Pronunciation
(me toe PROE lole)

Trade Name(s)

• Metoprolol Succinate
• Metoprolol Tartrate

• Antianginal Agent
• Beta-Blocker, Beta-1 Selective

Indications

Use: Labeled Indications
Treatment of angina pectoris, hypertension, or hemodynamically-stable acute myocardial infarction

Extended release: Treatment of angina pectoris or hypertension; to reduce mortality/hospitalization in patients with heart failure (stable NYHA Class II or III) already receiving ACE inhibitors, diuretics, and/or digoxin

Use: Unlabeled
Treatment of ventricular arrhythmias, atrial ectopy; migraine prophylaxis, essential tremor; prevention of reinfarction and sudden death after myocardial infarction; prevention and treatment of atrial fibrillation and atrial flutter; multifocal atrial tachycardia; symptomatic treatment of hypertrophic obstructive cardiomyopathy; management of thyrotoxicosis

Contraindications

Hypersensitivity to metoprolol, any component of the formulation, or other beta-blockers

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

Immediate release tablets/injectable formulation:

Hypertension and angina: Sinus bradycardia; second- and third-degree heart block; cardiogenic shock; overt heart failure; sick sinus syndrome (except in patients with a functioning artificial pacemaker); severe peripheral arterial disease; pheochromocytoma (without alpha blockade)

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

Extended release tablet: Severe bradycardia, second- and third degree heart block; cardiogenic shock; decompensated heart failure; sick sinus syndrome (except in patients with a functioning artificial pacemaker)

Dosing and Administration

Children: Hypertension: Oral:

1-17 years: Immediate release tablet: (National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents, 2004): Initial: 1-2 mg/kg/day; maximum 6 mg/kg/day (≤200 mg/day); administer in 2 divided doses

≥6 years: Extended release tablet: Initial: 1 mg/kg once daily (maximum initial dose: 50 mg/day). Adjust dose based on patient response (maximum: 2 mg/kg/day or 200 mg/day)

Adults:

Angina: Oral:

Immediate release: Initial: 50 mg twice daily; usual dosage range: 50-200 mg twice daily; maximum: 400 mg/day; increase dose at weekly intervals to desired effect

Extended release: Initial: 100 mg/day (maximum: 400 mg/day)

Atrial fibrillation/flutter (ventricular rate control), supraventricular tachycardia (SVT) (acute treatment; unlabeled use; Antman, 2004; Fuster, 2006; Neumar, 2010): I.V.: 2.5-5 mg every 2-5 minutes (maximum total dose: 15 mg over a 10-15 minute period). Note: Initiate cautiously in patients with concomitant heart failure; avoid in patients with decompensated heart failure.

Maintenance: Oral (immediate release): 25-100 mg twice daily

Heart failure: Oral (extended release): Initial: 25 mg once daily (reduce to 12.5 mg once daily in NYHA class higher than class II); may double dosage every 2 weeks as tolerated (target dose: 200 mg/day)

Hypertension: Oral:

Immediate release: Initial: 50 mg twice daily; effective dosage range: 100-450 mg/day in 2-3 divided doses; increase dose at weekly intervals to desired effect; maximum: 450 mg/day; usual dosage range (JNC 7): 50-100 mg/day

Extended release: Initial: 25-100 mg once daily; increase doses at weekly (or longer) intervals to desired effect; maximum: 400 mg/day; usual dosage range (JNC 7): 50-100 mg/day

Hypertension/ventricular rate control: I.V. (in patients having nonfunctioning GI tract): Initial: 1.25-5 mg every 6-12 hours; titrate initial dose to response. Initially, low doses may be appropriate to establish response; however, although not routine, up to 15 mg administered as frequently as every 3 hours has been employed in patients with refractory tachycardia.

Myocardial infarction:

Acute: I.V.: 5 mg every 2 minutes for 3 doses in early treatment of myocardial infarction; thereafter, give 50 mg orally every 6 hours beginning 15 minutes after last I.V. dose and continue for 48 hours; then administer a maintenance dose of 100 mg twice daily. Note: Do not initiate this regimen in those with signs of heart failure, a low output state, increased risk of cardiogenic shock, or other contraindications (eg, second- or third-degree heart block). If initial I.V. dosing is not tolerated, may give 25-50 mg orally (depending on degree of intolerance) every 6 hours beginning 15 minutes after the last I.V. dose or as soon as clinical condition permits.

Secondary prevention (unlabeled use; Olsson, 1992): Oral: Immediate release: 25-100 mg twice daily; optimize dose based on heart rate and blood pressure; continue indefinitely.

