CATEGORIES: Hypertension, essential; Myocardial infarction; Heart failure, congestive; Angina pectoris; Pregnancy Category C; FDA Approved August 1978
Drug Classes: Antiadrenergics, beta blocking
BRAND NAMES: Lopressor; Toprol XL
FOREIGN BRAND AVAILABILITY:
Apo-Metoprolol (Canada);
Beloc (Austria, Colombia, Germany);
Beloc Duriles (Austria);
Beloc Zok (Switzerland);
Betaloc (New Zealand, Canada, China, England, Hong Kong, Hungary, India, Ireland, Korea, Malaysia, Philippines, Russia, Taiwan, Thailand);
Betaloc CR (New Zealand);
Betaloc Zok (Hong Kong, Singapore, Taiwan);
Betazok (Philippines);
Betoprolol (Colombia);
Cardeloc (Thailand);
Cardiosel (Indonesia, Philippines);
Cardiostat (Philippines);
Denex (Hong Kong, Thailand);
Jutabloc (Germany);
Kenaprol (Mexico);
Lofarbil (Greece);
Lopresor (South Africa, Austria, Belgium, Bulgaria, Canada, Colombia, Czech Republic, England, Germany, Greece, Indonesia, Ireland, Italy, Japan, Mexico, Netherlands, Portugal, Russia, South Africa, Spain, Turkey);
Lopresor Oros (Taiwan);
Lopresor Retard (Austria, Bulgaria, Greece, Italy, Portugal, Switzerland);
Lopresor SR (England);
Meto-Hennig (Germany);
Metohexal (Australia);
Metolol (Australia, Thailand);
Metopress Retard (Israel);
Metoprim (Philippines);
Metoprogamma (Germany);
Minax (Hong Kong, Taiwan);
Montebloc (Philippines);
Neobloc (Israel);
Prolaken (Mexico);
Ritmolol (Mexico);
Sefloc (Hong Kong);
Selokeen (Netherlands);
Seloken (Belgium, Denmark, Finland, France, Indonesia, Italy, Japan, Mexico, Norway, Spain, Sweden);
Seloken Retard (Austria, Italy);
Seloken Zoc (Finland, Mexico, Sweden);
Selopral (Finland);
Selozok (Belgium);
Selo-zok (Denmark, Norway);
Slow-Lopresor (New Zealand);
Vasocardin (China)
COST OF THERAPY:
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Note: The trade names have been used throughout this monograph for clarity.
Lopressor
Lopressor, metoprolol tartrate, is a selective beta1-adrenoreceptor blocking agent, available as 50 and 100 mg tablets for oral administration and in 5 ml ampuls for intravenous (IV) administration. Each ampul contains a sterile solution of metoprolol tartrate, 5 mg, and sodium chloride, 45 mg. Metoprolol tartrate is (±)-1-(isopropylamino)-3-[p-(2-methoxyethyl)phenoxy]-2-propanol (2:1) dextro-tartrate salt.
Metoprolol tartrate 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.
Toprol-XL
Toprol-XL, metoprolol succinate, is a beta1-selective (cardioselective) adrenoceptor blocking agent, for oral administration, available as extended release tablets. Toprol-XL has been formulated to provide a controlled and predictable release of metoprolol for once daily administration. The tablets comprise a multiple unit system containing metoprolol succinate in a multitude of controlled release pellets. Each pellet acts as a separate drug delivery unit and is designed to deliver metoprolol continuously over the dosage interval. The tablets contain 23.75, 47.5, 95 and 190 mg of metoprolol succinate equivalent to 25, 50, 100 and 200 mg of metoprolol tartrate, respectively. Its chemical name is (±)1-(isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol succinate (2:1) (salt).
Metoprolol succinate is a white crystalline powder with a molecular weight of 652.8. It is freely soluble in water; soluble in methanol; sparingly soluble in ethanol; slightly soluble in dichloromethane and 2-propanol; practically insoluble in ethylacetate, acetone, diethylether and heptane. Inactive ingredients: silicon dioxide, cellulose compounds, sodium stearyl fumarate, polyethylene glycol, titanium dioxide, paraffin.
Lopressor
Lopressor is a beta-adrenergic receptor blocking agent. In vitro and in vivo animal studies have shown that it has a preferential effect on beta1 adrenoreceptors, chiefly located in cardiac muscle. This preferential effect is not absolute, however, and at higher doses, Lopressor also inhibits beta2 adrenoreceptors, chiefly located in the bronchial and vascular musculature.
Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in man, as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia.
Relative beta1 selectivity has been confirmed by the following: (1) In normal 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 FEV1 and FVC significantly less than a nonselective beta blocker, propranolol, at equivalent beta1-receptor blocking doses.
Lopressor has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable only at doses much greater than required for beta blockade. Lopressor crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration. Animal and human experiments indicate that Lopressor slows the sinus rate and decreases AV nodal conduction.
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 100-450 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, and to be equally effective in supine and standing positions.
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.
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 of angina pectoris. However, in patients with heart failure, beta-adrenergic blockade may increase oxygen requirements by increasing left ventricular fiber length and end-diastolic pressure.
Although beta-adrenergic receptor blockade is useful in the treatment of angina and hypertension, there are situations in which sympathetic stimulation is vital. In patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. In the presence of AV block, beta blockade may prevent the necessary facilitating effect of sympathetic activity on conduction. Beta2-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients.
In controlled clinical trials, Lopressor, 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 100-400 mg daily. A controlled, comparative, clinical trial showed that Lopressor was indistinguishable from propranolol in the treatment of angina pectoris.
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 IV 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 IV therapy were also observed with Lopressor and were independent of the interval between onset of symptoms and initiation of therapy.
The precise mechanism of action of Lopressor in patients with suspected or definite myocardial infarction is not known.
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 IV 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.
Pharmacokinetics
In man, absorption of Lopressor is rapid and complete. Plasma levels following oral administration, however, approximate 50% of levels following IV administration, indicating about 50% first-pass metabolism.
Plasma levels achieved are highly variable after oral administration. Only a small fraction of the drug (about 12%) is bound to human serum albumin. Elimination is mainly by biotransformation in the liver, and the plasma half-life ranges from approximately 3-7 hours. Less than 5% of an oral dose of Lopressor is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no clinical significance. 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 with chronic renal failure.
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 registered 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.
Following IV administration of Lopressor, the urinary recovery of unchanged drug is approximately 10%. When the drug was infused over a 10 minute period, in normal volunteers, maximum beta blockade was achieved at approximately 20 minutes. Doses of 5 mg and 15 mg yielded a maximal reduction in exercise-induced heart rate of approximately 10% and 15%, respectively. The effect on exercise heart rate decreased linearly with time at the same rate for both doses, and disappeared at approximately 5 hours and 8 hours for the 5 mg and 15 mg doses, respectively.
Equivalent maximal beta-blocking effect is achieved with oral and IV 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, IV 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.
In patients with angina pectoris, plasma concentration measured at 1 hour is linearly related to the oral dose within the range of 50-400 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.
Toprol-XL
General
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.
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 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.
In five controlled studies in normal healthy subjects, the same daily doses of Toprol-XL and immediate release metoprolol were compared in terms of the extent and duration of beta1-blockade produced. Both formulations were given in a dose range equivalent to 100-400 mg of immediate release metoprolol per day. In these studies, Toprol-XL was administered once a day and immediate release metoprolol was administered once to 4 times a day. A sixth controlled study compared the beta1-blocking effects of a 50 mg daily dose of the 2 formulations. In each study, beta1-blockade was expressed as the percent change from baseline in exercise heart rate following standardized submaximal exercise tolerance tests at steady-state. Toprol-XL administered once a day, and immediate release metoprolol administered once to 4 times a day, provided comparable total beta1- blockade over 24 hours (area under the beta1-blockade versus time curve) in the dose range 100-400 mg. At a dosage of 50 mg once daily, Toprol-XL produced significantly higher total beta1-blockade over 24 hours than immediate release metoprolol. For Toprol-XL, the percent reduction in exercise heart rate was relatively stable throughout the entire dosage interval and the level of beta1-blockade increased with increasing doses from 50-300 mg daily. The effects at peak/trough (i.e., at 24 hours post dosing) were; 14/9, 16/10, 24/14, 27/22 and 27/20% reduction in exercise heart rate for doses of 50, 100, 200, 300 and 400 mg Toprol-XL once a day, respectively. In contrast to Toprol-XL, immediate release metoprolol given at a dose of 50-100 mg once a day produced a significantly larger peak effect on exercise tachycardia, but the effect was not evident at 24 hours. To match the peak to trough ratio obtained with Toprol-XL over the dosing range of 200-400 mg, a tid to qiddivided dosing regimen was required for immediate release metoprolol. A controlled cross-over study in heart failure patients compared the plasma concentrations and beta1-blocking effects of 50 mg immediate release metoprolol administered tid, 100 and 200 mg Toprol-XL once daily. A 50 mg dose of immediate release metoprolol tid produced a peak plasma level of metoprolol similar to the peak level observed with 200 mg of Toprol-XL. A 200 mg dose of Toprol-XL produced a larger effect on suppression of exercise-induced and Holter-monitored heart rate over 24 hours compared to 50 mg tid of immediate release metoprolol.
