metoprolol succinate 200 MG 24 HR Extended Release Oral Tablet
Generic Name: METOPROLOL SUCCINATE
Brand Name: TOPROL XL
- Substance Name(s):
- METOPROLOL SUCCINATE
7 •Catecholamine-depleting drugs may have an additive effect when given with beta-blocking agents. (7.1) •CYP2D6 Inhibitors are likely to increase metoprolol concentration. (7.2) •Concomitant use of glycosides, clonidine, and diltiazem and verapamil with beta-blockers can increase the risk of bradycardia. (7.3) •Beta-blockers including metoprolol, may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. (7.3) 7.1 Catecholamine Depleting Drugs Catecholamine depleting drugs (eg, reserpine, monoamine oxidase (MAO) inhibitors) may have an additive effect when given with beta-blocking agents. Observe patients treated with TOPROL-XL plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension. 7.2 CYP2D6 Inhibitors 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 four patients with cardiovascular disease, coadministration of propafenone 150 mg t.i.d. with immediate-release metoprolol 50 mg t.i.d. resulted in two- to five-fold increases in the steady-state concentration of metoprolol. These increases in plasma concentration would decrease the cardioselectivity of metoprolol. 7.3 Digitalis, Clonidine, and Calcium Channel Blockers 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 [see Warnings and Precautions (5.11) ].
10 Signs and Symptoms – Overdosage of TOPROL-XL 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. Seek consultation with a regional poison control center and a medical toxicologist as needed. 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. There is very limited experience with the use of hemodialysis to remove metoprolol, however metoprolol is not highly protein bound. Bradycardia: Administer intravenous atropine; repeat to effect. If the response is inadequate, consider intravenous isoproterenol or other positive chronotropic agents. Evaluate the need for transvenous pacemaker insertion. Hypotension: Treat underlying bradycardia. Consider intravenous vasopressor infusion, such as dopamine or norepinephrine. Bronchospasm: Administer a beta2-agonist, including albuterol inhalation, or an oral theophylline derivative. Cardiac Failure: Administer diuretics or digoxin for congestive heart failure. For cardiogenic shock, consider IV dobutamine, isoproterenol, or glucagon.
11 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, USP, respectively. Its chemical name is (±)1- (isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol succinate (2:1) (salt). Its structural formula is: 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 ethyl-acetate, acetone, diethylether and heptane. Inactive ingredients: silicon dioxide, cellulose compounds, sodium stearyl fumarate, polyethylene glycol, titanium dioxide, paraffin.
14 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 four times a day. A sixth controlled study compared the beta1-blocking effects of a 50 mg daily dose of the two 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 four 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 to 300 mg daily. The effects at peak/trough (ie, 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 to 400 mg, a t.i.d. to q.i.d. divided 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 t.i.d., 100 mg and 200 mg TOPROL-XL once daily. A 50 mg dose of immediate-release metoprolol t.i.d. 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 t.i.d. of immediate-release metoprolol. In a double-blind study, 1092 patients with mild-to-moderate hypertension were randomized to once daily TOPROL-XL (25, 100, or 400 mg), PLENDIL® (felodipine extended-release tablets), the combination, or placebo. After 9 weeks, TOPROL-XL alone decreased sitting blood pressure by 6-8/4-7 mmHg (placebo-corrected change from baseline) at 24 hours post-dose. The combination of TOPROL-XL with PLENDIL has greater effects on blood pressure. In controlled clinical studies, an immediate-release dosage form of metoprolol was 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 to 400 mg once daily, produces similar β1-blockade as conventional metoprolol tablets administered two to four times daily. In addition, TOPROL-XL administered at a dose of 50 mg once daily lowered 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 a consistent relationship of antihypertensive activity to drug plasma concentration, selection of proper dosage requires individual titration. 14.1 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. 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 to 400 mg daily. TOPROL-XL, in dosages of 100 to 400 mg once daily, has been shown to possess beta-blockade similar to conventional metoprolol tablets administered two to four times daily. 