Lopressor

Description for Lopressor

Lopressor, metoprolol tartrate USP, is a selective beta1-adrenoreceptor blocking agent, available in 5- mL ampuls for intravenous administration. Each ampul contains a sterile solution of metoprolol tartrate USP, 5 mg, and sodium chloride USP, 45 mg, and water for injection USP. 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.

Uses for Lopressor

Hypertension

LOPRESSOR is indicated for the treatment of hypertension in adult patients, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including metoprolol.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

LOPRESSOR may be administered with other antihypertensive agents.

Angina Pectoris

LOPRESSOR is indicated in the long-term treatment of angina pectoris, to reduce angina attacks and to improve exercise tolerance.

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 metoprolol.

Dosage for Lopressor

Hypertension

Individualize the dosage of Lopressor tablets. Lopressor tablets should be taken with or immediately following meals.

The usual initial dosage is 100 mg daily in single or divided doses. Adjust 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 mg to 450 mg per day. Dosages above 450 mg per day have not been studied. While once-daily dosing 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. Larger or more frequent daily doses may be required. Measure blood pressure near the end of the dosing interval to determine whether satisfactory control is being maintained throughout the day.

Angina Pectoris

The dosage of Lopressor tablets should be individualized. Lopressor tablets should be taken with or immediately following meals.

The usual initial dosage 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 a 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, reduce the dosage gradually over a period of 1 – 2 weeks [see WARNINGS AND PRECAUTIONS].

Myocardial Infarction

See prescribing information of intravenous metoprolol for dosage instructions for intravenous therapy.

In patients who tolerate the full intravenous dose, initiate Lopressor tablets, 50 mg every 6 hours, 15 minutes after the last intravenous dose of metoprolol and continue for 48 hours. In the case of intolerance, reduce dose to 25 mg and administer for 48 hours. Titrate, based on tolerability, to a maintenance dosage of 100 mg twice daily. 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.

HOW SUPPLIED

Dosage Forms And Strengths

LOPRESSOR is supplied as:

50 mg tablet - capsule shaped, biconvex, pink, scored (imprinted GEIGY on one side and 51 twice on the scored side)

100 mg tablet - capsule shaped, biconvex, light blue, scored (imprinted with GEIGY on one side and 71 twice on the scored side)

Storage And Handling

Lopressor (Metoprolol Tartrate) 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, Parsippany, NJ 07054. Revised: Sep 2023

Side Effects for Lopressor

The following adverse reactions are described elsewhere in labeling:

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

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Hypertension And Angina

Most adverse effects have been mild and transient.

Central Nervous System: Tiredness and dizziness have occurred in about 10% of 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 patients. Cold extremities; arterial insufficiency, usually of the Raynaud type; palpitations; heart failure exacerbations; peripheral edema; and hypotension have been reported in about 1% of patients. Gangrene in patients with pre-existing severe peripheral circulatory disorders has also been reported. [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

Respiratory: Wheezing (bronchospasm) and dyspnea have been reported in about 1% of patients [see WARNINGS AND PRECAUTIONS]. Rhinitis has also been reported.

Gastrointestinal: Diarrhea has occurred in about 5% of patients. Nausea, dry mouth, gastric pain, constipation, flatulence, and heartburn have been reported in about 1% of patients. Vomiting was a common occurrence.

Hypersensitive Reactions: Pruritus or rash have occurred in about 5% of patients. Photosensitivity and worsening of psoriasis has been reported.

Miscellaneous: Peyronie’s disease, musculoskeletal pain, blurred vision, and tinnitus has been reported.

Myocardial Infarction

In general, the adverse reactions observed in trials with metoprolol in MI are consistent with the hypertension and angina experience.

In a randomized comparison of Lopressor and placebo in the setting of acute MI the following adverse reactions were reported:

	Lopressor®	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%

Post-Marketing Experience

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

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.

Laboratory Findings

Increase in blood triglycerides, elevated transaminase and decrease in High Density Lipoprotein (HDL)

Drug Interactions for Lopressor

Catecholamine Depleting Drugs

Catecholamine depleting drugs (e.g., reserpine, monoamine oxidase (MAO) inhibitors) may have an additive effect when given with beta-blocking agents. Observe patients treated with LOPRESSOR plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

Epinephrine

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

CYP2D6 Inhibitors

Drugs that are strong inhibitors of CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone were shown to double metoprolol concentrations. While there is no information about moderate or weak inhibitors, these too are likely to increase metoprolol concentration. Increases in plasma concentration decrease the cardioselectivity of metoprolol [see CLINICAL PHARMACOLOGY]. Monitor patients closely, when the combination cannot be avoided.

Negative Chronotropes

Digitalis glycosides, clonidine, diltiazem and verapamil slow atrioventricular conduction and decrease heart rate. Concomitant use with beta-blockers can increase the risk of bradycardia.

