METOPROLOL SUCCINATE tablet, extended release

United States - English - NLM (National Library of Medicine)

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Active ingredient:
METOPROLOL SUCCINATE (UNII: TH25PD4CCB) (METOPROLOL - UNII:GEB06NHM23)
Available from:
Aphena Pharma Solutions - Tennessee, LLC
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Metoprolol succinate is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including metoprolol. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with differe
Product summary:
Tablets containing metoprolol succinate equivalent to the indicated weight of metoprolol tartrate, USP, are white, biconvex, film-coated, and scored. Tablet Shape Engraving Bottle of 100 NDC 50816- Bottle of 1000 NDC 50816- 25 mg Oval A/β 025-03 50 mg Round A/mo 050-03 100 mg Round A/ms 100-02 100-03 200 mg Oval A/my 200-02 200-03 Store at 25°C (77°F). Excursions permitted to 15-30°C (59- 86°F). (See USP Controlled Room Temperature.)
Authorization status:
New Drug Application Authorized Generic
Authorization number:
71610-496-45, 71610-496-60

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METOPROLOL SUCCINATE- metoprolol succinate tablet, extended release

Aphena Pharma Solutions - Tennessee, LLC

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use Metoprolol Succinate safely and effectively.

See full prescribing information for Metoprolol Succinate.

Metoprolol Succinate Tablet, Extended-Release for Oral Use

Initial U.S. Approval: 2006

WARNING: ISCHEMIC HEART DISEASE

(See Full Prescribing Information for complete boxed warning)

Following abrupt cessation of therapy with beta-blocking agents, exacerbations of angina pectoris and

myocardial infarction have occurred. Warn patients against interruption or discontinuation of therapy

without the physician’s advice. (5.1)

INDICATIONS AND USAGE

Metoprolol Succinate is a beta -selective adrenoceptor blocking agent.

Metoprolol Succinate is indicated for the treatment of:

DOSAGE AND ADMINISTRATION

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular

events, primarily strokes and myocardial infarctions. (1.1)

Angina Pectoris. (1.2)

Heart Failure - for the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive,

or cardiomyopathic origin. (1.3)

Administer once daily. Dosing of metoprolol succinate should be individualized. (2)

Heart Failure: Recommended starting dose is 12.5 mg or 25 mg doubled every two weeks to the highest dose

tolerated or up to 200 mg. (2.3)

Hypertension: Usual initial dosage is 25 to 100 mg once daily. The dosage may be increased at weekly (or longer)

intervals until optimum blood pressure reduction is achieved. Dosages above 400 mg per day have not been studied.

(2.1)

Angina Pectoris: Usual initial dosage is 100 mg once daily. Gradually increase the dosage at weekly intervals until

optimum clinical response has been obtained or there is an unacceptable bradycardia. Dosages above 400 mg per day

have not been studied. (2.2)

Switching from immediate-release metoprolol to metoprolol succinate extended-release tablet: use the same total

daily dose of metoprolol succinate extended-release tablet. (2)

Metoprolol Succinate Extended-Release Tablets: 25 mg, 50 mg, 100 mg and 200 mg. (3)

Known hypersensitivity to product components. (4)

Severe bradycardia. (4)

Heart block greater than first degree. (4)

Cardiogenic shock. (4)

Decompensated cardiac failure. (4)

Sick sinus syndrome without a pacemaker. (4)

Heart Failure: Worsening cardiac failure may occur. (5.2)

Bronchospastic Disease: Avoid beta blockers. (5.3)

Pheochromocytoma: If required, first initiate therapy with an alpha blocker. (5.4)

Major Surgery: Avoid initiation of high-dose extended-release metoprolol in patients undergoing non-cardiac surgery

ADVERSE REACTIONS

Most common adverse reactions: tiredness, dizziness, depression, shortness of breath, bradycardia, hypotension,

diarrhea, pruritus, rash. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Aralez Pharmaceuticals US, Inc. at 1-833-694-8235 or

FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

USE IN SPECIFIC POPULATIONS

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 10/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: ISCHEMIC HEART DISEASE:

