METOPROLOL TARTRATE- metoprolol tablet

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

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Active ingredient:
METOPROLOL TARTRATE (UNII: W5S57Y3A5L) (METOPROLOL - UNII:GEB06NHM23)
Available from:
Alembic Pharmaceuticals Limited
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Hypertension Metoprolol tartrate tablets are indicated for the treatment of hypertension. They may be used alone or in combination with other antihypertensive agents. Angina Pectoris Metoprolol tartrate tablets are indicated in the long-term treatment of angina pectoris. Myocardial Infarction Metoprolol tartrate tablets are indicated in the treatment of hemodynamically stable patients with definite or suspected acute myocardial infarction to reduce cardiovascular mortality when used alone or in conjunction with intravenous metoprolol. Oral metoprolol therapy can be initiated after intravenous metoprolol therapy or, alternatively, oral treatment can begin within 3 to 10 days of the acute event (see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS. Hypertension and Angina Metoprolol tartrate tablets are contraindicated in sinus bradycardia, heart block greater than first degree, cardiogenic shock, and overt cardiac failure (see WARNINGS). Hypersensitivity to metoprolol and related deriv
Product summary:
Metoprolol Tartrate Tablets, USP are available containing 25 mg, 50 mg or 100 mg of metoprolol tartrate, USP. The 25 mg tablets are white to off white film coated, round, biconvex tablets debossed with ‘L150’ on one side and breakline on other side. They are available as follows:   NDC 46708-290-30      bottles of 30 tablets NDC 46708-290-31      bottles of 100 tablets NDC 46708-290-71      bottles of 500 tablets NDC 46708-290-91      bottles of 1000 tablets NDC 46708-290-10      100 (10 x 10) Tablets Unit-dose blisters   The 50 mg tablets are pink, film coated, round, biconvex tablets debossed with ‘L151’ on one side and breakline on other side. They are available as follows: NDC 46708-291-30      bottles of 30 tablets NDC 46708-291-31      bottles of 100 tablets NDC 46708-291-91      bottles of 1000 tablets NDC 46708-291-10      100 (10 x 10) Tablets Unit-dose blisters   The 100 mg tablets are blue, film coated, round, biconvex tablets debossed with ‘L152’ on one side and breakline on other side. They are available as follows: NDC 46708-292-30      bottles of 30 tablets NDC 46708-292-31      bottles of 100 tablets NDC 46708-292-91      bottles of 1000 tablets NDC 46708-292-10      100 (10 x 10) Tablets Unit-dose blisters   Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from moisture.   Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Manufactured by: Alembic Pharmaceuticals Limited (Formulation Division), Village Panelav, P. O. Tajpura, Near Baska, Taluka-Halol, Panchmahal, Gujarat, India. Revised: 06/2013
Authorization status:
Abbreviated New Drug Application
Authorization number:
46708-290-10, 46708-290-30, 46708-290-31, 46708-290-71, 46708-290-91, 46708-291-10, 46708-291-30, 46708-291-31, 46708-291-91, 46708-292-10, 46708-292-30, 46708-292-31, 46708-292-91

METOPROLOL TARTRATE - metoprolol tablet

Alembic Pharmaceuticals Limited

----------

Metoprolol Tartrate Tablets USP

Rx Only

Prescribing Information

DESCRIPTION

Metoprolol tartrate, USP is a selective beta1-adrenoreceptor blocking agent, available as 25 mg, 50 mg

and 100 mg tablets for oral administration. Metoprolol tartrate USP is (±)-1-(Isopropylamino)-3-[p-2-

methoxyethyl)phenoxy]-2-propanol L-(+)-tartrate (2:1) salt, its structural formula is:

Metoprolol tartrate USP is a white, practically odorless, crystalline powder with a molecular weight of

684.82. It is very soluble in water; freely soluble in methylene chloride, in chloroform, and in alcohol;

slightly soluble in acetone; and insoluble in ether.

Each tablet for oral administration contains 25 mg, 50 mg or 100 mg of metoprolol tartrate and the

following inactive ingredients: microcrystalline cellulose, lactose monohydrate, povidone,

croscarmellose sodium, colloidal silicon dioxide, magnesium stearate hypromellose, titanium dioxide

and polyethylene glycol. In addition, the 50 mg product contains D&C Red No. 30 Aluminum Lake and

the 100 mg product contains FD&C Blue No. 2 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake

as coloring agents.

CLINICAL PHARMACOLOGY

Mechanism of Action:

Metoprolol tartrate is a beta1- selective (cardioselective) adrenergic receptor blocker. This

preferential effect is not absolute, however, and at higher plasma concentrations, metoprolol also

inhibits beta2- adrenoreceptors, chiefly located in the bronchial and vascular musculature.

Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in man, as

shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of

systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4)

reduction of reflex orthostatic tachycardia.

