用来治疗高血压的美托洛尔

DESCRIPTION

用来治疗高血压的美托洛尔, 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, inchloroform, and in alcohol; slightly soluble in acetone; and insoluble in ether.

INDICATIONS

Myocardial Infarction

用来治疗高血压的美托洛尔ampuls are indicated in the treatment of hemodynamically stable patients with definite or suspected acute myocardialinfarctionto reducecardiovascularmortality when used in conjunction with oral Lopressormaintenance therapy. Treatment with intravenous Lopressor can be initiated as soon as the patient's clinical condition allows (seeDOSAGE AND ADMINISTRATION,CONTRAINDICATIONS, andWARNINGS).

DOSAGE AND ADMINISTRATION

Myocardial Infarction

Early Treatment:During the early phase of definite or suspectedacute myocardial infarction,尽快启动用来治疗高血压的美托洛尔治疗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, andelectrocardiogram.

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 orally twice daily.

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 (seeWARNINGS).

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:用来治疗高血压的美托洛尔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

Parenteraladministration of Lopressor (ampoule) should be done in a setting with intensive monitoring.

Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED

用来治疗高血压的美托洛尔® Injection
metoprolol tartrate injection, USP

Ampuls 5 mL -each containing 5 mg of metoprolol tartrate

Carton of 10 ampuls…………………….NDC0078-0400-01

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [seeUSP Controlled Room Temperature]. Protect from light and heat.

To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

Ampuls manufactured by: Novartis Pharma Stein AG, Stein, Switzerland. Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936. Revised: July 2015

SIDE EFFECTS

Hypertension And Angina

这些不良反应报道混乱关系atment with oral Lopressor. 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 andbradycardiahave occurred in approximately 3 of 100 patients. Cold extremities; arterial insufficiency, usually of the Raynaud type;palpitations;充血性心力failure; peripheral edema; andhypotensionhave been reported in about 1 of 100 patients.坏疽in patients with pre-existing severe peripheralcirculatorydisorders has also been reported very rarely. (SeeCONTRAINDICATIONS,WARNINGS, andPRECAUTIONS.)

Respiratory

Wheezing(bronchospasm) anddyspneahave been reported in about 1 of 100 patients (seeWARNINGS).Rhinitishas also been reported.

Gastrointestinal

Diarrhea has occurred in about 5 of 100 patients. Nausea,dry mouth,gastricpain, constipation,flatulence, andheartburnhave been reported in about 1 of 100 patients. Vomiting was a common occurrence. Postmarketing experience reveals very rare reports ofhepatitis,jaundiceand nonspecific hepatic dysfunction. Isolated cases of transaminase, alkaline phosphatase, and lactic dehydrogenase elevations have also been reported.

Hypersensitive Reactions

Pruritusor rash have occurred in about 5 of 100 patients. Very rarely,photosensitivityand worsening ofpsoriasishas been reported.

Miscellaneous

Peyronie's disease has been reported in fewer than 1 of 100,000 patients. Musculoskeletal pain, blurred vision, andtinnitushave also been reported.

There have been rare reports of reversiblealopecia,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 Lopressor has not been definitely established).

The oculomucocutaneous syndrome associated with thebeta blockerpractolol has not been reported with Lopressor.

Myocardial Infarction

These adverse reactions were reported from treatment regimens where intravenous Lopressor was administered, when tolerated.

Central Nervous System:Tiredness has been reported in about 1 of 100 patients.Vertigo, sleep disturbances, hallucinations, headache, dizziness, visual disturbances, confusion, and reducedlibidohave also been reported, but a drug relationship is not clear.

Cardiovascular:In the randomized comparison of Lopressor and placebo described in theCLINICAL PHARMACOLOGYsection, the following adverse reactions were reported:

	用来治疗高血压的美托洛尔®	Placebo
Hypotension (systolicBP < 90 mmHg)	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-degreeheart 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:Unstablediabetesandclaudicationhave been reported, but a drug relationship is not clear.

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 Lopressor.

Central Nervous System:Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotionallability, slightly cloudedsensorium, and decreased performance on neuropsychometrics.