The relationship between plasma metoprolol levels and reduction in exercise heart rate is independent of the pharmaceutical formulation. Using the Emax model, the maximal beta1-blocking effect has been estimated to produce a 30% reduction in exercise heart rate. Beta1-blocking effects in the range of 30-80% of the maximal effect (corresponding to approximately 8-23% reduction in exercise heart rate) are expected to occur at metoprolol plasma concentrations ranging from 30-540 nmol/L. The concentration-effect curve begins reaching a plateau between 200-300 nmol/L, and higher plasma levels produce little additional beta1-blocking effect. The relative beta1-selectivity of metoprolol diminishes and blockade of beta2-adrenoceptors increases at higher plasma concentrations.
Although beta-adrenergic receptor blockade is useful in the treatment of angina, hypertension, and heart failure there are situations in which sympathetic stimulation is vital. In patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. In the presence of AV block, beta-blockade may prevent the necessary facilitating effect of sympathetic activity on conduction. Beta2-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients.
In other studies, treatment with Toprol-XL produced an improvement in left ventricular ejection fraction. Toprol-XL was also shown to delay the increase in left ventricular end-systolic and end-diastolic volumes after 6 months of treatment.
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.
Clinical Trials
In controlled clinical studies, an immediate release dosage form of metoprolol has been shown to be an effective antihypertensive agent when used alone or as concomitant therapy with thiazide-type diuretics at dosages of 100-450 mg daily. Toprol-XL, in dosages of 100-400 mg once daily, has been shown to possess comparable β1-blockade as conventional metoprolol tablets administered 2-4 times daily. In addition, Toprol-XL administered at a dose of 50 mg once daily has been shown to lower blood pressure 24 hours post dosing in placebo-controlled studies. In controlled, comparative, clinical studies, immediate release metoprolol appeared comparable as an antihypertensive agent to propranolol, methyldopa, and thiazide-type diuretics, and affected both supine and standing blood pressure. Because of variable plasma levels attained with a given dose and lack of consistent relationship of antihypertensive activity to drug plasma concentration, selection of proper dosage requires individual titration.
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.
Clinical Trials
In controlled clinical trials, an immediate release formulation of metoprolol 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 100-400 mg daily. Toprol-XL, in dosages of 100-400 mg once daily, has been shown to possess beta-blockade similar to conventional metoprolol tablets administered 2-4 times daily.
Heart Failure
The precise mechanism for the beneficial effects of beta-blockers in heart failure has not been elucidated.
Clinical Trials
MERIT-HF was a double-blind, placebo-controlled study of Toprol-XL conducted in 14 countries including the US. It randomized 3991 patients (1990 to Toprol-XL) with ejection fraction ≤0.40 and NYHA Class II-IV heart failure attributable to ischemia, hypertension, or cardiomyopathy. The protocol excluded patients with contraindications to beta-blocker use, those expected to undergo heart surgery, and those within 28 days of myocardial infarction or unstable angina. The primary endpoints of the trial were (1) all-cause mortality plus all-cause hospitalization (time to first event) and (2) all-cause mortality. Patients were stabilized on optimal concomitant therapy for heart failure, including diuretics, ACE inhibitors, cardiac glycosides, and nitrates. At randomization, 41% of patients were NYHA Class II, 55% NYHA Class III; 65% of patients had heart failure attributed to ischemic heart disease; 44% had a history of hypertension; 25% had diabetes mellitus; 48% had a history of myocardial infarction. Among patients in the trial, 90% were on diuretics, 89% were on ACE inhibitors, 64% were on digitalis, 27% were on a lipid-lowering agent, 37% were on an oral anticoagulant, and the mean ejection fraction was 0.28. The mean duration of follow-up was 1 year. At the end of the study, the mean daily dose of Toprol-XL was 159 mg.
