unexplained syncope; the mean effective dose was 1.5 mg/kg/day (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

Children and Adolescents: No dosage adjustment necessary

Dosing: Hepatic Impairment: Pediatric

Children and Adolescents: There are no specific dosage adjustments provided in the manufacturer's labeling. Consider initiating with reduced doses and gradual dosage titration due to extensive hepatic metabolism.

Dosing: Older Adult

Refer to adult dosing. In the management of hypertension, consider lower initial doses and titrate to response (Ref).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule ER 24 Hour Sprinkle, Oral:

Kapspargo Sprinkle: 25 mg, 50 mg, 100 mg, 200 mg [contains corn starch]

Solution, Intravenous, as tartrate:

Generic: 5 mg/5 mL (5 mL)

Solution, Intravenous, as tartrate [preservative free]:

Generic: 5 mg/5 mL (5 mL)

Solution Cartridge, Intravenous, as tartrate:

Generic: 5 mg/5 mL (5 mL [DSC])

Tablet, Oral, as tartrate:

Lopressor: 50 mg [scored]

Lopressor: 100 mg [scored; contains fd&c blue #2 (indigo carm) aluminum lake]

Generic: 25 mg, 37.5 mg, 50 mg, 75 mg, 100 mg

Tablet Extended Release 24 Hour, Oral, as succinate:

Toprol XL: 25 mg, 50 mg, 100 mg, 200 mg

Generic: 25 mg, 50 mg, 100 mg, 200 mg

Generic Equivalent Available: US

May be product dependent

Dosage Forms Considerations

The extended release metoprolol succinate products' strengths are expressed as metoprolol tartrate equivalents.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous, as tartrate:

Lopresor: 5 mg/5 mL ([DSC])

Generic: 1 mg/mL (5 mL); 5 mg/5 mL (5 mL)

Tablet, Oral, as tartrate:

Lopresor: 50 mg [DSC], 100 mg [DSC]

Generic: 25 mg, 50 mg, 100 mg

Tablet Extended Release 24 Hour, Oral:

Lopresor SR: 100 mg [DSC], 200 mg [DSC]

Generic: 100 mg, 200 mg

Administration: Adult

Oral:

Immediate release (metoprolol tartrate): Administer with or immediately following meals.

Extended release (metoprolol succinate): According to the manufacturer, it is preferable to administer with or immediately following meals; however, may administer without regard to meals (Ref). May divide tablets in half; do not crush or chew.

Bariatric surgery: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. ER tablet (metoprolol succinate) may be divided in half but not crushed or chewed. IR tablet, oral solution, and injectable formulations are available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, selection of IR formulation or alternative therapy is advised for cardiovascular and other high-risk labeled and off-label indications.

Sprinkle capsule: May be swallowed whole or the capsule may be opened and contents sprinkled on a small amount (1 teaspoonful) of soft food (eg, applesauce, pudding, or yogurt) to be used within 60 minutes (do not store for future use).

Nasogastric tube administration: Open capsule and add contents to an all plastic oral tip syringe; add 15 mL of water. Gently shake the syringe for ~10 seconds. Immediately deliver mixture through a ≥12 French nasogastric tube. No granules should remain in the syringe; rinse syringe with additional water if necessary.

IV: May administer undiluted by rapid infusion (IV push) over 1 minute for acute treatment. May also be administered by slow infusion (ie, 5 to 10 mg of metoprolol in 50 mL of fluid) over ~30 to 60 minutes during less urgent situations (eg, substitution for oral metoprolol).

Administration: Pediatric

Oral:

Immediate release (metoprolol tartrate): Tablets: Administer with food or immediately after meals; swallow whole with a glass of water.

Extended release (metoprolol succinate):

Sprinkle capsules: Administer without regard to meals; may be swallowed whole or the capsule may be opened and the contents sprinkled on small amount (1 teaspoonful) of soft food (eg, pudding, applesauce, yogurt) and used within 60 minutes of preparation; do not store drug-food mixture for later use.

Nasogastric tube administration: Open capsule and add contents to an all plastic oral syringe and add 15 mL of water; gently shake syringe for ~10 seconds to disperse granules. Administer immediately through ≥12-french nasogastric tube. No granules should remain in syringe; rinse syringe with additional water if necessary.

Tablets: May be administered without regard to meals; Toprol-XL tablets are scored and may be divided; do not chew or crush the half or whole tablets; swallow whole. Do not chew, crush, or break generic nonscored extended-release tablets; swallow whole.

Parenteral: IV dose is much smaller than oral dose. When administered acutely for cardiac treatment, monitor ECG and blood pressure

Children ≥7 years and Adolescents: Limited data available; dose was administered over 10 minutes in one study (Ref)

Adults: May administer undiluted by rapid infusion (IV push) over 1 minute. May also be administered by slow infusion (ie, 5 to 10 mg of metoprolol in 50 mL of fluid) over ~30 to 60 minutes during less urgent situations (eg, substitution for oral metoprolol).

Use: Labeled Indications

Angina: Long-term treatment of angina pectoris.

Heart failure with reduced ejection fraction (ER oral formulation): Treatment of stable, symptomatic (NYHA class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin to reduce the rate of mortality plus hospitalization in patients already receiving angiotensin-converting enzyme inhibitors, diuretics, and/or digoxin.