Hypertension

The mechanism of the antihypertensive effects of beta-blocking agents has not been fully

elucidated.However, several possible mechanisms have been proposed: (1) competitive antagonism of

catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leadingto decreased cardiac

output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and (3) suppression

of renin activity.

Angina Pectoris

By blocking catecholamine-induced increases in heart rate, in velocity and extent of myocardial

contraction, and in blood pressure, metoprolol reduces the oxygen requirements of the heart at any

given level of effort, thus making it useful in the long-term management of angina pectoris.

Myocardial Infarction

The precise mechanism of action of metolrolol in patients with suspected or definite myocardial

infarction is not known.

Pharmacodynamics

Relative beta1 selectivity is demonstrated by the following: (1) In healthy subjects, metoprolol is unable

to reverse the beta2-mediated vasodilating effects of epinephrine. This contrasts with the effect of

nonselective (beta1 plus beta2) beta blockers, which completely reverse the vasodilating effects of

epinephrine. (2) In asthmatic patients, metoprolol reduces FEV1 and FVC significantly less than a

nonselective beta-blocker, propranolol, at equivalent beta1-receptor blocking doses.

Metoprolol has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable

only at doses much greater than required for beta-blockade. Animal and human experiments indicate that

metoprolol slows the sinus rate and decreases AV nodal conduction.

Significant beta-blocking effect (as measured by reduction of exercise heart rate) occurs within 1 hour

after oral administration, and its duration is dose-related. For example, a 50% reduction of the maximum

effect after single oral doses of 20, 50, and 100 mg occurred at 3.3, 5, and 6.4 hours, respectively, in

normal subjects. After repeated oral dosages of 100 mg twice daily, a significant reduction in exercise

systolic blood pressure was evident at 12 hours. When the drug was infused over a 10-minute period, in

normal volunteers, maximum beta blockade was achieved at approximately 20 minutes. Equivalent

maximal beta-blocking effect is achieved with oral and intravenous doses in the ratio of approximately

2.5:1.

There is a linear relationship between the log of plasma levels and reduction of exercise heart rate.

However, antihypertensive activity does not appear to be related to plasma levels. Because of variable

plasma levels attained with a given dose and lack of a consistent relationship of antihypertensive activity

to dose, selection of proper dosage requires individual titration.

In several studies of patients with acute myocardial infarction, intravenous followed by oral

administration of metoprolol caused a reduction in heart rate, systolic blood pressure and cardiac

output. Stroke volume, diastolic blood pressure and pulmonary artery end diastolic pressure remained

unchanged.

In patients with angina pectoris, plasma concentration measured at 1 hour is linearly related to the oral

dose within the range of 50 to 400 mg. Exercise heart rate and systolic blood pressure are reduced in

relation to the logarithm of the oral dose of metoprolol. The increase in exercise capacity and the

reduction in left ventricular ischemia are also significantly related to the logarithm of the oral dose.

Pharmacokinetics

Absorption: The estimated oral bioavailability of immediate release metoprolol is about 50% because

of pre-systemic metabolism which is saturable leading to non-proportionate increase in the exposure

with increased dose.

Distribution: Metoprolol is extensively distributed with a reported volume of distribution of 3.2 to 5.6

L/kg. About 10% of metoprolol in plasma is bound to serum albumin. Metoprolol is known to cross the

placenta and is found in breast milk. Metoprolol is also known to cross the blood brain barrier

following oral administration and CSF concentrations close to that observed in plasma have been

reported. Metoprolol is not a significant P-glycoprotein substrate

Metabolism: Metoprolol is primarily metabolized by CYP2D6. Metoprolol is a racemic mixture of R-

and S- enantiomers, and when administered orally, it exhibits stereoselective metabolism that is

dependent on oxidation phenotype. CYP2D6 is absent (poor metabolizers) in about 8% of Caucasians

and about 2% of most other populations. Poor CYP2D6 metabolizers exhibit several-fold higher plasma

concentrations of metoprolol than extensive metabolizers with normal CYP2D6 activity thereby

decreasing metoprolol’s cardioselectivity.

Elimination: Elimination of metoprolol is mainly by biotransformation in the liver. The mean elimination

half-life of metoprolol is 3 to 4 hours; in poor CYP2D6 metabolizers the half-life may be 7 to 9 hours.

Approximately 95% of the dose can be recovered in urine. In most subjects (extensive metabolizers),

less than 5% of an oral dose are excreted as unchanged drug in the urine. In poor metabolizers, up to

30% of oral doses,may be excreted unchanged; the rest is excreted by the kidneys as metabolites that

appear to have no beta blocking activity. The renal clearance of the stereo-isomers does not exhibit

stereo-selectivity in renal excretion.

Special populations

Geriatric patients: The geriatric population may show slightly higher plasma concentrations of

metoprolol as a combined result of a decreased metabolism of the drug in elderly population and a

decreased hepatic blood flow. However, this increase is not clinically significant or therapeutically

relevant.

