Generic Name: METOPROLOL TARTRATE
Brand Name: Lopressor
- Substance Name(s):
- METOPROLOL TARTRATE
Heart Failure Beta-blockers, like Lopressor, 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 Lopressor or to discontinue it.
Ischemic Heart Disease Do not abruptly discontinue Lopressor 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 Lopressor, 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, Lopressor 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 Lopressor 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Use During Major Surgery Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and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 Lopressor.
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 Lopressor.
If severe bradycardia develops, reduce or stop Lopressor.
Exacerbation of Bronchospastic Disease Patients with bronchospastic disease, should in general, not receive beta-blockers, including Lopressor.
Because of its relative beta 1 selectivity, however, Lopressor may be used in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment.
Because beta 1 selectivity is not absolute use the lowest possible dose of Lopressor and consider administering Lopressor 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 beta 2 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 Lopressor 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 Lopressor may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism.
Avoid abrupt withdrawal of beta blockade, which might precipitate a thyroid storm.
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 Lopressor 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 Lopressor which would mimic the pharmacokinetics of CYP2D6 poor metabolizer ( 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 Lopressor.
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 Lopressor concurrently, and clonidine treatment is to be discontinued, stop Lopressor 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.
Acute Toxicity Several cases of overdosage have been reported, some leading to death.
Oral LD 50 ’s (mg/kg): mice, 1158-2460; rats, 3090-4670.
Signs and Symptoms Potential signs and symptoms associated with overdosage with Lopressor 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 Lopressor, 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 beta 2 -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.
Lopressor, metoprolol tartrate USP is a selective beta 1 -adrenoreceptor blocking agent, available as 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, and 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.
Inactive Ingredients: Tablets contain cellulose compounds, colloidal silicon dioxide, D&C Red No.
30 aluminum lake (50 mg tablets), FD&C Blue No.
2 aluminum lake (100 mg tablets), lactose, magnesium stearate, polyethylene glycol, propylene glycol, povidone, sodium starch glycolate, talc, and titanium dioxide.
The structural formula for Lopressor, metoprolol tartrate USP is a selective beta1-adrenoreceptor blocking agent, available as 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.
Clinical Studies: Hypertension In controlled clinical studies, Lopressor 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, Lopressor 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, Lopressor, 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 Lopressor was indistinguishable from propranolol in the treatment of angina pectoris.
Myocardial Infarction In a large (1395 patients randomized), double-blind, placebo-controlled clinical study, Lopressor 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 Lopressor or placebo, given in a coronary care or comparable unit.
Oral maintenance therapy with Lopressor or placebo was then continued for 3 months.
After this double-blind period, all patients were given Lopressor 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 Lopressor- and placebo-treatment groups.
Among patients treated with Lopressor, 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 Lopressor 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.
Lopressor Tablets m etoprolol tartrate USP Tablets Tablets 50 mg – capsule-shaped, biconvex, pink, scored (imprinted LOPRESSOR on one side and 458 twice on the scored side) Bottles of 100………………………………………….………NDC 30698-458-01 Tablets 100 mg – capsule-shaped, biconvex, light blue, scored (imprinted LOPRESSOR on one side and 459 twice on the scored side) Bottles of 100………………………………………………….NDC 30698-459-01 Storage: Store at 77°F (25°C); excursions permitted to 59° to 86°F (15° to 30°C) [See USP Controlled Room Temperature].
Protect from moisture and heat.
Dispense in a tight, light-resistant container (USP).
Manufactured for and Distributed by: Validus Pharmaceuticals LLC 119 Cherry Hill Road, Suite 310 Parsippany, NJ 07054 firstname.lastname@example.org www.validuspharma.com 1-866-982-5438 (1-866-9VALIDUS) Product of Spain © 2017 Validus Pharmaceuticals LLC 60025-01September 2017
Geriatric Use Clinical trials of Lopressor 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 Lopressor.
Other reported clinical experience in elderly hypertensive patients has not identified any difference in response from younger patients.
In worldwide clinical trials of Lopressor 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 Lopressor cannot be categorically ruled out.
Therefore, in general, it is recommended that dosing proceed with caution in this population.
MECHANISM OF ACTION
Mechanism of Action: Lopressor is a beta 1 -selective (cardioselective) adrenergic receptor blocker.
This preferential effect is not absolute, however, and at higher plasma concentrations, Lopressor also inhibits beta 2 -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.
INDICATIONS AND USAGE
Hypertension Lopressor tablets are indicated for the treatment of hypertension.
They may be used alone or in combination with other antihypertensive agents.
Angina Pectoris Lopressor is indicated in the long-term treatment of angina pectoris.
Myocardial Infarction Lopressor 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 Lopressor.
Oral Lopressor therapy can be initiated after intravenous Lopressor therapy or, alternatively, oral treatment can begin within 3 to 10 days of the acute event (see DOSAGE AND ADMINISTRATION , CONTRAINDICATIONS , and WARNINGS ).
Pediatric Use Safety and effectiveness in pediatric patients have not been established.
Pregnancy Category C Upon confirming the diagnosis of pregnancy, women should immediately inform the doctor.
Lopressor 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 Lopressor 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 Lopressor is excreted in breast milk in a very small quantity.
An infant consuming 1 liter of breast milk daily would receive a dose of less than 1 mg of the drug.
INFORMATION FOR PATIENTS
Information for Patients Advise patients to take Lopressor 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 Lopressor 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 Lopressor 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 Lopressor.
DOSAGE AND ADMINISTRATION
Hypertension Individualize the dosage of Lopressor tablets.
Lopressor tablets should be taken with or immediately following meals.
The usual initial dosage of Lopressor 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 1 week of therapy.
The effective dosage range of Lopressor 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.
Beta 1 selectivity diminishes as the dose of Lopressor is increased.
Angina Pectoris The dosage of Lopressor tablets should be individualized.
Lopressor tablets should be taken with or immediately following meals.
The usual initial dosage of Lopressor 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 Lopressor 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, initiate treatment with Lopressor 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 Lopressor each; give the injections at approximately 2-minute intervals.
During the intravenous administration of Lopressor, monitor blood pressure, heart rate, and electrocardiogram.
In patients who tolerate the full intravenous dose (15 mg), initiate Lopressor 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 Lopressor 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 Lopressor (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 Lopressor tablets, 100 mg twice daily, as soon as their clinical condition allows.
Continue therapy for at least 3 months.
Although the efficacy of Lopressor 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 Lopressor in pediatric patients have not been established.
Renal impairment: No dose adjustment of Lopressor is required in patients with renal impairment.
Hepatic impairment: Lopressor blood levels are likely to increase substantially in patients with hepatic impairment.
Therefore, Lopressor 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.
Lopressor should always be taken in standardized relation with meals.
If the physician asks the patient to take Lopressor either before breakfast or with breakfast, then the patient should continue taking Lopressor with the same schedule during the course of therapy.