Hypertension, chronic: Management of hypertension. Note: Beta-blockers are not recommended as first-line therapy (ACC/AHA [Whelton 2018]).

Myocardial infarction: Treatment of hemodynamically stable acute myocardial infarction to reduce cardiovascular mortality (injection to be used in combination with metoprolol oral maintenance therapy).

Use: Off-Label: Adult

Atrial fibrillation/flutter; Atrial fibrillation prevention after cardiac surgery; Hypertrophic cardiomyopathy; Marfan syndrome with aortic aneurysm; Migraine, prevention; Supraventricular tachycardia (eg, atrioventricular nodal reentrant tachycardia, atrioventricular reentrant tachycardia, focal atrial tachycardia, multifocal atrial tachycardia); Thyrotoxicosis; Ventricular arrhythmias

Medication Safety Issues
Sound-alike/look-alike issues:

Lopressor may be confused with Lyrica

Metoprolol may be confused with metaproterenol, metoclopramide, metOLazone, miSOPROStol

Metoprolol succinate may be confused with metoprolol tartrate

Toprol-XL may be confused with TEGretol, TEGretol-XR, Topamax

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication (IV formulation) among its list of drugs which have a heightened risk of causing significant patient harm when used in error.

Administration issues:

Significant differences exist between oral and IV dosing. Use caution when converting from one route of administration to another.

Adverse Reactions (Significant): Considerations
Bradyarrhythmias

Beta-blockers may cause bradycardia, sinus pause, first-degree atrioventricular (AV) block, second-degree atrioventricular block, or complete heart block (Ref). At maintenance dosing, second- or third-degree AV block are less likely (Ref). Beta-blocking agents with intrinsic sympathomimetic activity (eg, pindolol) may cause fewer AV conduction abnormalities than those without intrinsic sympathomimetic activity (eg, metoprolol) due to their partial agonist effects (Ref). In most cases (up to 72%), AV block associated with a beta-blocker will resolve upon discontinuation; however, there are reported cases of recurrent AV block and nearly 50% of patients with more severe AV block may require a permanent pacemaker (Ref).

Mechanism: Dose-related; related to the pharmacologic action. Blockade of cardiac beta-1 adrenergic receptors results in slowed conduction and prolongation in the refractory period of the AV node. Slowing of AV conduction can lead to AV block (Ref).

Onset: Varied; one study included patients who were on beta-blocker for more than one month (Ref); however, other studies noted prolongation of the PR interval or AV nodal refractory period occurring anywhere from one dose to several days following treatment initiation (Ref).

Risk factors:

Impaired AV node conduction or sinus node dysfunction (Ref).

Acute myocardial infarction (MI) (especially inferior and posterior MI) or heart failure (Ref)

Concurrent use of other agents that impair AV nodal conduction (eg, non-dihydropyridine calcium channel blockers, digoxin, ivabradine, select antiarrhythmic agents) (Ref)

Older patients (Ref)

Bronchospasm

Selective beta-blockers (eg, metoprolol) have a lower risk of bronchospasm compared to non-cardioselective beta-blockers (Ref). Concurrent use of inhaled bronchodilators and/or corticosteroids are protective against beta-blocker-induced bronchospasm in patients with COPD or asthma (Ref). Bronchospasm is reversible upon discontinuation or use of bronchodilators (Ref).

Mechanism: Dose-related; related to pharmacologic action. Beta-blocking agents can lead to airway smooth muscle constriction by antagonism of beta-2 receptors (Ref).

Onset: Rapid; reports suggest that single doses or acute use are more likely to cause changes in FEV1 compared to chronic use (Ref).

Risk factors:

• Moderate to severe COPD (Ref)

• Acute use (Ref)

CNS effects

Beta-blockers may cause reversible CNS effects such as fatigue, sleep disturbance, insomnia, vivid dreams, and memory impairment (Ref). Sexual disorders may occur; however, patients who require beta-blocker therapy have risk factors for erectile dysfunction (eg, coronary artery disease, heart failure) (Ref). In addition, there may be a psychosomatic component (Ref). Lipophilic beta-blockers (such as metoprolol, which is moderately lipophilic) penetrate the blood-brain barrier to a greater extent than hydrophilic beta-blockers, possibly leading to a greater incidence of CNS effects; however, other studies have refuted this theory (Ref). CNS effects generally resolve with dose reduction or discontinuation (Ref).

Mechanism: Dose-related; exact mechanism is not fully understood. Proposed mechanisms include presence of beta receptors in the brain, affinity and in some instances, inhibition of beta-blocking agents towards serotonin (5-HT) receptors in the brain (affecting mood and sleep), and beta-blocker-induced decreases in central sympathetic output (Ref). Beta-1 blockade may also impact sleep by blocking sympathetic signaling to the pineal gland, resulting in suppression of nighttime levels of melatonin (Ref). Beta-blockers may cause erectile dysfunction through decreased sympathetic nervous system output and subsequent decreases in luteinizing hormone secretion and testosterone stimulation (Ref).

Onset: Intermediate; CNS effects often occur within the first few weeks of treatment (Ref).

Risk factors:

• Higher starting doses (Ref)

• Older patients (Ref)

Potentiation/masking of hypoglycemia

Beta-blockers may worsen, prolong, or cause hypoglycemia (Ref). Additionally, beta-blockers may mask symptoms of hypoglycemia (tremor, irritability, palpitations), making diaphoresis the only symptom unaffected by beta-blockers (Ref). It is unclear if non-selective or selective beta-blockers are more likely to cause hypoglycemia as data are conflicting (Ref).