1 INDICATIONS AND USAGE

1.1 Hypertension

1.2 Angina Pectoris

1.3 Heart Failure

2 DOSAGE AND ADMINISTRATION

2.1 Hypertension

2.2 Angina Pectoris

2.3 Heart Failure

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Ischemic Heart Disease

Major Surgery: Avoid initiation of high-dose extended-release metoprolol in patients undergoing non-cardiac surgery

because it has been associated with bradycardia, hypotension, stroke and death. Do not routinely withdraw chronic

beta blocker therapy prior to surgery. (5.5, 6.1)

Diabetes and Hypoglycemia: May mask tachycardia occurring with hypoglycemia. (5.6)

Patients with Hepatic Impairment: (5.7)

Thyrotoxicosis: Abrupt withdrawal in patients with thyrotoxicosis might precipitate a thyroid storm. (5.8)

Anaphylactic Reactions: Patients may be unresponsive to the usual doses of epinephrine used to treat allergic

reaction. (5.9)

Peripheral Vascular Disease: Can aggravate symptoms of arterial insufficiency. (5.10)

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. (5.11)

Catecholamine-depleting drugs may have an additive effect when given with beta-blocking agents. (7.1)

CYP2D6 Inhibitors are likely to increase metoprolol concentration. (7.2)

Concomitant use of glycosides, clonidine, and diltiazem and verapamil with beta-blockers can increase the risk of

bradycardia. (7.3)

Beta-blockers including metoprolol, may exacerbate the rebound hypertension that can follow the withdrawal of

clonidine. (7.3)

Pregnancy: There are no adequate and well-controlled studies in pregnant women. Use this drug during pregnancy

only if clearly needed. (8.1)

Nursing Mothers: Consider possible infant exposure. (8.3)

Pediatrics: Safety and effectiveness have not been established in patients < 6 years of age. (8.4)

Geriatrics: No notable difference in efficacy or safety vs. younger patients. (8.5)

Hepatic Impairment: Consider initiating metoprolol succinate therapy at low doses and gradually increase dosage to

optimize therapy, while monitoring closely for adverse events. (8.6)

5.2 Heart Failure

5.3 Bronchospastic Disease

5.4 Pheochromocytoma

5.5 Major Surgery

5.6 Diabetes and Hypoglycemia

5.7 Hepatic Impairment

5.8 Thyrotoxicosis

5.9 Anaphylactic Reaction

5.10 Peripheral Vascular Disease

5.11 Calcium Channel Blockers

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Post-Marketing Experience

6.3 Laboratory Test Findings

7 DRUG INTERACTIONS

7.1 Catecholamine Depleting Drugs

7.2 CYP2D6 Inhibitors

7.3 Digitalis, Clonidine, and Calcium Channel Blockers

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Angina Pectoris

14.2 Heart Failure

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

WARNING: 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 tablets,

particularly in patients with ischemic heart disease, the dosage should be gradually reduced

over a period of 1 - 2 weeks and the patient should be carefully monitored. If angina

markedly worsens or acute coronary insufficiency develops, metoprolol succinate

extended-release tablet administration should be reinstated promptly, at least temporarily,

and other measures appropriate for the management of unstable angina should be taken.

Warn patients against interruption or discontinuation of therapy without the physician’s

advice. Because coronary artery disease is common and may be unrecognized, it may be

prudent not to discontinue metoprolol succinate extended-release tablet therapy abruptly

even in patients treated only for hypertension (5.1).

1 INDICATIONS AND USAGE

1.1 Hypertension

Metoprolol succinate is indicated for the treatment of hypertension, to lower blood pressure. Lowering

blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and

myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs

from a wide variety of pharmacologic classes including metoprolol.

Control of high blood pressure should be part of comprehensive cardiovascular risk management,

including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation,

exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood

pressure goals. For specific advice on goals and management, see published guidelines, such as those

of the National High Blood Pressure Education Program’s Joint National Committee on Prevention,

Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different

mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular

morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other

pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and

most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions

in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk

increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe

hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is

similar across populations with varying absolute risk, so the absolute benefit is greater in patients who

are at higher risk independent of their hypertension (for example, patients with diabetes or

hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a

lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and

many antihypertensive drugs have additional approved indications and effects (e.g. on angina, heart

failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Metoprolol succinate extended-release tablet may be administered with other antihypertensive agents.