The trial was terminated early for a statistically significant reduction in all-cause mortality (34%, nominal p=0.00009). The risk of all-cause mortality plus all-cause hospitalization was reduced by 19% (p=0.00012). The trial also showed improvements in heart failure-related mortality and heart failure-related hospitalizations, and NYHA functional class.
TABLE 1 shows the principal results for the overall study population. The combined endpoints of all-cause mortality plus all-cause hospitalization and of mortality plus heart failure hospitalization showed consistent effects in the overall study population and the subgroups, including women and the US population. However, in the US subgroup (n=1071) and women (n=898), overall mortality and cardiovascular mortality appeared less affected. Analyses of female and US patients were carried out because they each represented about 25% of the overall population. Nonetheless, subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects.
Pharmacokinetics
In man, absorption of metoprolol is rapid and complete. Plasma levels following oral administration of conventional metoprolol tablets, however, approximate 50% of levels following intravenous (IV) administration, indicating about 50% first-pass metabolism. Metoprolol crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration.
Plasma levels achieved are highly variable after oral administration. Only a small fraction of the drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of R- and S-enantiomers, and is primarily metabolized by CYP2D6. When administered orally, it exhibits stereoselective metabolism that is dependent on oxidation phenotype. Elimination is mainly by biotransformation in the liver, and the plasma half-life ranges from approximately 3-7 hours. Less than 5% of an oral dose of metoprolol is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no beta-blocking activity. Following IV administration of metoprolol, the urinary recovery of unchanged drug is approximately 10%. The systemic availability and half-life of metoprolol in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. Consequently, no reduction in dosage is usually needed in patients with chronic renal failure.
Metoprolol is metabolized predominantly by CYP2D6, an enzyme that is absent in about 8% of Caucasians (poor metabolizers) and about 2% of most other populations. CYP2D6 can be inhibited by a number of drugs. Concomitant use of inhibiting drugs in poor metabolizers will increase blood levels of metoprolol several-fold, decreasing metoprolol's cardioselectivity. (See DRUG INTERACTIONS, Toprol-XL.)
In comparison to conventional metoprolol, the plasma metoprolol levels following administration of Toprol-XL are characterized by lower peaks, longer time to peak and significantly lower peak to trough variation. The peak plasma levels following once daily administration of Toprol-XL average one-fourth to one-half the peak plasma levels obtained following a corresponding dose of conventional metoprolol, administered once daily or in divided doses. At steady-state the average bioavailability of metoprolol following administration of Toprol-XL, across the dosage range of 50-400 mg once daily, was 77% relative to the corresponding single or divided doses of conventional metoprolol. Nevertheless, over the 24 hour dosing interval, β1-blockade is comparable and dose-related (see CLINICAL PHARMACOLOGY, Toprol-XL). The bioavailability of metoprolol shows a dose-related, although not directly proportional, increase with dose and is not significantly affected by food following Toprol-XL administration.
Lopressor
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 ampuls and tablets are indicated in the treatment of hemodynamically stable patients with definite or suspected acute myocardial infarction to reduce cardiovascular mortality. Treatment with IV Lopressor can be initiated as soon as the patient's clinical condition allows (see DOSAGE AND ADMINISTRATION, Lopressor; CONTRAINDICATIONS, Lopressor; and WARNINGS, Lopressor). Alternatively, treatment can begin within 3-10 days of the acute event (see DOSAGE AND ADMINISTRATION, Lopressor).
Toprol-XL
Hypertension
Toprol-XL is indicated for the treatment of hypertension. They may be used alone or in combination with other antihypertensive agents.
Angina Pectoris
Toprol-XL is indicated in the long-term treatment of angina pectoris.
Heart Failure
Toprol-XL is indicated for the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. It was studied in patients already receiving ACE inhibitors, diuretics, and, in the majority of cases, digitalis. In this population, Toprol-XL decreased the rate of mortality plus hospitalization, largely through a reduction in cardiovascular mortality and hospitalizations for heart failure.
Lopressor
Hypertension and Angina
Lopressor is contraindicated in sinus bradycardia, heart block greater than first degree, cardiogenic shock, and overt cardiac failure (see WARNINGS, Lopressor).