Thyrotoxicosis (unlabeled use): Oral: Immediate release: 25-50 mg every 6 hours; may also consider administering extended release formulation (Bahn, 2011)

Elderly: Hypertension: Initiate at the lower end of the dosage range and titrate to response

Note: Switching dosage forms:

When switching from immediate release metoprolol to extended release, the same total daily dose of metoprolol should be used.

When switching between oral and intravenous dosage forms, equivalent beta-blocking effect is achieved when doses in a 2.5:1 (Oral:I.V.) ratio is used. For example, if the patient is receiving an oral dose of 25 mg twice daily (50 mg/day), this would translate to 5 mg I.V. every 6 hours; consider reducing initial I.V. dose to evaluate patient response.

Dosing adjustment in renal impairment: No adjustment required.

Dosing adjustment in hepatic impairment: Reduced dose may be necessary

General Administration
Oral: Extended release tablets may be divided in half; do not crush or chew.

I.V.: I.V. dose is much smaller than oral dose. When administered acutely for cardiac treatment, monitor ECG and blood pressure; may administer by rapid infusion (I.V. push) over 1 minute. May also be administered by slow infusion (ie, 5-10 mg of metoprolol in 50 mL of fluid) over ~30-60 minutes during less urgent situations (eg, substitution for oral metoprolol).

Storage
Injection: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.

Tablet: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture.

Dosage Forms/Strengths

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, solution, as tartrate: 1 mg/mL (5 mL)

Lopressor®: 1 mg/mL (5 mL)

Injection, solution, as tartrate [preservative free]: 1 mg/mL (5 mL)

Tablet, oral, as tartrate: 25 mg, 50 mg, 100 mg

Lopressor®: 50 mg, 100 mg [scored]

Tablet, extended release, oral, as succinate: 25 mg [expressed as mg equivalent to tartrate], 50 mg [expressed as mg equivalent to tartrate], 100 mg [expressed as mg equivalent to tartrate], 200 mg [expressed as mg equivalent to tartrate]

Toprol-XL®: 25 mg, 50 mg, 100 mg, 200 mg [scored; expressed as mg equivalent to tartrate]

Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

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

Alpha-/Beta-Agonists (Direct-Acting): Beta-Blockers may enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Epinephrine used as a local anesthetic for dental procedures will not likely cause clinically relevant problems. Management: Cardioselective beta-blockers and lower doses of epinephrine may confer a more limited risk. Patients who may require acute subcutaneous epinephrine (e.g., bee sting kits) should probably avoid beta blockers. Exceptions: Dipivefrin. Consider therapy modification

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. Consider therapy modification

Alpha2-Agonists: Beta-Blockers may enhance the rebound hypertensive effect of Alpha2-Agonists. This effect can occur when the alpha₂-agonist is abruptly withdrawn. Exceptions: Apraclonidine; Brimonidine. Consider therapy modification

Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Consider therapy modification

Aminoquinolines (Antimalarial): May decrease the metabolism of Beta-Blockers. Monitor therapy

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. Monitor therapy

Anilidopiperidine Opioids: May enhance the bradycardic effect of Beta-Blockers. Anilidopiperidine Opioids may enhance the hypotensive effect of Beta-Blockers. Monitor therapy

Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Monitor therapy

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

ARIPiprazole: CYP2D6 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult product labeling for specific recommendations. Monitor therapy

Barbiturates: May decrease the serum concentration of Beta-Blockers. 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. Monitor therapy

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

Calcium Channel Blockers (Dihydropyridine): May enhance the hypotensive effect of Beta-Blockers. Bradycardia and signs of heart failure have also been reported. Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May enhance the hypotensive effect of Beta-Blockers. Bradycardia and signs of heart failure have also been reported. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Beta-Blockers. Exceptions: Bepridil [Off Market]. Monitor therapy

Cardiac Glycosides: Beta-Blockers may enhance the bradycardic effect of Cardiac Glycosides. Monitor therapy

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. Management: Administer these agents in combination with caution, and monitor for conduction disturbances. Avoid methacholine with any beta blocker due to the potential for additive bronchoconstriction. Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Consider therapy modification

Darunavir: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Antihypertensives. Monitor therapy

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

Disopyramide: May enhance the bradycardic effect of Beta-Blockers. 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. Consider therapy modification

Fingolimod: Beta-Blockers may enhance the bradycardic effect of Fingolimod. Monitor therapy

Floctafenine: May enhance the adverse/toxic effect of Beta-Blockers. Avoid combination

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Monitor therapy

Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive Agents. Monitor therapy

Insulin: Beta-Blockers may enhance the hypoglycemic effect of Insulin. Monitor therapy