1.2 Angina Pectoris

Metoprolol succinate extended-release tablet is indicated in the long-term treatment of angina pectoris,

to reduce angina attacks and to improve exercise tolerance.

1.3 Heart Failure

Metoprolol succinate extended-release tablet is indicated for the treatment of stable, symptomatic

(NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. It was

studied in patients already receiving ACE inhibitors, diuretics, and, in the majority of cases, digitalis. In

this population, metoprolol succinate extended-release tablet decreased the rate of mortality plus

hospitalization, largely through a reduction in cardiovascular mortality and hospitalizations for heart

failure.

2 DOSAGE AND ADMINISTRATION

Metoprolol succinate extended-release tablets are intended for once daily administration. For treatment

of hypertension and angina, when switching from immediate-release metoprolol to metoprolol succinate

extended-release tablet, use the same total daily dose of metoprolol succinate extended-release tablet.

Individualize the dosage of metoprolol succinate extended-release tablets. Titration may be needed in

some patients.

Metoprolol succinate extended-release tablets are scored and can be divided; however, do not crush or

chew the whole or half tablet.

2.1 Hypertension

Adults: The usual initial dosage is 25 to 100 mg daily in a single dose. The dosage may be increased at

weekly (or longer) intervals until optimum blood pressure reduction is achieved. In general, the

maximum effect of any given dosage level will be apparent after 1 week of therapy. Dosages above 400

mg per day have not been studied.

Pediatric Hypertensive Patients ≥ 6 Years of age: A pediatric clinical hypertension study in patients 6 to

16 years of age did not meet its primary endpoint (dose response for reduction in SBP); however, some

other endpoints demonstrated effectiveness [see Use in Specific Populations (8.4)]. If selected for

treatment, the recommended starting dose of metoprolol succinate extended-release tablets is 1 mg/kg

once daily, but the maximum initial dose should not exceed 50 mg once daily. Dosage should be

adjusted according to blood pressure response. Doses above 2 mg/kg (or in excess of 200 mg) once

daily have not been studied in pediatric patients [see Clinical Pharmacology (12.3)].

Metoprolol succinate extended-release tablet is not recommended in pediatric patients < 6 years of age

[see Use in Specific Populations (8.4)].

2.2 Angina Pectoris

Individualize the dosage of metoprolol succinate extended-release tablets. The usual initial dosage is

100 mg daily, given in a single dose. Gradually increase the dosage at weekly intervals until optimum

clinical response has been obtained or there is a pronounced slowing of the heart rate. Dosages above

400 mg per day have not been studied. If treatment is to be discontinued, reduce the dosage gradually

over a period of 1 - 2 weeks [see Warnings and Precautions (5)].

2.3 Heart Failure

Dosage must be individualized and closely monitored during up-titration. Prior to initiation of

metoprolol succinate extended-release tablet, stabilize the dose of other heart failure drug therapy. The

recommended starting dose of metoprolol succinate extended-release tablet is 25 mg once daily for two

weeks in patients with NYHA Class II heart failure and 12.5 mg once daily in patients with more severe

heart failure. Double the dose every two weeks to the highest dosage level tolerated by the patient or

up to 200 mg of metoprolol succinate extended-release tablet. Initial difficulty with titration should not

preclude later attempts to introduce metoprolol succinate extended-release tablet. If patients experience

symptomatic bradycardia, reduce the dose of metoprolol succinate extended-release tablet. If transient

worsening of heart failure occurs, consider treating with increased doses of diuretics, lowering the

worsening of heart failure occurs, consider treating with increased doses of diuretics, lowering the

dose of metoprolol succinate extended-release tablet or temporarily discontinuing it. The dose of

metoprolol succinate extended-release tablet should not be increased until symptoms of worsening heart

failure have been stabilized.

3 DOSAGE FORMS AND STRENGTHS

25 mg tablets White, oval, biconvex, film-coated scored tablet engraved with “A/β”.