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.

Hepatic Impairment: Since the drug is primarily eliminated by hepatic metabolism, hepatic impairment

may impact the pharmacokinetics of metoprolol. The elimination half-life of metoprolol is considerably

prolonged, depending on severity (up to 7.2 h).

Clinical Studies:

Hypertension

In controlled clinical studies, metoprolol has been shown to be an effective antihypertensive agent when

used alone or as concomitant therapy with thiazide-type diuretics, at dosages of 100 to 450 mg daily. In

controlled, comparative, clinical studies, metoprolol has been shown to be as effective an

antihypertensive agent as propranolol, methyldopa, and thiazide-type diuretics, to be equally effective in

supine and standing positions.

Angina Pectoris

In controlled clinical trials, metoprolol, administered two or four times daily, has been shown to be an

effective antianginal agent, reducing the number of angina attacks and increasing exercise tolerance.

The dosage used in these studies ranged from 100 to 400 mg daily. A controlled, comparative, clinical

trial showed that metoprolol was indistinguishable from propranolol in the treatment of angina pectoris.

Myocardial Infarction

In a large (1,395 patients randomized), double-blind, placebo-controlled clinical study, metoprolol was

shown to reduce 3-month mortality by 36% in patients with suspected or definite myocardial infarction.

Patients were randomized and treated as soon as possible after their arrival in the hospital, once their

clinical condition had stabilized and their hemodynamic status had been carefully evaluated. Subjects

were ineligible if they had hypotension, bradycardia, peripheral signs of shock, and/or more than

minimal basal rales as signs of congestive heart failure. Initial treatment consisted of intravenous

followed by oral administration of metoprolol or placebo, given in a coronary care or comparable unit.

Oral maintenance therapy with metoprolol or placebo was then continued for 3 months. After this

double-blind period, all patients were given metoprolol and followed up to 1 year.

The median delay from the onset of symptoms to the initiation of therapy was 8 hours in both the

metoprolol- and placebo-treatment groups. Among patients treated with metoprolol, there were

comparable reductions in 3-month mortality for those treated early (≤8 hours) and those in whom

treatment was started later. Significant reductions in the incidence of ventricular fibrillation and in chest

pain following initial intravenous therapy were also observed with metoprolol and were independent of

the interval between onset of symptoms and initiation of therapy.

In this study, patients treated with metoprolol received the drug both very early (intra-venously) and

during a subsequent 3-month period, while placebo patients received no beta-blocker treatment for this

period. The study thus was able to show a benefit from the overall metoprolol regimen but cannot

separate the benefit of very early intravenous treatment from the benefit of later beta-blocker therapy.

Nonetheless, because the overall regimen showed a clear beneficial effect on survival without

evidence of an early adverse effect on survival, one acceptable dosage regimen is the precise regimen

used in the trial. Because the specific benefit of very early treatment remains to be defined however, it

is also reasonable to administer the drug orally to patients at a later time as is recommended for certain

other beta- blockers.

INDICATIONS & USAGE

Hypertension

Metoprolol tartrate tablets are indicated for the treatment of hypertension. They may be used alone or in

combination with other antihypertensive agents.

Angina Pectoris

Metoprolol tartrate tablets are indicated in the long-term treatment of angina pectoris.

Myocardial Infarction

Metoprolol tartrate tablets are indicated in the treatment of hemodynamically stable patients with definite

or suspected acute myocardial infarction to reduce cardiovascular mortality when used alone or in

conjunction with intravenous metoprolol. Oral metoprolol therapy can be initiated after intravenous

metoprolol therapy or, alternatively, oral treatment can begin within 3 to 10 days of the acute event (see

DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS.

CONTRAINDICATIONS

Hypertension and Angina

Metoprolol tartrate tablets are contraindicated in sinus bradycardia, heart block greater than first degree,

cardiogenic shock, and overt cardiac failure (see WARNINGS).

Hypersensitivity to metoprolol and related derivatives, or to any of the excipients; hypersensitivity to

other beta-blockers (crosssensitivity between beta-blockers can occur).

Sick-sinus syndrome.

Severe peripheral arterial circulatory disorders.

Myocardial Infarction

Metoprolol is contraindicated in patients with a heart rate < 45 beats/min; second- and third-degree heart

block; significant first-degree heart block (P-R interval ≥ 0.24 sec); systolic blood pressure < 100

mmHg; or moderate to severe cardiac failure (see WARNINGS).

WARNINGS

Heart Failure

Beta blockers, like metoprolol, can cause depression of myocardial contractility and may precipitate

heart failure and cardiogenic shock. If signs or symptoms of heart failure develop, treat the patient

according to recommended guidelines. It may be necessary to lower the dose of metoprolol or to

discontinue it.