Lidocaine: Beta-Blockers may increase the serum concentration of Lidocaine. Monitor therapy

Lidocaine (Systemic): Beta-Blockers may decrease the metabolism of Lidocaine (Systemic). Monitor therapy

Lidocaine (Topical): Beta-Blockers may decrease the metabolism of Lidocaine (Topical). Monitor therapy

MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Monitor therapy

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

Methacholine: Beta-Blockers may enhance the adverse/toxic effect of Methacholine. Avoid combination

Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Monitor therapy

Midodrine: Beta-Blockers may enhance the bradycardic effect of Midodrine. Monitor therapy

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

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

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Monitor therapy

Propafenone: May increase the serum concentration of Beta-Blockers. Propafenone possesses some independent beta blocking activity. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Monitor therapy

QuiNIDine: May decrease the metabolism of Beta-Blockers. Monitor therapy

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

Rifamycin Derivatives: May decrease the serum concentration of Beta-Blockers. Exceptions: Rifabutin. Monitor therapy

RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Consider therapy modification

Selective Serotonin Reuptake Inhibitors: May increase the serum concentration of Beta-Blockers. Exceptions: Citalopram; Escitalopram; FluvoxaMINE. 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. Monitor therapy

Theophylline Derivatives: Beta-Blockers (Beta1 Selective) may diminish the bronchodilatory effect of Theophylline Derivatives. Management: Monitor for reduced theophylline efficacy during concomitant use with any beta-blocker. Beta-1 selective agents are less likely to antagonize theophylline than nonselective agents, but selectivity may be lost at higher doses. Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Monitor therapy

Adverse Reactions

Frequency may not be defined.

Cardiovascular: Hypotension (1% to 27%), bradycardia (2% to 16%), first-degree heart block (P-R interval ≥0.26 sec; 5%), arterial insufficiency (usually Raynaud type; 1%), chest pain (1%), CHF (1%), edema (peripheral; 1%), palpitation (1%), syncope (1%)

Central nervous system: Dizziness (2% to 10%), fatigue (1% to 10%), depression (5%), confusion, hallucinations, headache, insomnia, memory loss (short-term), nightmares, sleep disturbances, somnolence, vertigo

Dermatology: Pruritus (5%), rash (5%), photosensitivity, psoriasis exacerbated

Endocrine & metabolic: Libido decreased, Peyronie’s disease (<1%), diabetes exacerbated

Gastrointestinal: Diarrhea (5%), constipation (1%), flatulence (1%), gastrointestinal pain (1%), heartburn (1%), nausea (1%), xerostomia (1%), vomiting

Hematologic: Claudication

Neuromuscular & skeletal: Musculoskeletal pain

Ocular: Blurred vision, visual disturbances

Otic: Tinnitus

Respiratory: Dyspnea (1% to 3%), bronchospasm (1%), wheezing (1%), rhinitis, shortness of breath

Miscellaneous: Cold extremities (1%)

Postmarketing and/or case reports: Agranulocytosis, alkaline phosphatase increased, alopecia (reversible), anxiety, arthralgia, arthritis, cardiogenic shock, diaphoresis increased, dry eyes, gangrene, hepatitis, HDL decreased, impotence, jaundice, lactate dehydrogenase increased, nervousness, paresthesia, retroperitoneal fibrosis, second-degree heart block, taste disturbance, third-degree heart block, thrombocytopenia, transaminases increased, triglycerides increased, urticaria, vomiting, weight gain

Other events reported with beta-blockers: Catatonia, emotional lability, fever, hypersensitivity reactions, laryngospasm, nonthrombocytopenic purpura, respiratory distress, thrombocytopenic purpura

Precautions

Boxed warnings:

• Abrupt withdrawal: See “Other warnings/precautions” below.

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.

• Atrioventricular (AV) block: Metoprolol commonly produces mild first-degree heart block (P-R interval >0.2-0.24 sec). Metoprolol may also produce severe first- (P-R interval ≥0.26 sec), second-, or third-degree heart block. Patients with acute myocardial infarction (especially right ventricular myocardial infarction) have a high risk of developing heart block of varying degrees. If severe heart block occurs, metoprolol should be discontinued and measures to increase heart rate should be employed.

• Hypotension: Symptomatic hypotension may occur with use.

Disease-related concerns:

• Bronchospastic disease: In general, patients with bronchospastic disease should not receive beta-blockers; however, metoprolol, with B₁ selectivity, has been used cautiously with close monitoring.

• Conduction abnormality: Consider pre-existing conditions such as sick sinus syndrome before initiating.