Mechanism: Dose-related; related to the pharmacologic action. Beta-blockers inhibit hepatic gluconeogenesis and glycogenolysis (Ref). Beta-blockers also reduce activation of the sympathetic nervous system, therefore masking hypoglycemic symptoms that are catecholamine-mediated (Ref).

Onset: Varied; blood glucose recovery was significantly reduced following one dose or one day of therapy (Ref). In another study, episodes of severe hypoglycemia were reported over the course of 4 years (Ref).

Risk factors:

• Insulin-dependent diabetes (Ref)

• Type 2 diabetes mellitus (Ref)

• Patients who are hospitalized and not requiring basal insulin (Ref)

Withdrawal

Beta-blocker therapy should not be withdrawn abruptly, but gradually tapered to avoid acute tachycardia, hypertension, and/or ischemia in patients with underlying cardiovascular disease (Ref). Some studies have found an increase in propensity-adjusted mortality and cardiovascular events; however, one study did not find changes in infarct size and left ventricular function when beta-blocker was abruptly withdrawn in patients with myocardial infarction (Ref).

Mechanism: Dose-dependent; related to the pharmacologic action. Beta blockade causes upregulation of beta-receptors, enhanced receptor sensitivity, and decreased sympathetic nervous system response. Abrupt withdrawal leads to a transient sympathetic hyper-response (Ref). Another proposed mechanism involves increased platelet aggregability to epinephrine and thrombin (Ref).

Onset: Rapid/varied and transient; increases in heart rate and blood pressure appear 24 hours after abrupt withdrawal, peak after 48 hours, and subside after 7 days (Ref). Anginal symptoms reported to begin 12 to 24 hours after discontinuation (Ref). Development of adverse reactions also reported to occur 1 to 21 days after withdrawal (Ref).

Risk factors:

• Abrupt withdrawal in chronic users (Ref)

• Past medical history of coronary artery disease (including chronic stable angina) (Ref)

• Past medical history of hypertension (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%: Cardiovascular: Bradycardia (including sinus pause: 2% to 16%) (table 1), hypotension (1% to 27%)

Metoprolol: Adverse Reaction: Bradycardia

Drug (Metoprolol)

Placebo

Indication

Number of Patients (Metoprolol)

Number of Patients (Placebo)

2%

0.4%

Cardiac failure

1,990

2,001

16%

7%

Myocardial infarction

N/A

N/A

1% to 10%:

Cardiovascular: Arterial insufficiency (usually Raynaud type: 1%), cold extremity (1%), first-degree atrioventricular block (5%) (table 2), heart failure (1%), palpitations (1%), peripheral edema (1%)

Metoprolol: Adverse Reaction: First-Degree Atrioventricular Block

Drug (Metoprolol)

Placebo

Indication

5%

2%

Myocardial infarction

Dermatologic: Gangrene of skin and/or subcutaneous tissues (1%), pruritus (5%), skin rash (>2% to 5%)

Gastrointestinal: Constipation (1%), diarrhea (>2% to 5%), flatulence (1%), heartburn (1%), nausea (≤1%), stomach pain (1%), xerostomia (1%)

Nervous system: Cerebrovascular accident (1%), depression (>2% to 5%), dizziness (2% to 10%), fatigue (1% to 10%), vertigo (≤2%)

Respiratory: Bronchospasm (1%), dyspnea (≤3%), wheezing (1%)

Miscellaneous: Accidental injury (1%)

<1%:

Dermatologic: Alopecia

Gastrointestinal: Abdominal pain

Genitourinary: Peyronie disease

Nervous system: Anxiety

Neuromuscular & skeletal: Arthralgia, arthritis

Frequency not defined:

Cardiovascular: Claudication

Dermatologic: Exacerbation of psoriasis (Yilmaz 2002)

Endocrine & metabolic: Unstable diabetes, weight gain

Gastrointestinal: Vomiting

Genitourinary: Retroperitoneal fibrosis

Nervous system: Sleep disturbance (McAnish 1990), temporary amnesia

Ophthalmic: Visual disturbance

Otic: Tinnitus

Respiratory: Rhinitis

Postmarketing:

Cardiovascular: Chest pain, syncope

Dermatologic: Bullous pemphigoid (Perry 2005), diaphoresis, erythroderma (Doyon 2017), lichenoid dermatitis (Nguyen 2011), pemphigoid-like lesion (Patel 2019)

Endocrine & metabolic: Decreased HDL cholesterol (Day 1982: Rössner 1983), decreased libido (Ko 2002), increased serum triglycerides (Day 1982; Kim 2014)

Genitourinary: Erectile dysfunction (Cocco 2009), impotence (Ko 2002)

Hepatic: Hepatic insufficiency (Philips 2017), hepatitis (Larrey 1988), increased serum alkaline phosphatase (Larrey 1988), increased serum transaminases (Larrey 1988), jaundice (Hansen 2017; Phillis 2017)

Nervous system: Confusion (Fisher 2002), drowsiness, hallucination (Fisher 2002; Sirois 2006), headache (Nicpon 2006), insomnia (McAnish 1990), nervousness (Ahmed 2010), nightmares (Ahmed 2010), paresthesia

Neuromuscular & skeletal: Arthropathy (psoriatic) (Tatu 2017), musculoskeletal pain (Snyder 1991)

Contraindications

Hypersensitivity to metoprolol, any component of the formulation, or other beta-blockers; second- or third-degree heart block

Note: Additional contraindications are formulation and/or indication specific.