Ischemic Heart Disease

Do not abruptly discontinue metoprolol therapy in patients with coronary artery disease. Severe

exacerbation of angina, myocardial infarction and ventricular arrhythmias have been reported in patients

with coronary artery disease following the abrupt discontinuation of therapy with beta-blockers.

When discontinuing chronically administered metoprolol, particularly in patients with coronary artery

disease, the dosage should be gradually reduced over a period of 1 to 2 weeks and the patient should be

carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, metoprolol

administration should be reinstated promptly, at least temporarily, and other measures appropriate for the

management of unstable angina should be taken. Patients should be warned against interruption or

discontinuation of therapy without the physicians 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.

Use During Major Surgery

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.

Bradycardia

Bradycardia, including sinus pause, heart block, and cardiac arrest have occurred with the use of

metoprolol. Patients with first-degree atrioventricular block, sinus node dysfunction, or conduction

disorders may be at increased risk. Monitor heart rate and rhythm in patients receiving metoprolol. If

severe bradycardia develops, reduce or stop metoprolol.

Exacerbation of Bronchospastic Diseases

Patients with bronchospastic diseases, should, in general, not receive beta blockers, including

metoprolol. Because of its relative beta1 selectivity, however, metoprolol 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 tartrate and

consider administering metoprolol in smaller doses three times daily, instead of larger doses two times

daily, to avoid the higher plasma levels associated with the longer dosing interval (see DOSAGE AND

ADMINISTRATION). Bronchodilators, including beta2 agonists, should be readily available or

administered concomitantly.

Diabetes and Hypoglycemia

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

dizziness and sweating may not be significantly affected.

Pheochromocytoma

If metoprolol 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.

Thyrotoxicosis

Metoprolol tartrate tablets may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Avoid

abrupt withdrawal of beta-blockade, which might precipitate a thyroid storm.

PRECAUTIONS

Risk of Anaphylactic Reactions

While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of

allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic.

Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

Information for patients

Advise patients to take metoprolol regularly and continuously, as directed, with or immediately

following meals. If a dose should be missed, the patient should take only the next scheduled dose

(without doubling it). Patients should not discontinue metoprolol 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 metoprolol 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 metoprolol.

DRUG INTERACTIONS

Catecholamine-depleting drugs: Catecholamine-depleting drugs (e.g., reserpine) may have an additive

effect when given with beta-blocking agents or monoamine oxidase (MAO) inhibitors. Observe patients

treated with metoprolol plus a catecholamine depletor for evidence of hypotension or marked

bradycardia, which may produce vertigo, syncope, or

postural hypotension.

In addition, possibly significant hypertension may theoretically occur up to 14 days following

discontinuation of the concomitant administration with an irreversible MAO inhibitor.

Digitalis glycosides and beta blockers:Both digitalis glycosides and beta blockers slow

atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of

bradycardia. Monitor heart rate and PR interval.

Calcium channel blockers:Concomitant administration of a beta-adrenergic antagonist with a calcium

channel blocker may produce an additive reduction in myocardial contractility because of negative

chronotropic and inotropic effects.

CYP2D6 Inhibitors:Potent inhibitors of the CYP2D6 enzyme may increase the plasma concentration of

metoprolol which would mimic the pharmacokinetics of CYP2D6 poormetabolizer (see

Pharmacokinetics section). Increase in plasma concentrations of metoprolol would decrease the

cardioselectivity of metoprolol. Known clinically significant potent inhibitors of CYP2D6 are

antidepressants such as fluvoxamine, fluoxetine, paroxetine, sertraline, bupropion, clomipramine, and

desipramine; antipsychotics such as chlorpromazine, fluphenazine, haloperidol, and thioridazine;

antiarrhythmics such as quinidine or propafenone; antiretrovirals such as ritonavir; antihistamines such

as diphenhydramine; antimalarials such as hydroxychloroquine or quinidine; antifungals such as

terbinafine.

Hydralazine:Concomitant administration of hydralazine may inhibit presystemic metabolism of

metoprolol leading to increased concentrations of metoprolol.

Alpha-adrenergic agents:Antihypertensive effect of alpha-adrenergic blockers such as guanethidine,

betanidine, reserpine, alpha-methyldopa or clonidine may be potentiated by beta-blockers including

metoprolol. Beta-adrenergic blockers may also potentiate the postural hypotensive effect of the first

dose of prazosin, probably by preventing reflex tachycardia. On the contrary, beta adrenergic blockers

may also potentiate the hypertensive response to withdrawal of clonidine in patients receiving

concomitant clonidine and beta-adrenergic blocker. If a patient is treated with clonidine and metoprolol

concurrently, and clonidine treatment is to be discontinued, stop metoprolol several days before

clonidine is withdrawn. Rebound hypertension that can follow withdrawal of clonidine may be increased

in patients receiving concurrent beta-blocker treatment.

Ergot alkaloid:Concomitant administration with beta-blockers may enhance the vasoconstrictive action

of ergot alkaloids.

