Metoprolol Succinate

The following adverse reactions are described elsewhere in labeling:

• Worsening angina or myocardial infarction [see WARNINGS AND PRECAUTIONS].
• Worsening heart failure [see WARNINGS AND PRECAUTIONS].
• Worsening AV block [see CONTRAINDICATIONS].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Most adverse reactions have been mild and transient. The most common ( > 2%) adverse reactions are tiredness, dizziness, depression, diarrhea, shortness of breath, bradycardia, and rash.

In the MERIT-HF study comparing TOPROL-XL in daily doses up to 200 mg (mean dose 159 mg once-daily; n=1990) to placebo (n=2001), 10.3% of TOPROL-XL patients discontinued for adverse reactions vs. 12.2% of placebo patients.

The table below lists adverse reactions in the MERIT-HF study that occurred at an incidence of ≥ 1% in the TOPROL-XL group and greater than placebo by more than 0.5%, regardless of the assessment of causality.

Adverse Reactions Occurring in the MERIT-HF Study at an Incidence ≥ 1% in the TOPROL-XL Group and Greater Than Placebo by More Than 0.5%

In a randomized, double-blind, placebo-controlled trial of 8351 patients with or at risk for atherosclerotic disease undergoing non-vascular surgery and who were not taking beta–blocker therapy, TOPROL-XL 100 mg was started 2 to 4 hours prior to surgery then continued for 30 days at 200 mg per day. TOPROL-XL use was associated with a higher incidence of bradycardia (6.6% vs. 2.4%; HR, 2.74; 95% CI 2.19, 3.43), hypotension (15% vs. 9.7%; HR 1.55; 95% CI 1.37, 1.74), stroke (1.0% vs. 0.5%; HR 2.17; 95% CI 1.26, 3.74) and death (3.1% vs. 2.3%; HR 1.33; 95% CI 1.03, 1.74) compared to placebo.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of TOPROL-XL or immediate-release metoprolol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular: Cold extremities, arterial insufficiency (usually of the Raynaud type), palpitations, peripheral edema, syncope, chest pain and hypotension.

Respiratory: Wheezing (bronchospasm), dyspnea.

Central Nervous System: Confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety/nervousness, hallucinations, paresthesia.

Gastrointestinal: Nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, vomiting.

Hypersensitive Reactions: Pruritus.

Miscellaneous: Musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, tinnitus, reversible alopecia, agranulocytosis, dry eyes, worsening of psoriasis, Peyronie’s disease, sweating, photosensitivity, taste disturbance.

In addition, there are adverse reactions not listed above that have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to TOPROL-XL.

Central Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, clouded sensorium, and decreased performance on neuropsychometrics.

Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.

Hypersensitive Reactions: Laryngospasm, respiratory distress.

Laboratory Test Findings

Clinical laboratory findings may include elevated levels of serum transaminase, alkaline phosphatase, and lactate dehydrogenase.

Advise patients to take TOPROL-XL regularly and continuously, as directed, preferably with or immediately following meals. If a dose is missed, the patient should take only the next scheduled dose (without doubling it). Patients should not interrupt or discontinue TOPROL-XL without consulting the physician.

Advise patients (1) to avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient's response to therapy with TOPROL-XL has been determined; (2) to contact the physician if any difficulty in breathing occurs; (3) to inform the physician or dentist before any type of surgery that he or she is taking TOPROL-XL.

Heart failure patients should be advised to consult their physician if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath.

Metoprolol may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Drinking alcohol can increase certain side effects of metoprolol.

• Angina
• Atrial Fibrillation (AF, AFib)
• Calcium Channel Blockers (CCBs)
• Heart Attack
• Hyperthyroidism
• Mitral Valve Prolapse (MVP)
• Palpitations
• Raynaud's Phenomenon
• Treatment with Beta Blockers

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).157 161 500 501

β-Adrenergic blocking agents (β-blockers) generally not preferred for initial management of hypertension, but may be considered in patients who have a compelling indication (e.g., prior MI, ischemic heart disease, heart failure) for their use or as add-on therapy in those who do not respond adequately to the preferred drug classes (ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, or thiazide diuretics).242 501 502 503 504 515 523 524 527

Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to β-blockers.229 230 233 265 266 500 501 504 However, diminished response to β-blockers is largely eliminated when administered concomitantly with a thiazide diuretic.500

Angina

Management of chronic stable angina pectoris.109 147

A component of the standard therapeutic measures in the management of unstable angina or non-ST-segment elevation/non-Q-wave MI.158 218 219

MI

Secondary prevention following acute MI to reduce the risk of reinfarction and mortality.109 123 124 126 127 144 158

Supraventricular Arrhythmias

Has been used in the treatment of supraventricular tachycardia† (SVT) (e.g., atrial flutter†, junctional tachycardia†, focal atrial tachycardia†, paroxysmal supraventricular tachycardia† [PSVT]).300 301