Myocardial Infarction
Lopressor 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 seconds); systolic blood pressure <100 mm Hg; or moderate-to-severe cardiac failure (see WARNINGS, Lopressor).
Toprol-XL
Toprol-XL is contraindicated in severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place) (see WARNINGS, Toprol-XL) and in patients who are hypersensitive to any component of this product.
Lopressor
Hypertension and Angina
Cardiac Failure
Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure, and beta blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. In hypertensive and angina patients who have congestive heart failure controlled by digitalis and diuretics, Lopressor should be administered cautiously. Both digitalis and Lopressor slow AV conduction.
In Patients Without a History of Cardiac Failure
Continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or given a diuretic. The response should be observed closely. If cardiac failure continues, despite adequate digitalization and diuretic therapy, Lopressor should be withdrawn.
Ischemic Heart Disease
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Bronchospastic Diseases
PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA BLOCKERS. Because of its relative beta1 selectivity, however, Lopressor may be used with caution in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Since beta1 selectivity is not absolute, a beta2-stimulating agent should be administered concomitantly, and the lowest possible dose of Lopressor should be used. In these circumstances it would be prudent initially to administer Lopressor 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, Lopressor .)
Major Surgery
The necessity or desirability of withdrawing beta-blocking therapy prior to major surgery is controversial; the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
Lopressor, like other beta blockers, is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Difficulty in restarting and maintaining the heart beat has also been reported with beta blockers.
Diabetes and Hypoglycemia
Lopressor should be used with caution in diabetic patients if a beta-blocking agent is required. Beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.
Thyrotoxicosis
Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta blockade, which might precipitate a thyroid storm.
Myocardial Infarction
Cardiac Failure
Sympathetic stimulation is a vital component supporting circulatory function, and beta blockade carries the potential hazard of depressing myocardial contractility and precipitating or exacerbating minimal cardiac failure.
During treatment with Lopressor, the hemodynamic status of the patient should be carefully monitored. If heart failure occurs or persists despite appropriate treatment, Lopressor should be discontinued.
Bradycardia
Lopressor produces a decrease in sinus heart rate in most patients; this decrease is greatest among patients with high initial heart rates and least among patients with low initial heart rates. Acute myocardial infarction (particularly inferior infarction) may in itself produce significant lowering of the sinus rate. If the sinus rate decreases to <40 beats/min, particularly if associated with evidence of lowered cardiac output, atropine (0.25-0.5 mg) should be administered intravenously. If treatment with atropine is not successful, Lopressor should be discontinued, and cautious administration of isoproterenol or installation of a cardiac pacemaker should be considered.
AV Block
Lopressor slows AV conduction and may produce significant first- (P-R interval ≥0.26 seconds), second-, or third-degree heart block. Acute myocardial infarction also produces heart block.
If heart block occurs, Lopressor should be discontinued and atropine (0.25-0.5 mg) should be administered intravenously. If treatment with atropine is not successful, cautious administration of isoproterenol or installation of a cardiac pacemaker should be considered.
Hypotension
If hypotension (systolic blood pressure ≤90 mm Hg) occurs, Lopressor should be discontinued, and the hemodynamic status of the patient and the extent of myocardial damage carefully assessed. Invasive monitoring of central venous, pulmonary capillary wedge, and arterial pressures may be required. Appropriate therapy with fluids, positive inotropic agents, balloon counterpulsation, or other treatment modalities should be instituted. If hypotension is associated with sinus bradycardia or AV block, treatment should be directed at reversing these (see above).
Bronchospastic Diseases
PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA BLOCKERS. Because of its relative beta1 selectivity, Lopressor may be used with extreme caution in patients with bronchospastic disease. Because it is unknown to what extent beta2-stimulating agents may exacerbate myocardial ischemia and the extent of infarction, these agents should not be used prophylactically. If bronchospasm not related to congestive heart failure occurs, Lopressor should be discontinued. A theophylline derivative or a beta2 agonist may be administered cautiously, depending on the clinical condition of the patient. Both theophylline derivatives and beta2 agonists may produce serious cardiac arrhythmias.
Toprol-XL
Ischemic Heart Disease
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Bronchospastic Diseases
PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of its relative beta1-selectivity, however, Toprol-XL may be used with caution in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Since beta1- selectivity is not absolute, a beta2-stimulating agent should be administered concomitantly, and the lowest possible dose of Toprol-XL should be used (see DOSAGE AND ADMINISTRATION, Toprol-XL).