Dipyridamole:In general, administration of a beta-blocker should be withheld before dipyridamole

testing, with careful monitoring of heart rate following the dipyridamole injection.

Carcinogenesis & Mutagenesis & Impairment Of Fertility

Long-term studies in animals have been conducted to evaluate carcinogenic potential. In a 2-year study

in rats at three oral dosage levels of up to 800 mg/kg per day, there was no increase in the development

of spontaneously occurring benign or malignant neoplasms of any type. The only histologic changes

that appeared to be drug related were an increased incidence of generally mild focal accumulation of

foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia. In a 21-month

study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg per day, benign lung tumors

(small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated

control animals. There was no increase in malignant or total (benign plus malignant) lung tumors, or in

the overall incidence of tumors or malignant tumors. This 21-month study was repeated in CD-1 mice,

and no statistically or biologically significant differences were observed between treated and control

mice of either sex for any type of tumor.

All mutagenicity tests performed (a dominant lethal study in mice, chromosome studies in somatic cells,

a Salmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly test in somatic interphase

nuclei) were negative.

Reproduction toxicity studies in mice, rats and rabbits did not indicate teratogenic potential for

metoprolol tartrate. Embryotoxicity and/or fetotoxicity in rats and rabbits were noted starting at doses of

50 mg/kg in rats and 25 mg/kg in rabbits, as demonstrated by increases in preimplantation loss, decreases

in the number of viable fetuses per dose, and/or decreases in neonatal survival. High doses were

associated with some maternal toxicity, and growth delay of the offspring in utero, which was reflected

in minimally lower weights at birth. The oral NOAELs for embryo-fetal development in mice, rats, and

rabbits were considered to be 25, 200, and 12.5 mg/kg. This corresponds to dose levels that are

approximately 0.3, 4, and 0.5 times, respectively, when based on surface area, the maximum human oral

dose (8 mg/kg/day) of metoprolol tartrate. Metoprolol tartrate has been associated with reversible

adverse effects on spermatogenesis starting at oral dose levels of 3.5 mg/kg in rats (a dose that is only

0.1-times the human dose, when based on surface area), although other studies have shown no effect of

metoprolol tartrate on reproductive performance in male rats.

Pregnancy Category C

Upon confirming the diagnosis of pregnancy, women should immediately inform the doctor.

Metoprolol has been shown to increase postimplantation loss and decrease neonatal survival in rats at

doses up to 11 times the maximum daily human dose of 450 mg, when based on surface area.

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

pregnant animal. These limited animal studies do not indicate direct or indirect harmful effects with

respect to teratogenicity (see Carcinogenesis, Mutagenesis, Impairment of Fertility). There are no

adequate and well-controlled studies in pregnant women. The amount of data on the use of metoprolol in

pregnant women is limited. The risk to the fetus/mother is unknown. Because animal reproduction

studies are not always predictive of human response, this drug should be used during pregnancy only if

clearly needed.

Nursing Mothers

Metoprolol is excreted in breast milk in a very small quantity. An infant consuming one liter of breast

milk daily would receive a dose of less than 1 mg of the drug.

Fertility

The effects of Metoprolol on the fertility of human have not been studied.

Metoprolol showed effects on spermatogenesis in male rats at a therapeutic dose level, but had no

effect on rates of conception at higher doses in animal fertility studies (see Carcinogenesis,

Mutagenesis, Impairment of Fertility).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical trials of metoprolol in hypertension did not include sufficient numbers of elderly patients to

determine whether patients over 65 years of age differ from younger subjects in their response to

metoprolol. Other reported clinical experience in elderly hypertensive patients has not identified any

difference in response from younger patients.

In worldwide clinical trials of metoprolol in myocardial infarction, where approximately 478 patients

were over 65 years of age (0 over 75 years of age), no age-related differences in safety and

effectiveness were found. Other reported clinical experience in myocardial infarction has not identified

differences in response between the elderly and younger patients. However, greater sensitivity of some

elderly individuals taking metoprolol cannot be categorically ruled out. Therefore, in general, it is

recommended that dosing proceed with caution in this population.

ADVERSE REACTIONS

Hypertension and Angina

Most adverse effects have been mild and transient.

Central Nervous System: Tiredness and dizziness have occurred in about 10 of 100 patients.

Depression has been reported in about 5 of 100 patients. Mental confusion and short-term memory loss

have been reported. Headache, nightmares, and insomnia have also been reported.

Cardiovascular: Shortness of breath and bradycardia have occurred in approximately 3 of 100 patients.

Cold extremities; arterial insufficiency, usually of the Raynaud type; palpitations; congestive heart

failure; peripheral edema; and hypotension have been reported in about 1 of 100 patients. Gangrene in

patients with pre-existing severe peripheral circulatory disorders has also been reported very rarely

(see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS).