Immediate-release tablets/injectable formulation:

Hypertension and angina (oral only): Sinus bradycardia; cardiogenic shock; overt heart failure; sick sinus syndrome; severe peripheral arterial circulatory disorders

Myocardial infarction (oral and injection): Severe sinus bradycardia (heart rate <45 beats/minute); significant first-degree heart block (P-R interval ≥0.24 seconds); systolic blood pressure <100 mm Hg; moderate to severe cardiac failure

Extended-release formulation: Severe bradycardia, cardiogenic shock; decompensated heart failure; sick sinus syndrome (except in patients with a functioning artificial pacemaker)

Documentation of allergenic cross-reactivity for beta-blockers is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Canadian labeling: Additional contraindications (not in US labeling): Cor pulmonale; untreated pheochromocytoma; asthma and other obstructive respiratory disease (injection only); concomitant use with anesthesia agents that cause myocardial depression

Warnings/Precautions

Concerns related to adverse events:

• Anaphylactic reactions: Use caution with history of severe anaphylaxis to allergens; patients taking beta-blockers may become more sensitive to repeated allergen challenges. Treatment of anaphylaxis (eg, epinephrine) in patients taking beta-blockers may be ineffective or promote undesirable effects.

Disease-related concerns:

• Diabetes: Use with caution in patients with diabetes mellitus; may potentiate hypoglycemia and/or mask signs and symptoms.

• Heart failure with reduced ejection fraction: Stabilize patients on heart failure regimen prior to initiation or titration of beta-blocker. Beta-blocker therapy should be initiated at very low doses with gradual and careful titration. Worsening heart failure or fluid retention may occur during upward titration; dose reduction and/or slower titration may be necessary. Adjustment of other medications (angiotensin-converting enzyme inhibitors and/or diuretics) may be required. Only the ER formulation is indicated for use in heart failure.

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Myasthenia gravis: Use beta-blockers with caution in patients with myasthenia gravis.

• Peripheral vascular disease (PVD) and Raynaud disease: May precipitate or aggravate symptoms of arterial insufficiency in patients with PVD and Raynaud disease. Use with caution and monitor for progression of arterial obstruction.

• Pheochromocytoma (untreated): Adequate alpha-blockade is required prior to use of any beta-blocker.

• Prinzmetal variant angina: Beta-blockers without alpha1-adrenergic receptor blocking activity should be avoided in patients with Prinzmetal variant angina because unopposed alpha1-adrenergic receptors mediate coronary vasoconstriction and can worsen anginal symptoms (Mayer 1998).

• Psoriasis: Beta-blocker use has been associated with induction or exacerbation of psoriasis, but cause and effect have not been firmly established.

• Supraventricular tachycardia (SVT): If antidromic atrioventricular reentrant tachycardia (AVRT) or pre-excited atrial fibrillation is suspected, avoid AV node-specific blocking drugs (eg, adenosine, diltiazem, verapamil, digoxin, beta-blockers). For these types of SVT enhanced antegrade conduction from atria to ventricles may occur through an accessory pathway leading to ventricular arrhythmias if the AV node is blocked. It is safe to use AV node-specific blocking drugs for orthodromic AVRT because antegrade conduction occurs through the AV node and only retrograde conduction (from ventricles to atria) occurs through the accessory pathway.

• Thyroid disease: May mask signs of hyperthyroidism (eg, tachycardia). If hyperthyroidism is suspected, carefully manage and monitor; abrupt withdrawal may exacerbate symptoms of hyperthyroidism or precipitate thyroid storm. Alterations in thyroid function tests may be observed.

Other warnings/precautions:

• Abrupt withdrawal: In addition to US Boxed Warning, abrupt withdrawal may exacerbate underlying conditions, such as sinus tachycardia, hypertension, and arrhythmias.

• Major surgery: Chronic beta-blocker therapy should not be routinely withdrawn prior to major surgery.

Warnings: Additional Pediatric Considerations

Some dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).

Metabolism/Transport Effects

Substrate of CYP2C19 (minor), CYP2D6 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Acetylcholinesterase Inhibitors: May enhance the bradycardic effect of Beta-Blockers. Risk C: Monitor therapy

Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Alpha1-Blockers: Beta-Blockers may enhance the orthostatic hypotensive effect of Alpha1-Blockers. The risk associated with ophthalmic products is probably less than systemic products. Risk C: Monitor therapy

Alpha2-Agonists: May enhance the AV-blocking effect of Beta-Blockers. Sinus node dysfunction may also be enhanced. Beta-Blockers may enhance the rebound hypertensive effect of Alpha2-Agonists. This effect can occur when the Alpha2-Agonist is abruptly withdrawn. Management: Closely monitor heart rate during treatment with a beta blocker and clonidine. Withdraw beta blockers several days before clonidine withdrawal when possible, and monitor blood pressure closely. Recommendations for other alpha2-agonists are unavailable. Risk D: Consider therapy modification

