NDC 55700-667 Metoprolol Tartrate

NDC Product Code 55700-667

NDC CODE: 55700-667

Proprietary Name: Metoprolol Tartrate What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • Metoprolol is used with or without other medications to treat high blood pressure (hypertension). Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. This medication is also used to treat chest pain (angina) and to improve survival after a heart attack. Metoprolol belongs to a class of drugs known as beta blockers. It works by blocking the action of certain natural chemicals in your body, such as epinephrine, on the heart and blood vessels. This effect lowers the heart rate, blood pressure, and strain on the heart.

Product Characteristics

Color(s):
PINK (C48328)
Shape: ROUND (C48348)
Size(s):
9 MM
Imprint(s):
R50
Score: 2

NDC Code Structure

  • 55700 - Lake Erie Medical Dba Quality Care Products Llc

NDC 55700-667-30

Package Description: 30 TABLET, FILM COATED in 1 BOTTLE

This product is EXCLUDED from the official NDC directory because the listing data was inactivated by the FDA.

NDC Product Information

Metoprolol Tartrate with NDC 55700-667 is a product labeled by Lake Erie Medical Dba Quality Care Products Llc. The generic name of Metoprolol Tartrate is . The product's dosage form is and is administered via form.

Labeler Name: Lake Erie Medical Dba Quality Care Products Llc

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • HYPROMELLOSES (UNII: 3NXW29V3WO)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
  • POLYETHYLENE GLYCOLS (UNII: 3WJQ0SDW1A)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • TALC (UNII: 7SEV7J4R1U)
  • D&C RED NO. 30 (UNII: 2S42T2808B)
  • SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Lake Erie Medical Dba Quality Care Products Llc
Labeler Code: 55700
Start Marketing Date: 08-10-2018 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: I - INACTIVATED, the listing data was inactivated by the FDA. What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Information for Patients

Metoprolol

Metoprolol is pronounced as (me toe' proe lole)

Why is metoprolol medication prescribed?
Metoprolol is used alone or in combination with other medications to treat high blood pressure. It also is used to prevent angina (chest pain) and to improve survival aft...
[Read More]
Metoprolol

Metoprolol is pronounced as (me toe' proe lole)
Why is metoprolol medication prescribed?
Metoprolol is used alone or in combination with other medications to treat high blood pressure. It also is used to prevent angina (chest pain) and to improve survival aft...
[Read More]

* Please review the disclaimer below.

Metoprolol Tartrate Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Description

Metoprolol tartrate is a selective beta1-adrenoreceptor blocking agent, available as 25 mg, 50 mg, and 100 mg tablets for oral administration. Metoprolol tartrate is (±)-1-(isopropylamino)-3-[p-2-methoxyethyl)phenoxy]-2-propanol (2:1)


dextro-tartrate salt. Its structural formula is:


Metoprolol tartrate, USP is a white, 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: lactose monohydrate, colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, titanium dioxide, sodium starch glycolate, talc and D & C Red #30 Aluminium Lake.

Mechanism Of Action

Metoprolol 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 demonstrated the beta-blocking activity of metoprolol, 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.


HypertensionThe 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, leading to decreased cardiac output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and (3) suppression of renin activity.


Angina PectorisBy 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 InfarctionThe precise mechanism of action of metoprolol 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 one 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 mg, 50 mg, and 100 mg occurred at 3.3 hours, 5 hours 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 one hour is linearly related to the oral dose within the range of 50 mg 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.


DistributionMetoprolol is extensively distributed with a reported volume of distribution of 3.2 L/kg 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.MetabolismMetoprolol 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.EliminationElimination 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 and less than 10% of an intravenous dose are excreted as unchanged drug in the urine. In poor metabolizers, up to 30% or 40% of oral or intravenous doses, respectively, 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 stereoisomers does not exhibit stereo-selectivity in renal excretion.

Special Populations

Geriatric PatientsThe 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 ImpairmentThe 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 ImpairmentSince 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).

Pediatric PatientsNo pediatric studies have been performed. The safety and efficacy of metoprolol in pediatric patients have not been established.Renal ImpairmentNo dose adjustment of metoprolol tartrate tablets is required in patients with renal impairment.Hepatic ImpairmentMetoprolol blood levels are likely to increase substantially in patients with hepatic impairment. Therefore, metoprolol tartrate tablets 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.

Clinical Studies

HypertensionIn 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 mg 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 PectorisIn controlled clinical trials, metoprolol, administered 2 or 4 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 mg to 400 mg daily. A controlled, comparative, clinical trial showed that metoprolol was indistinguishable from propranolol in the treatment of angina pectoris.Myocardial InfarctionIn 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 one 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 (intravenously) 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 And Usage

HypertensionMetoprolol tartrate tablets are indicated for the treatment of hypertension. They may be used alone or in combination with other antihypertensive agents.Angina PectorisMetoprolol tartrate tablets are indicated in the long-term treatment of angina pectoris.Myocardial InfarctionMetoprolol 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 tartrate tablets 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 AnginaMetoprolol 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 (cross-sensitivity between beta-blockers can occur).


Sick-sinus syndrome.


Severe peripheral arterial circulatory disorders.