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

• Heart failure: Use with caution in patients with compensated heart failure; monitor for a worsening of heart failure (only the extended release product is indicated for use in heart failure).

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

• Myasthenia gravis: Use with caution in patients with myasthenia gravis.

• Peripheral vascular disease (PVD) and Raynaud's disease: Can precipitate or aggravate symptoms of arterial insufficiency in patients with PVD and Raynaud's 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.

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

• Psychiatric disease: Use with caution in patients with a history of psychiatric illness; may cause or exacerbate CNS depression.

• 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.

Concurrent drug therapy issues:

• Calcium channel blockers (nondihydropyridines): Use with caution in patients on concurrent verapamil or diltiazem; bradycardia or heart block can occur. Avoid concurrent I.V. use of both agents.

• Cardiac glycosides: Use with caution in patients receiving digoxin; bradycardia or heart block can occur.

• CYP2D6 inhibitors: Use with caution in patients receiving CYP2D6 inhibitors (eg, bupropion, chlorpromazine, cimetidine, diphenhydramine, hydroxychloroquine, fluoxetine, paroxetine, propafenone, propoxyphene, quinidine, ritonavir, terbinafine, thioridazine); concurrent use may increase metoprolol plasma concentrations.

• Inhaled anesthetic agents: Use with caution in patients receiving inhaled anesthetic agents known to depress myocardial contractility.

Special populations:

• Elderly: Bradycardia may be observed more frequently in elderly patients (>65 years of age); dosage reductions may be necessary.

Dosage form specific issues:

• Extended release: Use care in compensated heart failure and monitor closely for a worsening of the condition. May need to increase diuretics and wait until clinically stable to advance dose to target.

Other warnings/precautions:

• Abrupt withdrawal: [U.S. Boxed Warning]: Beta-blocker therapy should not be withdrawn abruptly (particularly in patients with CAD), but gradually tapered over 1-2 weeks to avoid acute tachycardia, hypertension, and/or ischemia. Severe exacerbation of angina, ventricular arrhythmias, and myocardial infarction (MI) have been reported following abrupt withdrawal of beta-blocker therapy. Temporary but prompt resumption of beta-blocker therapy may be indicated with worsening of angina or acute coronary insufficiency.

• Major surgery: Although perioperative beta-blocker therapy is recommended prior to elective surgery in selected patients, use of high-dose extended release metoprolol in patients naïve to beta-blocker therapy undergoing noncardiac surgery has been associated with bradycardia, hypotension, stroke, and death. Chronic beta-blocker therapy should not be routinely withdrawn prior to major surgery.

Monitoring
Acute cardiac treatment: Monitor ECG and blood pressure with I.V. administration; heart rate and blood pressure with oral administration. I.V. 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.

Pregnancy Risk Factor
C

Pregnancy Considerations
Adverse events were observed in animal studies; therefore, the manufacturer classifies metoprolol as pregnancy category C. Metoprolol crosses the placenta and can be detected in cord blood, amniotic fluid, and the serum of newborn infants. In a cohort study, an increased risk of cardiovascular defects was observed following maternal use of beta-blockers during pregnancy. Intrauterine growth restriction (IUGR), small placentas, as well as fetal/neonatal bradycardia, hypoglycemia, and/or respiratory depression have been observed following in utero exposure to beta-blockers as a class. Adequate facilities for monitoring infants at birth should be available. Untreated chronic maternal hypertension and pre-eclampsia are also associated with adverse events in the fetus, infant, and mother. The clearance of metoprolol is increased and serum concentrations and AUC of metoprolol are decreased during pregnancy. Metoprolol has been evaluated for the treatment of hypertension in pregnancy, but other agents may be more appropriate for use.

Lactation
Enters breast milk/use caution (AAP rates “compatible”; AAP 2001 update pending)

Action

Distribution
V_d: 5.5 L/kg

Excretion
Urine (<5% to 10% as unchanged drug)

Duration
Oral: Immediate release: 10-20 hours, Extended release: ~24 hours; I.V.: 5-8 hours

Patient and Family Education

I.V. use in emergency situations: Patient information is appropriate to patient condition.

Oral: Take pulse daily prior to medication and follow prescriber's instruction about holding medication. Do not skip doses. If you have diabetes, monitor serum sugar closely; drug may alter glucose tolerance or mask signs of hypoglycemia. May cause fatigue, dizziness, postural hypotension, or alteration in sexual performance (reversible). Report unresolved swelling of extremities, respiratory difficulty or new cough, unresolved fatigue, unusual weight gain, unresolved constipation, change in color of urine or stool, unusual bleeding or bruising, or unusual muscle weakness. Patient may notice an empty shell of medicine in toilet.