Vagal maneuvers and/or IV adenosine are considered first-line interventions for acute treatment of SVT when clinically indicated; if such measures are ineffective or not feasible, may consider an IV β-blocker.300 Oral β-blockers may be used for ongoing management.300 Although evidence of efficacy is limited, experts state that overall safety of β-adrenergic blockers warrants use.300

Used to slow ventricular rate in patients with atrial fibrillation or flutter.158 300 301

Ventricular Arrhythmias

β-Blockers have been used in patients with cardiac arrest precipitated by ventricular fibrillation† or pulseless VT†; however, routine administration after cardiac arrest is potentially harmful and not recommended.400

β-Blockers may be useful in the management of certain forms of polymorphic VT† (e.g., associated with acute ischemia).158 401

Heart Failure

Management of mild to moderately severe (NYHA class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin (in conjunction with other heart failure therapies [e.g., ACE inhibitors, diuretics, cardiac glycosides]).147 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 215 216 524 800 Used to increase survival and to reduce the risk of hospitalization.524 800

The American College of Cardiology Foundation (ACCF), AHA, and the Heart Failure Society of America (HFSA) recommend therapy with an ACE inhibitor, angiotensin II receptor antagonist, or angiotensin receptor-neprilysin inhibitor (ARNI) in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality in patients with symptomatic heart failure and reduced left ventricular ejection fraction (LVEF) (ACCF/AHA stage C heart failure).800

Initiate a clinical-trial proven β-blocker (carvedilol. bisoprolol, extended-release metoprolol succinate) to reduce the risk of death in patients with chronic heart failure; benefits shown with these β-blockers not considered indicative of a β-blocker class effect.524

Experts recommend that β-blockers be used in conjunction with ACE inhibitors in all patients with asymptomatic heart failure† (i.e., structural heart disease but no signs or symptoms; ACCF/AHA stage B heart failure) with reduced LVEF.524 800

Vascular Headache

Prophylaxis of migraine headache†; not recommended for the treatment of a migraine attack that has already started.231

General

• β1-Adrenergic blocking selectivity diminishes as dosage is increased.109 147

• If long-term therapy is discontinued, reduce dosage gradually over a period of 1–2 weeks.109 147 (See Abrupt Withdrawal of Therapy under Cautions.)

BP Monitoring and Treatment Goals

• Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.500 501

• When available, use evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) to determine target dosages; target dosages usually can be achieved within 2–4 weeks but may take up to several months.501

• Goal is to achieve and maintain optimal control of BP; individualize specific target BP based on consideration of multiple factors, including patient age and comorbidities, and currently available evidence from clinical studies.500 501

Administration

Administer orally109 147 or by IV injection.109

Oral Administration

Administer metoprolol tartrate conventional tablets daily as a single dose or in divided doses, with or immediately following meals.109

Administer metoprolol succinate extended-release tablets daily as a single dose.147

Extended-release tablets are scored and can be divided.147 However, swallow tablet or half tablet whole; do not chew or crush.147

When switching from conventional tablets to extended-release tablets, administer the same daily dosage.147

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Monitor heart rate, BP, and ECG during IV therapy.158

Discontinue IV therapy when therapeutic efficacy is achieved (e.g., slowing of ventricular rate in atrial fibrillation) or if systolic BP or heart rate declines to <100 mm Hg or 50 bpm, respectively.158 Discontinue therapy in patients with severe intolerance to IV therapy.109

Administer as a rapid IV injection.109 Administer over 1–2 minutes for the management of unstable angina or non-ST-segment elevation/non-Q-wave MI†.218

Dosage

Available as metoprolol tartrate and metoprolol succinate; dosage expressed in terms of the tartrate.109 147

Pediatric Patients

Some experts recommend an initial dosage of 1–2 mg/kg daily given in 2 divided doses.260 Increase dosage as necessary up to a maximum dosage of 6 mg/kg (up to 200 mg) daily given in 2 divided doses.260

Adults

JNC 8 expert panel recommends initial dosage of 50 mg daily and target dosage of 100–200 mg daily based on dosages used in randomized controlled studies; administer daily dosage in 1 or 2 divided doses.501

Conventional metoprolol tartrate tablets: Manufacturer states usual initial dosage is 100 mg daily in single or divided doses, either alone or in combination with a diuretic.600

Extended-release metoprolol succinate tablets: Manufacturer states usual initial dosage is 25–100 mg once daily.602

Increase dosage at weekly (or longer) intervals until optimum effect is achieved.600 602

If satisfactory BP response is not maintained throughout the day, larger doses, more frequent administration, or use of extended-release tablets may be required.a

If intolerable adverse effects occur, consider dosage reduction; if adverse effects worsen or fail to resolve, may need to discontinue and switch to another antihypertensive drug class.501