Respiratory: Wheezing (bronchospasm) and dyspnea have been reported in about 1 of 100 patients (see

WARNINGS). Rhinitis has also been reported.

Gastrointestinal: Diarrhea has occurred in about 5 of 100 patients. Nausea, dry mouth, gastric pain,

constipation, flatulence, and heartburn have been reported in about 1 of 100 patients. Vomiting was a

common occurrence. Post-marketing experience reveals very rare reports of hepatitis, jaundice and

nonspecific hepatic dysfunction. Isolated cases of transaminase, alkaline phosphatase, and lactic

dehydrogenase elevations have also been reported.

Hypersensitive Reactions: Pruritus or rash have occurred in about 5 of 100 patients. Very rarely,

photosensitivity and worsening of psoriasis have been reported.

Miscellaneous:

Peyronie’s disease has been reported in fewer than 1 of 100,000 patients. Musculoskeletal pain, blurred

vision, and tinnitus have also been reported.

There have been rare reports of reversible alopecia, agranulocytosis, and dry eyes. Discontinuation of

the drug should be considered if any such reaction is not otherwise explicable. There have been very

rare reports of weight gain, arthritis, and retroperitoneal fibrosis (relationship to metoprolol has not

been definitely established).

The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported

with metoprolol.

Myocardial Infarction

Central Nervous System: Tiredness has been reported in about 1 of 100 patients. Vertigo, sleep

disturbances, hallucinations, headache, dizziness, visual disturbances, confusion, and reduced libido

have also been reported, but a drug relationship is not clear.

Cardiovascular: In the randomized comparison of metoprolol and placebo described in the CLINICAL

PHARMACOLOGY section, the following adverse reactions were reported:

Metoprolol

Placebo

Hypotension (systolic BP <90 mm Hg)

27.4%

23.2%

Bradycardia (heart rate <40 beats/min)

15.9%

6.7%

Second- or third-degree heart block

4.7%

4.7%

First-degree heart block (P-R ≥0.26 sec)

5.3%

1.9%

Heart failure

27.5%

29.6%

Respiratory: Dyspnea of pulmonary origin has been reported in fewer than 1 of 100 patients.

Gastrointestinal: Nausea and abdominal pain have been reported in fewer than 1 of 100 patients.

Dermatologic: Rash and worsened psoriasis have been reported, but a drug relationship is not clear.

Miscellaneous: Unstable diabetes and claudication have been reported, but a drug relationship is not

clear.

Potential Adverse Reactions

A variety of adverse reactions not listed above has been reported with other beta-adrenergic blocking

agents and should be considered potential adverse reactions to metoprolol.

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,

slightly clouded sensorium, and decreased performance on neuropsychometrics.

Cardiovascular: Intensification of AV block (see CONTRAINDICATIONS).

Hematologic: Agranulocytosis, nonthrombocytopenic purpura and thrombocytopenic purpura.

Hypersensitive Reactions: Fever combined with aching and sore throat, laryngospasm and respiratory

distress.

Post-Marketing Experience

The following adverse reactions have been reported during post-approval use of metoprolol tartrate:

confusional state, an increase in blood triglycerides and a decrease in High Density Lipoprotein (HDL).

Because these reports are from a population of uncertain size and are subject to confounding factors, it

is not possible to reliably estimate their frequency.

OVERDOSAGE

Acute Toxicity

Several cases of overdosage have been reported, some leading to death.

Oral LD50’s (mg/kg): mice, 1,158 to 2,460; rats, 3,090 to 4,670.

Signs and Symptoms

Potential signs and symptoms associated with overdosage with metoprolol are bradycardia,

hypotension, bronchospasm, myocardial infarction, cardiac failure and death.

Management

There is no specific antidote.

In general, patients with acute or recent myocardial infarction may be more hemodynamically unstable

than other patients and should be treated accordingly (see WARNINGS: Myocardial Infarction).

On the basis of the pharmacologic actions of metoprolol, the following general measures should be

employed:

Elimination of the Drug:Gastric lavage should be performed.

Other clinical manifestations of overdose should be managed symptomatically based on modern methods

of intensive care.

Hypotension:Administer a vasopressor, e.g.,levarterenol or dopamine.

Bronchospasm:Administer a beta2-stimulating agent and/or a theophylline derivative.

Cardiac Failure:

Administer digitalis glycoside and diuretic. In shock resulting from inadequate cardiac contractility,

consider administration of dobutamine, isoproterenol or glucagon.

DOSAGE & ADMINISTRATION

Hypertension

Individualize the dosage of metoprolol tablets. Metoprolol tartrate tablets should be taken with or

immediately following meals.