14.2 Heart Failure 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 one 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. The table below shows the principal results for the overall study population. The figure below illustrates principal results for a wide variety of subgroup comparisons, including US vs. non-US populations (the latter of which was not pre-specified). 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. Clinical Endpoints in the MERIT-HF Study Clinical Endpoint Number of Patients Relative Risk (95% Cl) Risk Reduction With TOPROL-XL Nominal P-value Placebo n=2001 TOPROL-XL n=1990 All-cause mortality plus all-caused hospitalizationTime to first event 767 641 0.81(0.73- 0.90) 19% 0.00012 All-cause mortality 217 145 0.66(0.53- 0.81) 34% 0.00009 All-cause mortality plus heart failure hospitalization 439 311 0.69(0.60- 0.80) 31% 0.0000008 Cardiovascular mortality 203 128 0.62(0.50- 0.78) 38% 0.000022 Sudden death 132 79 0.59(0.45- 0.78) 41% 0.0002 Death due to worsening heart failure 58 30 0.51(0.33- 0.79) 49% 0.0023 Hospitalizations due to worsening heart failureComparison of treatment groups examines the number of hospitalizations (Wilcoxon test); relative risk and risk reduction are not applicable. 451 317 N/A N/A 0.0000076 Cardiovascular hospitalization 773 649 N/A N/A 0.00028
16 /STORAGE AND HANDLING Tablets containing metoprolol succinate equivalent to the indicated weight of metoprolol tartrate, USP, are white, biconvex, film-coated, and scored. Tablet Shape Engraving Bottle of 100 NDC 0186- Unit Dose Packages of 100 NDC 0186- 25 mg Oval A/ β 1088-05 1088-39 50 mg Round A/ mo 1090-05 1090-39 100 mg Round A/ ms 1092-05 1092-39 200 mg Oval A/ my 1094-05 N/A Store at 25°C (77°F). Excursions permitted to 15-30°C (59- 86°F). (See USP Controlled Room Temperature.)
RECENT MAJOR CHANGES
Indications and Usage: Benefits of lowering blood pressure (1.1) 10/2012
8.5 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 1,990 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 reactions between older and younger patients. 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.
DOSAGE FORMS AND STRENGTHS
3 25 mg tablets White, oval, biconvex, film-coated scored tablet engraved with “A/β”. 50 mg tablets: White, round, biconvex, film-coated scored tablet engraved with “A/mo”. 100 mg tablets: White, round, biconvex, film-coated scored tablet engraved with “A/ms”. 200 mg tablets: White, oval, biconvex, film-coated scored tablet engraved with “A/my”. •TOPROL-XL Extended-Release Tablets (metoprolol succinate): 25 mg, 50 mg, 100 mg and 200 mg. (3)
MECHANISM OF ACTION
12.1 Mechanism of Action 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. Heart Failure: The precise mechanism for the beneficial effects of beta-blockers in heart failure has not been elucidated.
INDICATIONS AND USAGE
1 TOPROL-XL, metoprolol succinate, is a beta1-selective adrenoceptor blocking agent. TOPROL-XL is indicated for the treatment of: •Hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. (1.1) •Angina Pectoris. (1.2) •Heart Failure – for the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. (1.3) 1.1 Hypertension TOPROL-XL is indicated for the treatment of hypertension, 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 (eg, on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. TOPROL-XL may be administered with other antihypertensive agents. 1.2 Angina Pectoris TOPROL-XL is indicated in the long-term treatment of angina pectoris, to reduce angina attacks and to improve exercise tolerance. 1.3 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.
8.4 Pediatric Use One hundred forty-four hypertensive pediatric patients aged 6 to 16 years were randomized to placebo or to one of three dose levels of TOPROL-XL (0.2, 1.0 or 2.0 mg/kg once daily) and followed for 4 weeks. The study did not meet its primary endpoint (dose response for reduction in SBP). Some pre-specified secondary endpoints demonstrated effectiveness including: •Dose-response for reduction in DBP, •mg/kg vs. placebo for change in SBP, and •mg/kg vs. placebo for change in SBP and DBP. The mean placebo corrected reductions in SBP ranged from 3 to 6 mmHg, and DBP from 1 to 5 mmHg. Mean reduction in heart rate ranged from 5 to 7 bpm but considerably greater reductions were seen in some individuals [see Dosage and Administration (2.1)]. No clinically relevant differences in the adverse event profile were observed for pediatric patients aged 6 to 16 years as compared with adult patients. Safety and effectiveness of TOPROL-XL have not been established in patients < 6 years of age.