Manufacturer states fixed-combination preparation should not be used for initial antihypertensive therapy; administer each drug separately, then use the fixed combination if the optimum maintenance dosage corresponds to the ratio of drugs in the combination preparation.a

Initially, 100 mg given once daily (extended-release tablets) or in 2 divided doses daily (conventional tablets).109 147 Increase dosage at weekly intervals until optimum response is obtained or pronounced slowing of heart rate occurs.109 147

Usual maintenance dosage is 100–400 mg daily.109

Patients at high risk for ischemic events should receive IV loading dose followed by conversion to an oral regimen; oral therapy is recommended for lower risk patients.218 219

5 mg IV every 5 minutes up to a total of 15 mg.218 If IV dose is tolerated, 25–50 mg orally, initiated 15 minutes after the last IV dose and repeated every 6 hours for 48 hours, followed by 100 mg twice daily.218 Target resting heart rate is 50–60 bpm in the absence of dose-limiting adverse effects.218

As soon as clinical condition allows, administer oral therapy (conventional tablets) to patients who have contraindications to or do not tolerate IV therapy during the early phase of definite or suspected acute MI or to patients in whom therapy is delayed.a

2.5–5 mg IV every 2–5 minutes up to a total of 15 mg over 10–15 minutes.a If total IV dose is tolerated, 50 mg orally, initiated 15 minutes after the last IV dose and repeated every 6 hours for 48 hours, followed by 100 mg twice daily.109 If total IV dose is not tolerated, 25 or 50 mg (depending on the degree of intolerance) orally every 6 hours beginning 15 minutes after the last IV dose or as soon as clinical condition allows.109

100 mg twice daily for at least 3 months.109

2.5–5 mg IV over 2 minutes; may repeat up to 3 doses.301 Then, 25–100 mg orally twice daily (as metoprolol tartrate) or 50–400 mg once daily (as metoprolol succinate) for long-term control.301

Experts recommend initial IV dose of 2.5–5 mg over 2 minutes; may repeat after 10 minutes, up to a total of 3 doses.300

Usual oral maintenance dosage for ongoing treatment is 200 mg twice daily (as metoprolol tartrate) or 400 mg once daily (as metoprolol succinate).300

Initially, 25 mg (extended-release tablets) once daily in adults with NYHA class II heart failure.147 In patients with more severe heart failure, use an initial dosage of 12.5 mg (extended-release tablets) once daily.147 Double the dosage every 2 weeks to a dosage of 200 mg or until highest tolerated dosage is reached.147

Some experts recommend initiation of therapy with 12.5–25 mg (extended-release tablets) once daily.524 If tolerated, gradually titrate dosage upward (maximum dosage 200 mg once daily).524

If deterioration occurs during titration, increase dosage of concurrent diuretic147 and decrease dosage of metoprolol or temporarily discontinue metoprolol.147 524 Do not continue dosage titration until symptoms of worsening heart failure have stabilized.147 524 Initial difficulty in dosage titration should not preclude subsequent attempts to successfully titrate the dosage.147

Reduce dosage in patients with heart failure who experience symptomatic bradycardia (e.g., dizziness) or 2nd or 3rd degree heart block.147 524

Dosages of 50–300 mg daily have been used in clinical studies; usual effective dosage was 200 mg daily.231

Prescribing Limits

Pediatric Patients

Maximum 6 mg/kg (up to 200 mg) daily.260

Adults

Dosages >400 mg (extended-release tablets) and 450 mg (conventional tablets) daily have not been studied.600 602

Dosages >400 mg daily have not been studied.109 147

Maximum 15 mg over 15 minutes in patients with unstable angina or non-ST-segment elevation MI†.218

Maximum 15 mg over 10–15 minutes.a

Up to 200 mg daily.147

Special Populations

Hepatic Impairment

Elimination occurs mainly in the liver; dosage reductions may be necessary.109 a

Renal Impairment

Dosage adjustments are not required.109 147

Geriatric Patients

Cautious dosage selection recommended; initiate therapy at the lower end of the dosage range.147

Metabolized by CYP2D6.147 200 201 202 208 210 211

Drugs Affecting Hepatic Microsomal Enzymes

CYP2D6 inhibitors: Potential pharmacodynamic (increased β-adrenergic blockade, decreased cardioselectivity of metoprolol) and pharmacokinetic interaction (prolonged half-life and increased plasma concentrations of metoprolol).147 200 201 202 208 210 211

Specific Drugs

Absorption

Bioavailability

Metoprolol tartrate is rapidly and almost completely absorbed from the GI tract.109 After an oral dose (as conventional tablets), about 50% of the drug undergoes first-pass metabolism in the liver.109

Peak plasma concentrations are reached in about 90 minutes following a single oral dose as conventional tabletsa or 7 hours following administration as extended-release tablets.148