The usual initial dosage of metoprolol tartrate tablets is 100 mg daily in single or divided doses,

whether used alone or added to a diuretic. Increase the dosage 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 one week of therapy. The effective dosage range of metoprolol tartrate

tablets is 100 to 450 mg per day. Dosages above 450 mg per day have not been studied. While once

daily dosing is effective and can maintain a reduction in blood pressure throughout the day, lower doses

(especially 100 mg) may not maintain a full effect at the end of the 24-hour period, and larger or more

frequent daily doses may be required. This can be evaluated by measuring blood pressure near the end

of the dosing interval to determine whether satisfactory control is being maintained throughout the day.

Beta1 selectivity diminishes as the dose of metoprolol is increased.

Angina Pectoris

The dosage of metoprolol tartrate tablets should be individualized. Metoprolol tartrate tablets should be

taken with or immediately following meals.

The usual initial dosage of metoprolol tartrate tablets is 100 mg daily, given in two divided doses.

gradually increased at weekly intervals until optimum clinical response has been obtained or there is

pronounced slowing of the heart rate.

The effective dosage range of metoprolol tartrate tablets is 100 to 400 mg per day. Dosages above

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

over a period of 1 to 2 weeks (see WARNINGS).

Myocardial Infarction

Early Treatment:During the early phase of definite or suspected acute myocardial infarction, treatment

with metoprolol tartrate tablets can be initiated as soon as possible after the patient’s arrival in the

hospital. Such treatment should be initiated in a coronary care or similar unit immediately after the

patient’s hemodynamic condition has stabilized.

Begin treatment in this early phase should begin with the intravenous administration of three bolus

injections of 5 mg of metoprolol tartrate each; the injections should be given at approximately 2 minute

intervals. During the intravenous administration of metoprolol, monitor blood pressure, heart rate, and

electrocardiogram.

In patients who tolerate the full intravenous dose (15 mg), initiate metoprolol tartrate tablets, 50 mg

every 6 hours, 15 minutes after the last intravenous dose and continue for 48 hours. Thereafter, the

maintenance dosage is 100 mg twice daily (see Late Treatment below).

Start patients who appear not to tolerate the full intravenous dose on metoprolol tablets either 25 mg or

50 mg every 6 hours (depending on the degree of intolerance) 15 minutes after the last intravenous dose

or as soon as their clinical condition allows. In patients with severe intolerance, discontinue

metoprolol(see WARNINGS).

Late Treatment:Start patients with contraindications to treatment during the early phase of suspected or

definite myocardial infarction, patients who appear not to tolerate the full early treatment, and patients in

whom the physician wishes to delay therapy for any other reason on metoprolol tartrate tablets, 100 mg

twice daily, as soon as their clinical condition allows. Continue therapy for at least 3 months. Although

the efficacy of metoprolol beyond 3 months has not been conclusively established, data from studies

with other beta-blockers suggest that treatment should be continued for 1 to 3 years.

Special populations

Pediatric patients:No pediatric studies have been performed. The safety and efficacy of metoprolol in

pediatric patients have not been established.

Renal impairment:No dose adjustment of metoprolol is required in patients with renal impairment.

Hepatic impairment:Metoprolol blood levels are likely to increase substantially in patients with

hepatic impairment. Therefore, metoprolol should be initiated at low doses with cautious gradual dose

titration according to clinical response.

Geriatric patients (>65 years):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.

Method of administration:

For oral treatment, the tablets should be swallowed un-chewed with a glass of water. Metoprolol

tartrate tablets should always be taken in standardized relation with meals. If the physician asks the

patient to take metoprolol tartrate tablets either before breakfast or with breakfast, then the patient

should continue taking metoprolol tartrate tablets with the same schedule during the course of therapy.

HOW SUPPLIED

Metoprolol Tartrate Tablets, USP are available containing 25 mg, 50 mg or 100 mg of metoprolol

tartrate, USP.

The 25 mg tablets are white to off white film coated, round, biconvex tablets debossed with ‘L150’ on

one side and breakline on other side. They are available as follows:

NDC 46708-290-30 bottles of 30 tablets

NDC 46708-290-31 bottles of 100 tablets

NDC 46708-290-71 bottles of 500 tablets

NDC 46708-290-91 bottles of 1000 tablets

NDC 46708-290-10 100 (10 x 10) Tablets Unit-dose blisters

The 50 mg tablets are pink, film coated, round, biconvex tablets debossed with ‘L151’ on one side and

breakline on other side. They are available as follows:

NDC 46708-291-30 bottles of 30 tablets

NDC 46708-291-31 bottles of 100 tablets

NDC 46708-291-91 bottles of 1000 tablets

NDC 46708-291-10 100 (10 x 10) Tablets Unit-dose blisters

The 100 mg tablets are blue, film coated, round, biconvex tablets debossed with ‘L152’ on one side and

breakline on other side. They are available as follows:

NDC 46708-292-30 bottles of 30 tablets

NDC 46708-292-31 bottles of 100 tablets

NDC 46708-292-91 bottles of 1000 tablets

NDC 46708-292-10 100 (10 x 10) Tablets Unit-dose blisters

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Protect from moisture.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-

FDA-1088.