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification

Amiodarone: May enhance the bradycardic effect of Beta-Blockers. Possibly to the point of cardiac arrest. Amiodarone may increase the serum concentration of Beta-Blockers. Risk C: Monitor therapy

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy

Antidiabetic Agents: Beta-Blockers (Beta1 Selective) may enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Beta-Blockers. Beta-Blockers may decrease the metabolism of Antipsychotic Agents (Phenothiazines). Antipsychotic Agents (Phenothiazines) may decrease the metabolism of Beta-Blockers. Risk C: Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy

Artemether and Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Beta2-Agonists: Beta-Blockers (Beta1 Selective) may diminish the bronchodilatory effect of Beta2-Agonists. Of particular concern with nonselective beta-blockers or higher doses of the beta1 selective beta-blockers. Risk C: Monitor therapy

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Risk C: Monitor therapy

Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination

Bupivacaine: Beta-Blockers may increase the serum concentration of Bupivacaine. Risk C: Monitor therapy

Cannabis: Beta-Blockers may enhance the adverse/toxic effect of Cannabis. Specifically, the risk of hypoglycemia may be increased. Risk C: Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Risk D: Consider therapy modification

Cholinergic Agonists: Beta-Blockers may enhance the adverse/toxic effect of Cholinergic Agonists. Of particular concern are the potential for cardiac conduction abnormalities and bronchoconstriction. Risk C: Monitor therapy

CYP2D6 Inhibitors (Moderate): May increase the serum concentration of Metoprolol. Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May increase the serum concentration of Metoprolol. Risk C: Monitor therapy

Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Dipyridamole: May enhance the bradycardic effect of Beta-Blockers. Risk C: Monitor therapy

Disopyramide: May enhance the bradycardic effect of Beta-Blockers. Beta-Blockers may enhance the negative inotropic effect of Disopyramide. Risk C: Monitor therapy

DOBUTamine: Beta-Blockers may diminish the therapeutic effect of DOBUTamine. Risk C: Monitor therapy

Dronedarone: May enhance the bradycardic effect of Beta-Blockers. Dronedarone may increase the serum concentration of Beta-Blockers. This likely applies only to those agents that are metabolized by CYP2D6. Management: Use lower initial beta-blocker doses; adequate tolerance of the combination, based on ECG findings, should be confirmed prior to any increase in beta-blocker dose. Increase monitoring for clinical response and adverse effects. Risk D: Consider therapy modification

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy

EPHEDrine (Systemic): Beta-Blockers may diminish the therapeutic effect of EPHEDrine (Systemic). Risk C: Monitor therapy

EPINEPHrine (Nasal): Beta-Blockers (Beta1 Selective) may diminish the therapeutic effect of EPINEPHrine (Nasal). Risk C: Monitor therapy

EPINEPHrine (Oral Inhalation): Beta-Blockers (Beta1 Selective) may diminish the therapeutic effect of EPINEPHrine (Oral Inhalation). Risk C: Monitor therapy

Epinephrine (Racemic): Beta-Blockers (Beta1 Selective) may diminish the therapeutic effect of Epinephrine (Racemic). Risk C: Monitor therapy

EPINEPHrine (Systemic): Beta-Blockers (Beta1 Selective) may diminish the therapeutic effect of EPINEPHrine (Systemic). Risk C: Monitor therapy

Ergot Derivatives (Vasoconstrictive CYP3A4 Substrates): Beta-Blockers may enhance the vasoconstricting effect of Ergot Derivatives (Vasoconstrictive CYP3A4 Substrates). Risk C: Monitor therapy

Etilefrine: May enhance the bradycardic effect of Beta-Blockers. Beta-Blockers may diminish the therapeutic effect of Etilefrine. Risk C: Monitor therapy

Etofylline: Beta-Blockers may diminish the therapeutic effect of Etofylline. Risk X: Avoid combination

Fexinidazole: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole. Risk X: Avoid combination

Fingolimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Fingolimod. Management: Consult with the prescriber of any bradycardia-causing agent to see if the agent could be switched to an agent that does not cause bradycardia prior to initiating fingolimod. If combined, perform continuous ECG monitoring after the first fingolimod dose. Risk D: Consider therapy modification

Flunarizine: May enhance the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy

Grass Pollen Allergen Extract (5 Grass Extract): Beta-Blockers may enhance the adverse/toxic effect of Grass Pollen Allergen Extract (5 Grass Extract). More specifically, Beta-Blockers may inhibit the ability to effectively treat severe allergic reactions to Grass Pollen Allergen Extract (5 Grass Extract) with epinephrine. Some other effects of epinephrine may be unaffected or even enhanced (e.g., vasoconstriction) during treatment with Beta-Blockers. Management: Consider alternatives to either grass pollen allergen extract (5 grass extract) or beta-blockers in patients with indications for both agents. Canadian product labeling specifically lists this combination as contraindicated. Risk D: Consider therapy modification

Herbal Products with Blood Pressure Increasing Effects: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy

Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Hydroxychloroquine: May increase the serum concentration of Metoprolol. Risk C: Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy

Isoproterenol: Beta-Blockers may diminish the therapeutic effect of Isoproterenol. Risk C: Monitor therapy

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Risk C: Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Risk C: Monitor therapy

Lercanidipine: May enhance the hypotensive effect of Metoprolol. Metoprolol may decrease the serum concentration of Lercanidipine. Risk C: Monitor therapy