Major Surgery
The necessity or desirability of withdrawing beta-blocking therapy prior to major surgery is controversial; the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
Toprol-XL, like other beta-blockers, is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Difficulty in restarting and maintaining the heart beat has also been reported with beta-blockers.
Diabetes and Hypoglycemia
Toprol-XL should be used with caution in diabetic patients if a beta-blocking agent is required. Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.
Thyrotoxicosis
Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-blockade, which might precipitate a thyroid storm.
Peripheral Vascular Disease
Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.
Calcium Channel Blockers
Because of significant inotropic and chronotropic effects in patients treated with beta-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be exercised in patients treated with these agents concomitantly.
Lopressor
General
Lopressor should be used with caution in patients with impaired hepatic function.
Information for the Patient
Patients should be advised 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.
Patients should be advised (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.
Carcinogenesis, Mutagenesis, and 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/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/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, nor 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.
No evidence of impaired fertility due to Lopressor was observed in a study performed in rats at doses up to 55.5 times the maximum daily human dose of 450 mg.
Pregnancy Category C
Lopressor has been shown to increase postimplantation loss and decrease neonatal survival in rats at doses up to 55.5 times the maximum daily human dose of 450 mg. Distribution studies in mice confirm exposure of the fetus when Lopressor is administered to the pregnant animal. These studies have revealed no evidence of impaired fertility or teratogenicity. There are no adequate and well-controlled studies in pregnant women. 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. Caution should be exercised when Lopressor is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Toprol-XL
General
Toprol-XL should be used with caution in patients with impaired hepatic function. In patients with pheochromocytoma, an alpha-blocking agent should be initiated prior to the use of any beta-blocking agent.
Worsening cardiac failure may occur during up-titration of Toprol-XL. If such symptoms occur, diuretics should be increased and the dose of Toprol-XL should not be advanced until clinical stability is restored (see DOSAGE AND ADMINISTRATION, Toprol-XL). It may be necessary to lower the dose of Toprol-XL or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of Toprol-XL.
Information for the Patient
Patients should be advised to take Toprol-XL regularly and continuously, as directed, preferably 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 interrupt or discontinue Toprol-XL without consulting the physician.
Patients should be advised (1) to avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient's response to therapy with Toprol-XL 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 Toprol-XL.
Heart failure patients should be advised to consult their physician if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath.
Laboratory Tests
Clinical laboratory findings may include elevated levels of serum transaminase, alkaline phosphatase, and lactate dehydrogenase.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term studies in animals have been conducted to evaluate the carcinogenic potential of metoprolol tartrate. In 2 year studies in rats at 3 oral dosage levels of up to 800 mg/kg/day (41 times, on a mg/m2 basis, the daily dose of 200 mg for a 60 kg patient), 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 3 oral dosage levels of up to 750 mg/kg/day (18 times, on a mg/m2 basis, the daily dose of 200 mg for 60 kg patient), 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, nor 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 genotoxicity tests performed on metoprolol tartrate (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) and metoprolol succinate (a Salmonella/mammalian-microsome mutagenicity test) were negative.
No evidence of impaired fertility due to metoprolol tartrate was observed in a study performed in rats at doses up to 22 times, on a mg/m2 basis, the daily dose of 200 mg in a 60 kg patient.
Pregnancy Category C
Metoprolol tartrate has been shown to increase post-implantation loss and decrease neonatal survival in rats at doses up to 22 times, on a mg/m2 basis, the daily dose of 200 mg in a 60 kg patient. Distribution studies in mice confirm exposure of the fetus when metoprolol tartrate is administered to the pregnant animal. These studies have revealed no evidence of impaired fertility or teratogenicity. There are no adequate and well-controlled studies in pregnant women. 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 very small quantities. An infant consuming 1 L of breast milk daily would receive a dose of less than 1 mg of the drug. Caution should be exercised when Toprol-XL is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of Toprol-XL in hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience in hypertensive patients has not identified differences in responses between elderly and younger patients.
Of the 1990 patients with heart failure randomized to Toprol-XL in the MERIT-HF trial, 50% (990) were 65 years of age and older and 12% (238) were 75 years of age and older. There were no notable differences in efficacy or the rate of adverse events between older and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Risk of Anaphylactic Reactions
While taking beta-blockers, patients with a history of severe anaphylactic reactions 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.