Manufactured by:

Alembic Pharmaceuticals Limited (Formulation Division),

Village Panelav, P. O. Tajpura, Near Baska,

Taluka-Halol, Panchmahal, Gujarat, India.

Revised: 06/2013

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 25 mg

Metoprolol Tartrate Tablets, USP 25 mg

Each film-coated tablet contains Metoprolol tartrate, USP 25 mg

30 Tablets in 1 HDPE Bottle

46708-290-30

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 50 mg

Metoprolol Tartrate Tablets, USP 50 mg

Each film-coated tablet contains Metoprolol tartrate, USP 50 mg

30 Tablets in 1 HDPE Bottle

46708-291-30

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 100 mg

Metoprolol Tartrate Tablets, USP 100 mg

Each film-coated tablet contains Metoprolol tartrate, USP 100 mg

30 Tablets in 1 HDPE Bottle

46708-292-30

METOPROLOL TARTRATE

metoprolol tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:46 70 8 -29 0

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

METO PRO LO L TARTRATE (UNII: W5S57Y3A5L) (METOPROLOL - UNII:GEB0 6 NHM23)

METOPROLOL TARTRATE

25 mg

Inactive Ingredients

Ingredient Name

Stre ng th

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

PO VIDO NE K3 0 (UNII: U725QWY32X)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

PO LYETHYLENE GLYCO L 3 3 50 (UNII: G2M7P15E5P)

Product Characteristics

Color

WHITE (WHITE TO OFF WHITE)

S core

2 pieces

S hap e

ROUND

S iz e

6 mm

Flavor

Imprint Code

L;150

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:46 70 8 -29 0 -30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/22/20 13

2

NDC:46 70 8 -29 0 -31

10 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/22/20 13

3

NDC:46 70 8 -29 0 -9 1

10 0 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/22/20 13

4

NDC:46 70 8 -29 0 -10

10 0 in 1 CARTON; Type 0 : No t a Co mbinatio n Pro duct

0 7/22/20 13

5

NDC:46 70 8 -29 0 -71

50 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/22/20 13

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 28 71

0 7/22/20 13

METOPROLOL TARTRATE

metoprolol tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:46 70 8 -29 1

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

METO PRO LO L TARTRATE (UNII: W5S57Y3A5L) (METOPROLOL - UNII:GEB0 6 NHM23)

METOPROLOL TARTRATE

50 mg

Inactive Ingredients

Ingredient Name

Stre ng th

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

PO VIDO NE K3 0 (UNII: U725QWY32X)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

PO LYETHYLENE GLYCO L 3 3 50 (UNII: G2M7P15E5P)

D&C RED NO . 3 0 (UNII: 2S42T28 0 8 B)

Product Characteristics

Color

PINK

S core

2 pieces

S hap e

ROUND

S iz e

8 mm

Flavor

Imprint Code

L;151

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:46 70 8 -29 1-30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/22/20 13

2

NDC:46 70 8 -29 1-31

10 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/22/20 13

3

NDC:46 70 8 -29 1-9 1

10 0 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/22/20 13

4

NDC:46 70 8 -29 1-10

10 0 in 1 CARTON; Type 0 : No t a Co mbinatio n Pro duct

0 7/22/20 13

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 28 71

0 7/22/20 13

METOPROLOL TARTRATE

metoprolol tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:46 70 8 -29 2

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

METO PRO LO L TARTRATE (UNII: W5S57Y3A5L) (METOPROLOL - UNII:GEB0 6 NHM23)

METOPROLOL TARTRATE

10 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

PO VIDO NE K3 0 (UNII: U725QWY32X)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

PO LYETHYLENE GLYCO L 3 3 50 (UNII: G2M7P15E5P)

FD&C BLUE NO . 2 (UNII: L0 6 K8 R7DQK)

FD&C BLUE NO . 1 (UNII: H3R47K3TBD)

Product Characteristics

Color

BLUE

S core

2 pieces

S hap e

ROUND

S iz e

10 mm

Flavor

Imprint Code

L;152

Alembic Pharmaceuticals Limited

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:46 70 8 -29 2-30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/22/20 13

2

NDC:46 70 8 -29 2-31

10 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/22/20 13

3

NDC:46 70 8 -29 2-9 1

10 0 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/22/20 13

4

NDC:46 70 8 -29 2-10

10 0 in 1 CARTON; Type 0 : No t a Co mbinatio n Pro duct

0 7/22/20 13

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 28 71

0 7/22/20 13

Labeler -

Alembic Pharmaceuticals Limited (650574663)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Alembic Pharmaceuticals Limited

6 50 5746 71

MANUFACTURE(46 70 8 -29 0 , 46 70 8 -29 1, 46 70 8 -29 2)

Revised: 9/2019

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