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Risk C: Monitor therapy

Lidocaine (Systemic): Beta-Blockers may increase the serum concentration of Lidocaine (Systemic). Risk C: Monitor therapy

Loop Diuretics: May enhance the hypotensive effect of Antihypertensive Agents. Risk C: Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Mavacamten: Beta-Blockers may enhance the adverse/toxic effect of Mavacamten. Specifically, negative inotropic effects may be increased. Risk C: Monitor therapy

Mepivacaine: Beta-Blockers may increase the serum concentration of Mepivacaine. Risk C: Monitor therapy

Methacholine: Beta-Blockers may enhance the adverse/toxic effect of Methacholine. Risk C: Monitor therapy

Methoxyflurane: May enhance the hypotensive effect of Beta-Blockers. Risk C: Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy

Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Mirabegron: May diminish the antihypertensive effect of Metoprolol. Mirabegron may increase the serum concentration of Metoprolol. Risk C: Monitor therapy

Mivacurium: Beta-Blockers may enhance the therapeutic effect of Mivacurium. Risk C: Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

NIFEdipine: May enhance the hypotensive effect of Beta-Blockers. NIFEdipine may enhance the negative inotropic effect of Beta-Blockers. Risk C: Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May diminish the antihypertensive effect of Beta-Blockers. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (Topical): May diminish the therapeutic effect of Beta-Blockers. Risk C: Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification

Ozanimod: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

PENTobarbital: May enhance the hypotensive effect of Metoprolol. PENTobarbital may decrease the serum concentration of Metoprolol. Risk C: Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Ponesimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Ponesimod. Management: Avoid coadministration of ponesimod with drugs that may cause bradycardia when possible. If combined, monitor heart rate closely and consider obtaining a cardiology consult. Do not initiate ponesimod in patients on beta-blockers if HR is less than 55 bpm. Risk D: Consider therapy modification

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Reserpine: May enhance the hypotensive effect of Beta-Blockers. Risk C: Monitor therapy

RifAMPin: May decrease the serum concentration of Metoprolol. Risk C: Monitor therapy

Rivastigmine: May enhance the bradycardic effect of Beta-Blockers. Risk X: Avoid combination

Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. If combined, consider obtaining a cardiology consult regarding patient monitoring. Risk D: Consider therapy modification

Succinylcholine: Beta-Blockers may enhance the neuromuscular-blocking effect of Succinylcholine. Risk C: Monitor therapy

Sulfonylureas: Beta-Blockers may enhance the hypoglycemic effect of Sulfonylureas. Cardioselective beta-blockers (eg, acebutolol, atenolol, metoprolol, and penbutolol) may be safer than nonselective beta-blockers. All beta-blockers appear to mask tachycardia as an initial symptom of hypoglycemia. Ophthalmic beta-blockers are probably associated with lower risk than systemic agents. Risk C: Monitor therapy

Tasimelteon: Beta-Blockers may diminish the therapeutic effect of Tasimelteon. Management: Consider avoiding nighttime administration of beta-blockers during tasimelteon therapy due to the potential for reduced tasimelteon efficacy. Risk D: Consider therapy modification

Theophylline Derivatives: Beta-Blockers (Beta1 Selective) may diminish the bronchodilatory effect of Theophylline Derivatives. Risk C: Monitor therapy

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

White Birch Allergen Extract: Beta-Blockers may enhance the adverse/toxic effect of White Birch Allergen Extract. Specifically, beta-blockers may reduce the effectiveness of beta-agonists that may be required to treat systemic reactions to white birch allergen extract. Risk X: Avoid combination

Food Interactions

Food increases absorption. Metoprolol serum levels may be increased if taken with food. Management: Take immediate release tartrate tablets with food; succinate can be taken with or without food.

Reproductive Considerations

Erectile dysfunction and inhibition of sperm motility are noted in product labeling following use of metoprolol. As a class, outcomes from available studies evaluating beta-blockers and sexual dysfunction are inconsistent, and the negative effects on erectile function and libido are considered controversial. A clear relationship between use of beta-blockers and erectile dysfunction has not been established. Hypertension itself is associated with erectile dysfunction. Patients on a beta-blocker presenting with sexual dysfunction should be evaluated for underlying disease (Farmakis 2021; Levine 2012; Semet 2017; Terentes-Printzios 2022; Viigimaa 2020).

Pregnancy Considerations

Metoprolol and the metabolite alpha-hydroxymetoprolol cross the placenta (Lindeberg 1987; Ryu 2016).

Exposure to beta-blockers during pregnancy may increase the risk for adverse events in the neonate. If maternal use of a beta-blocker is needed, fetal growth should be monitored during pregnancy and the newborn should be monitored for 48 hours after delivery for bradycardia, hypoglycemia, and respiratory depression (ESC [Regitz-Zagrosek 2018]).

Chronic maternal hypertension is also associated with adverse events in the fetus/infant. Chronic maternal hypertension may increase the risk of birth defects, low birth weight, premature delivery, stillbirth, and neonatal death. Actual fetal/neonatal risks may be related to duration and severity of maternal hypertension. Untreated chronic hypertension may also increase the risks of adverse maternal outcomes, including gestational diabetes, preeclampsia, delivery complications, stroke, and myocardial infarction (ACOG 203 2019).