Lopressor
Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients treated with Lopressor plus a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.
Risk of Anaphylactic Reaction
While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.
Toprol-XL
Catecholamine-depleting drugs (e.g., reserpine, mono amine oxidase (MAO) inhibitors) may have an additive effect when given with beta-blocking agents. Patients treated with Toprol-XL plus a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.
Drugs that inhibit CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone are likely to increase metoprolol concentration. In healthy subjects with CYP2D6 extensive metabolizer phenotype, coadministration of quinidine 100 mg and immediate release metoprolol 200 mg tripled the concentration of S-metoprolol and doubled the metoprolol elimination half-life. In 4 patients with cardiovascular disease, coadministration of propafenone 150 mg tid with immediate release metoprolol 50 mg tid resulted in 2- to 5-fold increases in the steady-state concentration of metoprolol. These increases in plasma concentration would decrease the cardioselectivity of metoprolol.
Beta-blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the 2 drugs are coadministered, the beta blocker should be withdrawn several days before the gradual withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, the introduction of beta-blockers should be delayed for several days after clonidine administration has stopped.
Lopressor
Hypertension and Angina
Most adverse effects have been mild and transient.
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.
The oculomucocutaneous syndrome associated with the beta blocker practolol has not been reported with Lopressor.
Myocardial Infarction
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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.
Toprol-XL
Hypertension and Angina
Most adverse effects have been mild and transient. The following adverse reactions have been reported for immediate release metoprolol tartrate.
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. The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with metoprolol.
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 Toprol-XL.
Heart Failure
In the MERIT-HF study, serious adverse events and adverse events leading to discontinuation of study medication were systematically collected. In the MERIT-HF study comparing Toprol-XL in daily doses up to 200 mg (mean dose 159 mg once daily) (n=1990) to placebo (n=2001), 10.3% of Toprol-XL patients discontinued for adverse events versus 12.2% of placebo patients.
TABLE 3 lists adverse events in the MERIT-HF study that occurred at an incidence of equal to or greater than 1% in the Toprol-XL group and greater than placebo by more than 0.5%, regardless of the assessment of causality.
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Other adverse events with an incidence of >1% on Toprol-XL and as common on placebo (within 0.5%) included myocardial infarction, pneumonia, cerebrovascular disorder, chest pain, dyspnea/dyspnea aggravated, syncope, coronary artery disorder, ventricular tachycardia/arrhythmia aggravated, hypotension, diabetes mellitus/ diabetes mellitus aggravated, abdominal pain, and fatigue.
Post-Marketing Experience
The following adverse reactions have been reported with Toprol-XL in worldwide post-marketing use, regardless of causality:
Lopressor
Acute Toxicity
Several cases of overdosage have been reported, some leading to death.
Oral LD50s (mg/kg): Mice, 1158-2460; rats, 3090-4670.
Signs and Symptoms
Potential signs and symptoms associated with overdosage with Lopressor are bradycardia, hypotension, bronchospasm, and cardiac failure.
Treatment
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, Lopressor, Myocardial Infarction).
On the basis of the pharmacologic actions of Lopressor, the following general measures should be employed:
Toprol-XL
Acute Toxicity
There have been a few reports of overdosage with Toprol-XL and no specific overdosage information was obtained with this drug, with the exception of animal toxicology data. However, since Toprol-XL (metoprolol succinate salt) contains the same active moiety, metoprolol, as conventional metoprolol tablets (metoprolol tartrate salt), the recommendations on overdosage for metoprolol conventional tablets are applicable to Toprol-XL.
Signs and Symptoms
Overdosage of Toprol-XL may lead to severe hypotension, sinus bradycardia, atrioventricular block, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, impairment of consciousness/coma, nausea, vomiting, and cyanosis.
Treatment
In general, patients with acute or recent myocardial infarction or congestive heart failure may be more hemodynamically unstable than other patients and should be treated accordingly. When possible the patient should be treated under intensive care conditions. On the basis of the pharmacologic actions of metoprolol, the following general measures should be employed:
Lopressor
Hypertension
The dosage of Lopressor should be individualized. Lopressor should be taken with or immediately following meals.
The usual initial dosage is 100 mg daily in single or divided doses, whether used alone or added to a diuretic. The dosage may be increased 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 is 100-450 mg/day. Dosages above 450 mg/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 Lopressor is increased.