Cardiovascular:Intensification of AV block (seeCONTRAINDICATIONS).

Hematologic:Agranulocytosis, nonthrombocytopenicpurpura, and thrombocytopenic purpura.

Hypersensitive Reactions:Fever combined with aching andsore throat, laryngospasm, and respiratory distress.

Postmarketing Experience

The following adverse reactions have been reported during postapproval use of Lopressor: confusional state, an increase in bloodtriglyceridesand a decrease in High DensityLipoprotein(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.

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, orpostural hypotension. In addition, possibly significanthypertensionmay theoretically occur up to 14 days following discontinuation of the concomitant administration with an irreversibleMAO inhibitor.

Digitalis Glycosides And Beta Blockers

Both digitalis glycosides and beta blockers slowatrioventricularconduction 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-adrenergicantagonistwith acalcium channel blockermay produce an additive reduction in myocardial contractility because of negative chronotropic andinotropiceffects.

General Anesthetics

Some inhalation anesthetics may enhance the cardiodepressant effect of beta blockers (seeWARNINGS,Major Surgery).

CYP2D6 Inhibitors

Potent inhibitors of the CYP2D6 enzyme may increase the plasma concentration of Lopressor which would mimic the pharmacokinetics of CYP2D6 poor metabolizer (seePharmacokineticssection). Increase in plasma concentrations of metoprolol would decrease the cardioselectivity of metoprolol. Known clinically significant potent inhibitors of CYP2D6 areantidepressantssuch 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;antihistaminessuch as diphenhydramine; antimalarials such as hydroxychloroquine or quinidine; antifungals such as terbinafine.

Hydralazine

Concomitant administration of hydralazine may inhibit presystemicmetabolismof metoprolol leading to increased concentrations of metoprolol.

Alpha-Adrenergic Agents

Antihypertensiveeffect 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 posturalhypotensiveeffect of the first dose of prazosin, probably by preventing reflextachycardia. On the contrary, beta adrenergic blockers may also potentiate thehypertensiveresponse 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 ofergotalkaloids.

Dipyridamole

一般来说,政府的β受体阻滞剂应当d be withheld before dipyridamole testing, with careful monitoring of heart rate following the dipyridamole injection.

WARNINGS

心脏衰竭

Beta blockers, like Lopressor, can cause depression of myocardial contractility and may precipitate heart failure and cardiogenicshock. 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 withcoronary artery disease. Severe exacerbation ofangina,myocardial infarction, andventricular arrhythmiashave been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with betablockers. When discontinuing chronically administered Lopressor, particularly in patients with coronary artery disease, the dosage should be gradually reduced over a period of 1-2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, 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

慢性的ly 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 ofgeneral anesthesiaand surgical procedures.

Bradycardia

Bradycardia, includingsinuspause, heart block, and cardiac arrest have occurred with the use of Lopressor. Patients with first-degree atrioventricular block,sinus nodedysfunction, 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 selectivity, however, Lopressor 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 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 (seeDOSAGE AND ADMINISTRATION). Bronchodilators, including beta2 agonists, should be readily available or administered concomitantly.

Diabetes And Hypoglycemia

Beta blockers may mask tachycardia occurring withhypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.

Pheochromocytoma

If Lopressor is used in the setting ofpheochromocytoma, 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 inskeletal muscle.

Thyrotoxicosis

用来治疗高血压的美托洛尔may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Avoid abrupt withdrawal of beta blockade, which might precipitate athyroidstorm.

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 ofepinephrineused to treat allergic reaction.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term studies in animals have been conducted to evaluatecarcinogenicpotential. 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 occurringbenignormalignantneoplasms of any type. The only histologic changes that appeared to be drug related were an increased incidence of generally mildfocalaccumulation of foamy macrophages in pulmonaryalveoliand a slight increase inbiliaryhyperplasia. In a 21-month study in Swissalbino小鼠口服剂量的三个层次上的750毫克/ 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 (adominantlethal study in mice, chromosome studies insomaticcells, a Salmonella/mammalian-microsome mutagenicity test, and anucleusanomalytest in somatic interphase nuclei) were negative.