The pharmacokinetics of metoprolol may be changed during pregnancy; the degree of changes may be dependent upon maternal CYP2D6 genotype (Ryu 2016).

When treatment of hypertension in pregnancy is indicated, beta-blockers may be used. Specific recommendations vary by guideline but use of metoprolol may be considered (ACOG 203 2019; ESC [Regitz-Zagrosek 2018]; Magee 2014). Patients with preexisting hypertension may continue their medication during pregnancy unless contraindications exist (ESC [Regitz-Zagrosek 2018]). Metoprolol may be used for the treatment of maternal ventricular arrhythmias, atrial fibrillation/atrial flutter, or supraventricular tachycardia during pregnancy; consult current guidelines for specific recommendations (ACC/AHA/HRS [Page 2016]; ESC [Regitz-Zagrosek 2018]).

Use of metoprolol may be considered if migraine prophylaxis is needed in a pregnant patient (CHS [Pringsheim 2012]).

Breastfeeding Considerations

Metoprolol is present in breast milk.

Data related to the presence of metoprolol in breast milk is available from 3 lactating patients, 4 to 6 months postpartum. They were administered oral metoprolol after they stopped breastfeeding, but lactation was maintained via breast pumping. Metoprolol 50 mg twice daily was administered on day 1, 100 mg twice daily on days 2 and 3, and 100 mg on day 4. Blood and milk samples were obtained immediately prior to the dose on day 4, then at intervals from 3 to 12 hours later. The maximum maternal metoprolol blood concentrations ranged from 27 to 259 ng/mL, and the maximum milk concentrations ranged from 102 to 690 ng/mL (Liedholm 1981). Using the highest milk concentration reported (690 ng/mL), the estimated exposure to the breastfeeding infant would be 0.1 mg/kg/day (relative infant dose [RID] 7%) compared to a weight-adjusted maternal dose of 100 mg/day. In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000).

A case report also notes the presence of the α-OH-metoprolol metabolite in breast milk (Grundman 2011). Metoprolol is measurable in the serum of some breastfed infants (Sandström 1983). Adverse events were not reported in 6 infants exposed to metoprolol via breast milk (Ho 1999).

The manufacturer recommends monitoring the breastfed infant for adverse events such as bradycardia; constipation; diarrhea; and dry mouth, skin, or eyes when metoprolol is administered to a mother who is a slow metabolizer. Use of a beta-blocker other than metoprolol may be preferred in lactating patients (Anderson 2017; Ito 2000).

Monitoring Parameters

Acute cardiac treatment: Monitor ECG, heart rate, and blood pressure with IV administration; heart rate, rhythm, and blood pressure with oral administration.

Mental alertness, signs and symptoms of bronchospasm in patients with existing bronchospastic disease.

IV use in a nonemergency situation: Necessary monitoring for surgical patients who are unable to take oral beta-blockers (because of prolonged ileus) has not been defined. Some institutions require monitoring of baseline and postinfusion heart rate and blood pressure when a patient's response to beta-blockade has not been characterized (ie, the patient's initial dose or following a change in dose). Consult individual institutional policies and procedures.

Hypertension: The 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults (ACC/AHA [Whelton 2018]):

Confirmed hypertension and known CVD or 10-year ASCVD risk ≥10%: Target blood pressure <130/80 mm Hg is recommended.

Confirmed hypertension without markers of increased ASCVD risk: Target blood pressure <130/80 mm Hg may be reasonable.

Mechanism of Action

Selective inhibitor of beta1-adrenergic receptors; competitively blocks beta1-receptors, with little or no effect on beta2-receptors at oral doses <100 mg (in adults); does not exhibit any membrane stabilizing or intrinsic sympathomimetic activity

Pharmacokinetics

Note: The pharmacokinetics of metoprolol succinate ER capsule or tablet in hypertensive children and adolescents 6 to 17 years of age were found to be similar to adults.

Onset of action: Oral: IR tablets: Within 1 hour; Peak effect: Oral: 1 to 2 hours (Regardh 1980); IV: ~20 minutes (when infused over 10 minutes).

Duration: Oral: Immediate release: Variable (dose-related; 50% reduction in maximum heart rate after single doses of 20, 50, and 100 mg occurred at 3.3, 5, and 6.4 hours, respectively); Extended release: ~24 hours.

Absorption: Rapid and complete.

Distribution: Vd: 3.2 to 5.6 L/kg; crosses the blood brain barrier; CSF concentrations are 78% of plasma concentrations.

Protein binding: ~10% to 12% to albumin.

Metabolism: Extensively hepatic via CYP2D6; significant first-pass effect (~50%).

Bioavailability: Oral: Immediate release: ~40% to 50% (Johnsson 1975); Extended release: 77% relative to immediate release.

Half-life elimination: Neonates: 5 to 10 hours (Morselli 1989); Adults: 3 to 4 hours (7 to 9 hours in poor CYP2D6 metabolizers or hepatic impairment).

Excretion: Urine (95%, <5% to 10% as unchanged drug; increased to 30% to 40% in poor CYP2D6 metabolizers).

Pharmacokinetics: Additional Considerations

Hepatic function impairment: Elimination half-life may be considerably prolonged, depending on severity.

Pharmacogenomics: Poor CYP2D6 metabolizers have several-fold higher metoprolol plasma concentrations.