Myocardial InfarctionMetoprolol 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 FailureBeta-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 DiseaseDo 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 physician’s advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue metoprolol therapy abruptly even in patients treated only for hypertension.Use During Major SurgeryChronically 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.BradycardiaBradycardia, 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 DiseasePatients with bronchospastic disease, 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 and consider administering metoprolol in smaller doses 3 times daily, instead of larger doses 2 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 HypoglycemiaBeta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.PheochromocytomaIf 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.ThyrotoxicosisMetoprolol may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Avoid abrupt withdrawal of beta-blockade, which might precipitate a thyroid storm. PRECAUTIONSRisk of Anaphylactic ReactionsWhile 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 PatientsAdvise 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 DrugsCatecholamine-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-BlockersBoth 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 BlockersConcomitant 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 InhibitorsPotent inhibitors of the CYP2D6 enzyme may increase the plasma concentration of metoprolol which would mimic the pharmacokinetics of CYP2D6 poor metabolizer (see


CLINICAL PHARMACOLOGY: Pharmacokinetics). 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.


HydralazineConcomitant administration of hydralazine may inhibit presystemic metabolism of metoprolol leading to increased concentrations of metoprolol.Alpha-Adrenergic AgentsAntihypertensive 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 AlkaloidConcomitant administration with beta-blockers may enhance the vasoconstrictive action of ergot alkaloids.DipyridamoleIn 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 mg/kg, 200 mg/kg and 12.5 mg/kg. This corresponds to dose levels that are approximately 0.3 times, 4 times, 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

Pregnancy Category CUpon confirming the diagnosis of pregnancy, women should immediately inform their 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


PRECAUTIONS: 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


PRECAUTIONS: 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.

Hypertension And Angina

Most adverse effects have been mild and transient.Central Nervous SystemTiredness 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.CardiovascularShortness 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 preexisting severe peripheral circulatory disorders has also been reported very rarely (see


CONTRAINDICATIONS,


WARNINGS, and PRECAUTIONS).


RespiratoryWheezing (bronchospasm) and dyspnea have been reported in about 1 of 100 patients (see


WARNINGS). Rhinitis has also been reported.


GastrointestinalDiarrhea 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 ReactionsPruritus or rash have occurred in about 5 of 100 patients. Very rarely, photosensitivity and worsening of psoriasis has been reported.MiscellaneousPeyronie’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 SystemTiredness 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.CardiovascularIn the randomized comparison of metoprolol and placebo described in the


CLINICAL PHARMACOLOGYsection, the following adverse reactions were reported:


Metoprolol Tartrate TabletsPlaceboHypotension (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%


RespiratoryDyspnea of pulmonary origin has been reported in fewer than 1 of 100 patients.GastrointestinalNausea and abdominal pain have been reported in fewer than 1 of 100 patients.DermatologicRash and worsened psoriasis have been reported, but a drug relationship is not clear.MiscellaneousUnstable diabetes and claudication have been reported, but a drug relationship is not clear.

Early TreatmentDuring the early phase of definite or suspected acute myocardial infarction, initiate treatment with metoprolol tartrate tablets 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 with the intravenous administration of three bolus injections of 5 mg of metoprolol tartrate each; give the injections 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 tartrate 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 tartrate tablets (see


WARNINGS).


Late TreatmentStart 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.

Potential Adverse Reactions

A variety of adverse reactions not listed above have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to metoprolol.Central Nervous SystemReversible 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.CardiovascularIntensification of AV block (see


CONTRAINDICATIONS).


HematologicAgranulocytosis, nonthrombocytopenic purpura and thrombocytopenic purpura.Hypersensitive ReactionsFever 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: 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.

Acute Toxicity

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


Oral LD


50'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 DrugGastric lavage should be performed.Other clinical manifestations of overdose should be managed symptomatically based on modern methods of intensive care.HypotensionAdminister a vasopressor, e.g., norepinephrine or dopamine.BronchospasmAdminister a beta2-stimulating agent and/or a theophylline derivative.


Cardiac FailureAdminister digitalis glycoside and diuretic. In shock resulting from inadequate cardiac contractility, consider administration of dobutamine, isoproterenol or glucagon.

Hypertension

Individualize the dosage of metoprolol tartrate 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 mg per day 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 increase the dosage 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 mg per day to 450 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).

Method Of Administration

For oral treatment, the tablets should be swallowed unchewed 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 film-coated, pink colored, round, biconvex tablets debossed with R 25 on one side and scored on the other side.The 50 mg tablets are film-coated, pink colored, round, biconvex tablets debossed with R 50 on one side and scored on the other side.55700-667-6055700-667-90The 100 mg tablets are film-coated, pink colored, round, biconvex tablets debossed with R 100 on one side and scored on the other side.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.To report SUSPECTED ADVERSE REACTIONS, contact Vensun Pharmaceuticals, Inc. at 1-800-385-1540 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.Manufactured for: Vensun Pharmaceuticals, Inc.Yardley, PA 19067Manufactured by: Rubicon Research Private LimitedAmbernath, Dist: Thane, 421506, INDIARev. 01, January 2017

* Please review the disclaimer below.