50 mg tablets: White, round, biconvex, film-coated scored tablet engraved with “A/mo”.

100 mg tablets: White, round, biconvex, film-coated scored tablet engraved with “A/ms”.

200 mg tablets: White, oval, biconvex, film-coated scored tablet engraved with “A/my”.

4 CONTRAINDICATIONS

Metoprolol succinate extended-release tablet is 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.

5 WARNINGS AND PRECAUTIONS

5.1 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 tablets, particularly in patients with ischemic heart

disease, gradually reduce the dosage over a period of 1 - 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 in patients treated only for

hypertension.

5.2 Heart Failure

Worsening cardiac failure may occur during up-titration of metoprolol succinate extended-release

tablets. If such symptoms occur, increase diuretics and restore clinical stability before advancing the

dose of metoprolol succinate extended-release tablets [see Dosage and Administration (2)]. It may be

necessary to lower the dose of metoprolol succinate extended-release tablet or temporarily discontinue

it. Such episodes do not preclude subsequent successful titration of metoprolol succinate extended-

release tablets.

5.3 Bronchospastic Disease

PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE

BETA-BLOCKERS. Because of its relative beta cardio-selectivity, however, metoprolol succinate

extended-release tablet may be used in patients with bronchospastic disease who do not respond to, or

cannot tolerate, other antihypertensive treatment. Because beta -selectivity is not absolute, use the

lowest possible dose of metoprolol succinate extended-release tablets. Bronchodilators, including

beta -agonists, should be readily available or administered concomitantly [see Dosage and

Administration (2)].

5.4 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.

5.5 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.

5.6 Diabetes and Hypoglycemia

Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as

dizziness and sweating may not be significantly affected.

5.7 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.

5.8 Thyrotoxicosis

Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism, such as tachycardia.

Abrupt withdrawal of beta-blockade may precipitate a thyroid storm.

5.9 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.

5.10 Peripheral Vascular Disease

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

vascular disease.

5.11 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.

6 ADVERSE REACTIONS

The following adverse reactions are described elsewhere in labeling:

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

Worsening angina or myocardial infarction. [see Warnings and Precautions (5)]

Worsening heart failure. [see Warnings and Precautions (5)]

Worsening AV block. [see Contraindications (4)]

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.

Hypertension and Angina: 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.

Heart Failure: In the MERIT-HF study comparing metoprolol succinate extended-release tablets in

daily doses up to 200 mg (mean dose 159 mg once-daily; n=1990) to placebo (n=2001), 10.3% of

metoprolol succinate extended-release tablet 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 metoprolol succinate extended-release tablet 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 Metoprolol

Succinate Extended-Release Tablet Group and Greater Than Placebo by More Than 0.5 %

Metoprolol Succinate Extended-release Tablets

n=1990 % of patients

Placebo

n=2001 % of patients

Dizziness/vertigo

Bradycardia

Accident and/or injury

Post-operative Adverse Events: 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, metoprolol succinate extended-release 100 mg was started 2 to 4 hours

prior to surgery then continued for 30 days at 200 mg per day. Metoprolol succinate extended-release

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.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of metoprolol succinate

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.

Potential Adverse Reactions: 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 metoprolol succinate.

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.

6.3 Laboratory Test Findings

Clinical laboratory findings may include elevated levels of serum transaminase, alkaline phosphatase,

and lactate dehydrogenase.

7 DRUG INTERACTIONS

7.1 Catecholamine Depleting Drugs

Catecholamine depleting drugs (e.g. reserpine, monoamine oxidase (MAO) inhibitors) may have an

additive effect when given with beta-blocking agents. Observe patients treated with metoprolol

succinate extended-release tablets plus a catecholamine depletor for evidence of hypotension or marked

bradycardia, which may produce vertigo, syncope, or postural hypotension.