Pricing: US

Capsule ER 24 Hour Sprinkle (Kapspargo Sprinkle Oral)

25 mg (per each): $2.16

50 mg (per each): $2.16

100 mg (per each): $2.50

200 mg (per each): $3.84

Solution (Metoprolol Tartrate Intravenous)

5 mg/5 mL (per mL): $0.19 - $0.65

Tablet, 24-hour (Metoprolol Succinate ER Oral)

25 mg (per each): $0.14 - $1.28

50 mg (per each): $0.12 - $1.28

100 mg (per each): $0.31 - $2.04

200 mg (per each): $0.30 - $3.06

Tablet, 24-hour (Toprol XL Oral)

25 mg (per each): $1.58

50 mg (per each): $1.58

100 mg (per each): $2.37

200 mg (per each): $3.77

Tablets (Lopressor Oral)

50 mg (per each): $3.02

100 mg (per each): $4.52

Tablets (Metoprolol Tartrate Oral)

25 mg (per each): $0.03 - $0.27

37.5 mg (per each): $1.46

50 mg (per each): $0.03 - $0.57

75 mg (per each): $2.44

100 mg (per each): $0.04 - $0.80

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Angilat (BD);
  • Angimet (PH);
  • Beloc (AR, AT, CH, CO, DE);
  • Beloc Duriles (AT);
  • Beloken (ES, IE);
  • Beloken Retard (ES);
  • Belozok (AR, CO, PE, UY);
  • Betacard (BD);
  • Betaloc (AU, BD, CN, CO, EG, GB, HK, HU, IE, IN, KR, LK, LT, LV, MY, NO, PH, PL, RO, RU, SI, SK, VN);
  • Betaloc CR (NZ);
  • Betaloc Zoc (BF, BJ, CI, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM, ZW);
  • Betaloc ZOK (BG, ET, LV, VN);
  • Betaloc Zok (CO, CY, CZ, DE, EC, EE, HK, HR, HU, JO, KW, LK, LT, PK, RO, SK, TR, TW);
  • Betaloc-ZOK (CL);
  • Betalok (UA);
  • Betawin (MY);
  • Betazok (PH);
  • Bloxan (HR, RO);
  • Bloxazoc (BG, CZ, DK, EE, HU, IS, PL, RO, SK);
  • Cancliol (TW);
  • Cardeloc (TH);
  • Cardiosel (PH);
  • Cardiosel-OD (PH);
  • Cardiostat (PH);
  • Cardiotab (PH);
  • Cardoxone (TR);
  • Cartaloc (TW);
  • Corvital (UA);
  • Corvitol (LV);
  • Denex (MY, SG, TR, TW);
  • Egilok (UA);
  • Egilok Succ (CZ);
  • Emzok (LV);
  • Fapresor (ID);
  • Huma-Metoprol (HU);
  • Hypetor (PH);
  • Lenopres (CR, DO, GT, HN, NI, PA, SV);
  • Lofarbil (GR);
  • Lopresor (AE, AR, AT, AU, BF, BH, BJ, BM, BS, BZ, CI, CY, ES, ET, GH, GM, GN, GR, GY, IE, IQ, IR, IT, JM, JO, KE, KW, LB, LR, LU, LY, MA, ML, MR, MU, MW, MX, NE, NG, NZ, OM, PT, PY, QA, SA, SC, SD, SL, SN, SR, SY, TN, TT, TZ, UG, UY, VE, YE, ZA, ZM, ZW);
  • Lopresor Divitab (IL);
  • Lopresor OROS (LU);
  • Lopresor Retard (AE, AT, CH, GR, PT);
  • Lopressor (BB, BR, FR);
  • Low Press (EG);
  • Metazero (LT, LV);
  • Metocell (NL);
  • Metocor (IE);
  • Metohexal (HU, LU);
  • MetoHEXAL (VN);
  • Metohexal Retard (AT);
  • Metolol-CP (HK);
  • Metoprim (PH);
  • Metoprolol Stada (HU);
  • Metoprolol-B (HU);
  • Metoprolol-rpm (LU);
  • Metostad (BG, PH);
  • Metracin (HK);
  • Metrol (AU);
  • Mezelol (MX);
  • Minax (HK, TW);
  • Minax XL (AU);
  • Myloc (NZ);
  • Neobloc (IL);
  • Neox (PH);
  • Nipresol (MX);
  • Prolol (BD);
  • Prolomet XL (LK);
  • Promiced (MX);
  • Prontol (CR, DO, GT, HN, NI, PA, SV);
  • Revelol XL (LK);
  • Revelol-XL-50 (ZW);
  • Ritmetol (HU);
  • Sefloc (TH);
  • Selo-zok (DK, NO);
  • Selokeen ZOC (NL);
  • Seloken (BE, FI, FR, IS, IT, JP, LU, NO, SE);
  • Seloken Retard (AT);
  • Seloken Zoc (SE);
  • Seloken Zok (CR, DO, GT, HN, IS, NI, PA, SV);
  • Seloken-Zok (MX);
  • Selozok (BE, BR, DK, LU);
  • Selozok LP (FR);
  • Slow-Lopresor (LU, NZ);
  • Succiprol (BG);
  • Topress (BD);
  • Toprol XL (AU);
  • Vasocardin (BG);
  • Voxuten (LV)


For country code abbreviations (show table)
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