Angina Pectoris
The dosage of Lopressor should be individualized. Lopressor should be taken with or immediately following meals.
The usual initial dosage is 100 mg daily, given in two divided doses. The dosage may be gradually increased at weekly intervals until optimum clinical response has been obtained or there is pronounced slowing of the heart rate. The effective dosage range is 100-400 mg/day. Dosages above 400 mg/day have not been studied. If treatment is to be discontinued, the dosage should be reduced gradually over a period of 1-2 weeks (see WARNINGS, Lopressor).
Myocardial Infarction
Early Treatment
During the early phase of definite or suspected acute myocardial infarction, treatment with Lopressor can be initiated as soon as possible after the patient's arrival in the hospital. Such treatment should be initiated in a coronary care or similar unit immediately after the patient's hemodynamic condition has stabilized.
Treatment in this early phase should begin with the IV administration of three bolus injections of 5 mg of Lopressor each; the injections should be given at approximately 2 minute intervals. During the IV administration of Lopressor, blood pressure, heart rate, and electrocardiogram should be carefully monitored.
In patients who tolerate the full IV dose (15 mg), Lopressor tablets, 50 mg every 6 hours, should be initiated 15 minutes after the last IV dose and continued for 48 hours. Thereafter, patients should receive a maintenance dosage of 100 mg twice daily (see Late Treatment).
Patients who appear not to tolerate the full IV dose should be started on Lopressor tablets either 25 or 50 mg every 6 hours (depending on the degree of intolerance) 15 minutes after the last IV dose or as soon as their clinical condition allows. In patients with severe intolerance, treatment with Lopressor should be discontinued (see WARNINGS, Lopressor).
Late Treatment
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 should be started on Lopressor tablets, 100 mg twice daily, as soon as their clinical condition allows. Therapy should be continued 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 1-3 years.
Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Toprol-XL
Toprol-XL is an extended release tablet intended for once a day administration. When switching from immediate release metoprolol tablet to Toprol-XL, the same total daily dose of Toprol-XL should be used.
As with immediate release metoprolol, dosages of Toprol-XL should be individualized and titration may be needed in some patients.
Toprol-XL tablets are scored and can be divided; however, the whole or half tablet should be swallowed whole and not chewed or crushed.
Hypertension
The usual initial dosage is 50-100 mg daily in a single dose, whether used alone or added to a diuretic. The dosage may be increased 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. Dosages above 400 mg/day have not been studied.
Angina Pectoris
The dosage of Toprol-XL should be individualized. The usual initial dosage is 100 mg daily, given in a single dose. The dosage may be gradually increased at weekly intervals until optimum clinical response has been obtained or there is a pronounced slowing of the heart rate. Dosages above 400 mg/day have not been studied. If treatment is to be discontinued, the dosage should be reduced gradually over a period of 1-2 weeks (see WARNINGS, Toprol-XL).
Heart Failure
Dosage must be individualized and closely monitored during up-titration. Prior to initiation of Toprol-XL, the dosing of diuretics, ACE inhibitors, and digitalis (if used) should be stabilized. The recommended starting dose of Toprol-XL is 25 mg once daily for 2 weeks in patients with NYHA Class II heart failure and 12.5 mg once daily in patients with more severe heart failure. The dose should then be doubled every 2 weeks to the highest dosage level tolerated by the patient or up to 200 mg of Toprol-XL. If transient worsening of heart failure occurs, it may be treated with increased doses of diuretics, and it may also be necessary to lower the dose of Toprol-XL or temporarily discontinue it. The dose of Toprol-XL should not be increased until symptoms of worsening heart failure have been stabilized. Initial difficulty with titration should not preclude later attempts to introduce Toprol-XL. If heart failure patients experience symptomatic bradycardia, the dose of Toprol-XL should be reduced.
Lopressor
Lopressor Tablets
Lopressor (metoprolol tartrate) tablets are available in:
Storage: Store between 15-30°C (59-86°F). Protect from moisture. Dispense in tight, light-resistant container.
Lopressor Injection
Lopressor (metoprolol tartrate) injection is available in:
Storage: Do not store above 30°C (86°F). Protect from light.
Toprol-XL Tablets
Storage: Store at 25°C (77°F). Excursions permitted to 15-30°C (59-86°F).
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