Steady-state oral bioavailability of extended-release tablets given once daily is about 77% of that of conventional tablets at corresponding dosages.147 148 Following oral administration as extended-release tablets, peak plasma metoprolol concentrations are about 25–50% of those attained after administration of conventional tablets.147

Plasma concentrations attained after IV administration are approximately twice those attained following oral administration.a

Onset

Reduction in systolic BP during exercise reported within 15 minutes after a single oral dose of metoprolol tartrate 50–80 mg; with chronic therapy, effect on systolic BP usually is maximal within 1 week.a

The extended-release tablets, given once daily, produce similar hypotensive effects as conventional tablets at similar dosages.147 148

Maximum β-adrenergic blocking activity occurs at 20 minutes after a 10-minute IV infusion.109

Duration

Reduction in systolic BP during exercise persisted for 6 hours following a single oral dose of metoprolol tartrate 50–80 mg.a Hypotensive effect of extended-release tablets may persist for 24 hours.147 Duration of β-adrenergic blocking effect is dose related.109

Following IV infusion of metoprolol tartrate 5 or 15 mg, β-adrenergic blocking activity persisted for approximately 5 or 8 hours, respectively.109

Food

Food does not affect bioavailability of extended-release tablets.147

When conventional tablets are administered with food, peak plasma concentrations are higher and the extent of absorption is increased.a

Distribution

Extent

Widely distributed into body tissues.a Concentrations in heart, liver, lungs, and saliva exceed plasma concentration.a Crosses the blood-brain barrier;147 concentration in CSF is about 78% of the simultaneous plasma concentration.a

Crosses the placenta.a

Concentration in milk is about 3–4 times the maternal plasma concentrations, but the actual amount distributed into milk appears to be very small.101 102

Plasma Protein Binding

11–12% (albumin).109

Elimination

Metabolism

Undergoes first-pass metabolism in the liver by CYP2D6 to inactive metabolites.109 147

Elimination Route

Excreted in urine, principally as metabolites.109

Half-life

3–4 hours.109

Special Populations

Half-life does not increase appreciably with impaired renal function.109

Half-life is about 7.6 hours in poor metabolizers of the drug.a Concomitant use of CYP2D6 inhibitors (see Drugs Affecting Hepatic Microsomal Enzymes under Interactions) in poor metabolizers will lead to increases in plasma metoprolol concentrations and a decrease in β1-selectivity.147

Metoprolol Succinate extended-release tablets are contraindicated in severe bradycardia, second or third degree heart block, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), and in patients who are hypersensitive to any component of this product.

Ischemic Heart Disease

Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing chronically administered Metoprolol Succinate extended-release, particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1 to 2 weeks and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, promptly reinstate Metoprolol Succinate extended-release, and take measures appropriate for the management of unstable angina. Warn patients not to interrupt therapy without their physician’s advice. Because coronary artery disease is common and may be unrecognized, avoid abruptly discontinuing Metoprolol Succinate extended-release in patients treated only for hypertension.

Heart Failure

Worsening cardiac failure may occur during up-titration of Metoprolol Succinate extended-release.  If such symptoms occur, increase diuretics and restore clinical stability before advancing the dose of Metoprolol Succinate extended-release [see Dosage and Administration (2)]. It may be necessary to lower the dose of Metoprolol Succinate extended-release or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of Metoprolol Succinate extended-release.

Bronchospastic Disease

PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of its relative beta1 cardio-selectivity, however, Metoprolol Succinate extended-release may be used in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Because beta1-selectivity is not absolute, use the lowest possible dose of Metoprolol Succinate extended-release. Bronchodilators, including beta2-agonists, should be readily available or administered concomitantly, [see Dosage and Administration (2)].

Pheochromocytoma

If Metoprolol Succinate extended-release is used in the setting of pheochromocytoma, it should be given in combination with an alpha blocker, and only after the alpha blocker has been initiated. Administration of beta-blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle.

Major Surgery

Avoid initiation of a high-dose regimen of extended release metoprolol in patients undergoing non-cardiac surgery, since such use in patients with cardiovascular risk factors has been associated with bradycardia, hypotension, stroke and death.

Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

Diabetes and Hypoglycemia 

Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.

Hepatic Impairment

Consider initiating Metoprolol Succinate extended-release therapy at doses lower than those recommended for a given indication; gradually increase dosage to optimize therapy, while monitoring closely for adverse events.

Thyrotoxicosis

Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may precipitate a thyroid storm.

Anaphylactic Reaction

While taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge and may be unresponsive to the usual doses of epinephrine used to treat an allergic reaction.

Peripheral Vascular Disease

Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.

Calcium Channel Blockers

Because of significant inotropic and chronotropic effects in patients treated with beta-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be exercised in patients treated with these agents concomitantly.