Reproduction toxicity studies in mice, rats and rabbits did not indicateteratogenicpotential 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 ofviablefetuses per dose, and/or decreases inneonatalsurvival. 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 onspermatogenesisstarting 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.

用来治疗高血压的美托洛尔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 (seeCarcinogenesis, Mutagenesis, Impairment of Fertility).

没有足够的、严谨的研究报告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

用来治疗高血压的美托洛尔is excreted in breast milk in a very small quantity. An infant consuming 1literof breast milk daily would receive a dose of less than 1 mg of the drug.

Fertility

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

用来治疗高血压的美托洛尔showed effects on spermatogenesis in male rats at a therapeutic dose level, but had no effect on rates ofconceptionat higher doses in animal fertility studies (seeCarcinogenesis, Mutagenesis, Impairment of Fertility).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

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.

OVERDOSE

Acute Toxicity

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

Oral LD50'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 specificantidote.

In general, patients with acute or recent myocardial infarction may be more hemodynamically unstable than other patients and should be treated accordingly (seeWARNINGS,Myocardial Infarction).

的基础上Lopre的药物的行为ssor, 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 ordopamine.

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

Cardiac Failure:Administer digitalis glycoside anddiuretic. In shock resulting from inadequate cardiac contractility, consider administration of dobutamine, isoproterenol, or glucagon.

CONTRAINDICATIONS

Hypersensitivity to Lopressor and related derivatives, or to any of the excipients; hypersensitivity to other beta blockers (cross sensitivity between beta blockers can occur).

Myocardial Infarction

用来治疗高血压的美托洛尔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 (seeWARNINGS).

CLINICAL PHARMACOLOGY

Mechanism Of Action

用来治疗高血压的美托洛尔is a beta1-selective (cardioselective) adrenergic receptor blocker. This preferential effect is not absolute, however, and at higher plasma concentrations, Lopressor also inhibits beta2- adrenoreceptors, chiefly located in the bronchial andvascularmusculature.

Clinical pharmacology studies have demonstrated the beta-blocking activity of metoprolol, as shown by (1) reduction in heart rate andcardiac outputat 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, 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, Lopressor reduces the oxygen requirements of the heart at any given level of effort, thus making it useful in the long-term management ofangina pectoris.

Myocardial Infarction

The precise mechanism of action of Lopressor in patients with suspected or definite myocardial infarction is not known.

Pharmacodynamics

Relative beta1 selectivity is demonstrated by the following: (1) In healthy subjects, Lopressor 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, Lopressor reduces FEV₁and FVC significantly less than a nonselective beta blocker, propranolol, at equivalent beta1-receptor blocking doses.

用来治疗高血压的美托洛尔has nointrinsicsympathomimetic activity, and membrane-stabilizing activity is detectable only at doses much greater than required for beta blockade. Animal and human experiments indicate that Lopressor slows the sinus rate and decreases AV nodal conduction.

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.

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.Strokevolume,diastolicblood 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 serumalbumin. 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 andCSFconcentrations close to that observed in plasma have been reported. Metoprolol is not a significant P-glycoproteinsubstrate.

Metabolism

用来治疗高血压的美托洛尔is primarily metabolized by CYP2D6. Metoprolol is a racemic mixture of Rand S- enantiomers, and when administered orally, it exhibits stereo selective 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 Lopressor than extensive metabolizers with normal CYP2D6 activity thereby decreasing Lopressor’s cardioselectivity.

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

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 Lopressor in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. Consequently, no reduction in dosage is usually needed in patients withchronic renal failure.

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, Lopressor has been shown to be an effective antihypertensive agent when used alone or as concomitant therapy with thiazide-type diuretics, at oral dosages of 100-450 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 insupineand standing positions.

Angina Pectoris

In controlled clinical trials, Lopressor, administered orally 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 oral dosage used in these studies ranged from 100-400 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 (1,395 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 ofventricular fibrillationand 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 (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 earlyadverse effecton 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

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.