If clonidine and a beta-blocker, such as metoprolol are coadministered, withdraw the beta-blocker several days before the gradual withdrawal of clonidine because beta-blockers may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, delay the introduction of beta-blockers for several days after clonidine administration has stopped.

Overdose Information for Lopressor

Signs and Symptoms

Overdosage of LOPRESSOR may lead to severe bradycardia, hypotension, and cardiogenic shock. Clinical presentation can also include: atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness/coma, nausea and vomiting.

Treatment

Consider treating the patient with intensive care. Patients with myocardial infarction or heart failure may be prone to significant hemodynamic instability. Beta-blocker overdose may result in significant resistance to resuscitation with adrenergic agents, including beta-agonists. On the basis of the pharmacologic actions of metoprolol, employ the following measures.

Hemodialysis is unlikely to make a useful contribution to metoprolol elimination [see CLINICAL PHARMACOLOGY].

Bradycardia: Evaluate the need for atropine, adrenergic-stimulating drugs or pacemaker to treat bradycardia and conduction disorders.

Hypotension: Treat underlying bradycardia. Consider intravenous vasopressor infusion, such as dopamine or norepinephrine.

Heart failure and shock: May be treated when appropriate with suitable volume expansion, injection of glucagon (if necessary, followed by an intravenous infusion of glucagon), intravenous administration of adrenergic drugs such as dobutamine, with α1 receptor agonistic drugs added in presence of vasodilation.

Bronchospasm: Can usually be reversed by bronchodilators.

Contraindications for Lopressor

LOPRESSOR is contraindicated in severe bradycardia, second-or third-degree heart block, cardiogenic shock, systolic blood pressure <100, decompensated heart failure, sick sinus syndrome (unless a permanent pacemaker is in place), and in patients who are hypersensitive to any component of this product.

Clinical Pharmacology for Lopressor

Mechanism Of Action

Metoprolol is a beta1-selective (cardioselective) adrenergic receptor blocking agent. 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.

Metoprolol has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable only at plasma concentrations much greater than required for beta-blockade. Animal and human experiments indicate that metoprolol slows the sinus rate and decreases AV nodal conduction.

The relative beta1-selectivity of metoprolol has been confirmed by the following: (1) In normal subjects, metoprolol is unable to reverse the beta₂-mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective 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.

Hypertension

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

Heart Failure

The precise mechanism for the beneficial effects of beta-blockers in heart failure has not been elucidated.

Pharmacodynamics

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.

The relationship between plasma metoprolol levels and reduction in exercise heart rate is independent of the pharmaceutical formulation. Beta1-blocking effects in the range of 30-80% of the maximal effect (approximately 8 to 23% reduction in exercise heart rate) correspond to metoprolol plasma concentrations from 30 to 540 nmol/L. The relative beta1-selectivity of metoprolol diminishes and blockade of beta₂-adrenoceptors increases at plasma concentration above 300 nmol/L.

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, 5.0, 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 Lopressor 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.

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.

Elimination

Elimination of Lopressor 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.

Metabolism

Lopressor 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 severalfold higher plasma concentrations of Lopressor than extensive metabolizers with normal CYP2D6 activity thereby decreasing Lopressor’s cardioselectivity.

Excretion

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 stereo-isomers does not exhibit stereo-selectivity in renal excretion.

Specific 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 Lopressor 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.

Drug Interactions

Metoprolol is metabolized predominantly by CYP2D6. In healthy subjects with CYP2D6 extensive metabolizer phenotype, coadministration of quinidine 100 mg, a potent CYP2D6 inhibitor, and immediate-release metoprolol 200 mg tripled the concentration of S-metoprolol and doubled the metoprolol elimination half-life. In four patients with cardiovascular disease, coadministration of propafenone 150 mg t.i.d. with immediate-release metoprolol 50 mg t.i.d. increased the steady-state metoprolol concentration 2-to 5-fold compared to metoprolol alone. Extensive metabolizers who concomitantly use CYP2D6 inhibiting drugs will have increased (several-fold) metoprolol blood levels, decreasing metoprolol's cardioselectivity [see DRUG INTERACTIONS].

Pharmacogenomics

CYP2D6 is absent in about 8% of Caucasians (poor metabolizers) and about 2% of most other populations. CYP2D6 can be inhibited by several drugs. Poor metabolizers of CYP2D6 will have increased (several-fold) metoprolol blood levels, decreasing metoprolol's cardioselectivity.

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 mg 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 mg 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.

Patient Information for Lopressor

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

Inform patients or caregivers that there is a risk of hypoglycemia when LOPRESSOR is given to patients who are fasting or who are vomiting. Monitor for symptoms of hypoglycemia.