7.2 CYP2D6 Inhibitors

Drugs that inhibit CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone are likely to

increase metoprolol concentration. In healthy subjects with CYP2D6 extensive metabolizer phenotype,

coadministration of quinidine 100 mg and immediate-release metoprolol 200 mg tripled the

concentration of S-metoprolol and doubled the metoprolol elimination half-life. In four patients with

cardiovascular disease, coadministration of propafenone 150 mg t.i.d. with immediate-release

metoprolol 50 mg t.i.d. resulted in two- to five-fold increases in the steady-state concentration of

metoprolol. These increases in plasma concentration would decrease the cardioselectivity of

metoprolol.

7.3 Digitalis, Clonidine, and Calcium Channel Blockers

Digitalis glycosides, clonidine, diltiazem and verapamil slow atrioventricular conduction and decrease

heart rate. Concomitant use with beta blockers can increase the risk of bradycardia.

If clonidine and a beta blocker, such as metoprolol are coadministered, withdraw the beta-blocker

several days before the gradual withdrawal of clonidine because beta-blockers may exacerbate the

rebound hypertension that can follow the withdrawal of clonidine. If replacing clonidine by beta-

blocker therapy, delay the introduction of beta-blockers for several days after clonidine administration

has stopped [see Warnings and Precautions (5.11)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

Metoprolol tartrate has been shown to increase post-implantation loss and decrease neonatal survival in

rats at doses up to 22 times, on a mg/m basis, the daily dose of 200 mg in a 60-kg patient. Distribution

studies in mice confirm exposure of the fetus when metoprolol tartrate is administered to the pregnant

animal. These studies have revealed no evidence of impaired fertility or teratogenicity. There are no

adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not

always predictive of human response, use this drug during pregnancy only if clearly needed.

8.3 Nursing Mothers

Metoprolol is excreted in breast milk in very small quantities. An infant consuming 1 liter of breast milk

daily would receive a dose of less than 1 mg of the drug. Consider possible infant exposure when

metoprolol succinate is administered to a nursing woman.

8.4 Pediatric Use

One hundred forty-four hypertensive pediatric patients aged 6 to 16 years were randomized to placebo

or to one of three dose levels of metoprolol succinate extended-release tablets (0.2, 1.0 or 2.0 mg/kg

once daily) and followed for 4 weeks. The study did not meet its primary endpoint (dose response for

reduction in SBP). Some pre-specified secondary endpoints demonstrated effectiveness including:

The mean placebo corrected reductions in SBP ranged from 3 to 6 mmHg, and DBP from 1 to 5 mmHg.

Mean reduction in heart rate ranged from 5 to 7 bpm but considerably greater reductions were seen in

some individuals [see Dosage and Administration (2.1)].

No clinically relevant differences in the adverse event profile were observed for pediatric patients

aged 6 to 16 years as compared with adult patients.

Safety and effectiveness of metoprolol succinate extended-release tablets have not been established in

patients < 6 years of age.

8.5 Geriatric Use

Clinical studies of metoprolol succinate extended-release tablets in hypertension did not include

sufficient numbers of subjects aged 65 and over to determine whether they respond differently from

younger subjects. Other reported clinical experience in hypertensive patients has not identified

differences in responses between elderly and younger patients.

Of the 1,990 patients with heart failure randomized to metoprolol succinate extended-release tablets in

the MERIT-HF trial, 50% (990) were 65 years of age and older and 12% (238) were 75 years of age

and older. There were no notable differences in efficacy or the rate of adverse reactions between older

and younger patients.

In general, use a low initial starting dose in elderly patients given their greater frequency of decreased

hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

No studies have been performed with metoprolol succinate extended-release tablets in patients with

hepatic impairment. Because metoprolol succinate is metabolized by the liver, metoprolol blood levels

are likely to increase substantially with poor hepatic function. Therefore, initiate therapy at doses lower

than those recommended for a given indication; and increase doses gradually in patients with impaired

hepatic function.

8.7 Renal Impairment

The systemic availability and half-life of metoprolol in patients with renal failure do not differ to a

clinically significant degree from those in normal subjects. No reduction in dosage is needed in patients

with chronic renal failure [see Clinical Pharmacology (12.3)].

Dose-response for reduction in DBP,

1 mg/kg vs. placebo for change in SBP, and

2 mg/kg vs. placebo for change in SBP and DBP.

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