8.1 Pregnancy 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, use this drug during pregnancy only if clearly needed.
8.3 Nursing Mothers Metoprolol is excreted in breast milk in very small quantities. An infant consuming 1 liter of breast milk daily would receive a dose of less than 1 mg of the drug. Consider possible infant exposure when TOPROL-XL is administered to a nursing woman.
WARNING: ISCHEMIC HEART DISEASE: Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing chronically administered TOPROL-XL, particularly in patients with ischemic heart 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, TOPROL-XL administration should be reinstated promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Warn patients 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 TOPROL-XL therapy abruptly even in patients treated only for hypertension (5.1). WARNING: ISCHEMIC HEART DISEASE (See Full Prescribing Information for complete boxed warning) Following abrupt cessation of therapy with beta-blocking agents, exacerbations of angina pectoris and myocardial infarction have occurred. Warn patients against interruption or discontinuation of therapy without the physician’s advice. (5.1)
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS •Heart Failure: Worsening cardiac failure may occur. (5.2) •Bronchospastic Disease: Avoid beta blockers. (5.3) •Pheochromocytoma: If required, first initiate therapy with an alpha blocker. (5.4) •Major Surgery: Avoid initiation of high-dose extended-release metoprolol in patients undergoing non-cardiac surgery because it has been associated with bradycardia, hypotension, stroke and death. Do not routinely withdraw chronic beta blocker therapy prior to surgery. (5.5, 6.1) •Diabetes and Hypoglycemia: May mask tachycardia occurring with hypoglycemia. (5.6) •Patients with Hepatic Impairment: (5.7) •Thyrotoxicosis: Abrupt withdrawal in patients with thyrotoxicosis might precipitate a thyroid storm. (5.8) •Anaphylactic Reactions: Patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. (5.9) •Peripheral Vascular Disease: Can aggravate symptoms of arterial insufficiency. (5.10) •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. (5.11) 5.1 Ischemic Heart Disease Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing chronically administered TOPROL-XL, particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1 – 2 weeks and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, promptly reinstate TOPROL-XL, and take measures appropriate for the management of unstable angina. Warn patients not to interrupt therapy without their physician’s advice. Because coronary artery disease is common and may be unrecognized, avoid abruptly discontinuing TOPROL-XL in patients treated only for hypertension. 5.2 Heart Failure Worsening cardiac failure may occur during up-titration of TOPROL-XL. If such symptoms occur, increase diuretics and restore clinical stability before advancing the dose of TOPROL-XL [see Dosage and Administration (2)]. 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. 5.3 Bronchospastic Disease PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of its relative beta1 cardio-selectivity, however, TOPROL-XL 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 TOPROL-XL. Bronchodilators, including beta2-agonists, should be readily available or administered concomitantly [see Dosage and Administration (2)]. 5.4 Pheochromocytoma If TOPROL-XL is used in the setting of pheochromocytoma, it should be given in combination with an alpha blocker, and only after the alpha blocker has been initiated. Administration of beta-blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle. 5.5 Major Surgery Avoid initiation of a high-dose regimen of extended-release metoprolol in patients undergoing non-cardiac surgery, since such use in patients with cardiovascular risk factors has been associated with bradycardia, hypotension, stroke and death. Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. 5.6 Diabetes and Hypoglycemia Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected. 5.7 Hepatic Impairment Consider initiating TOPROL-XL therapy at doses lower than those recommended for a given indication; gradually increase dosage to optimize therapy, while monitoring closely for adverse events. 5.8 Thyrotoxicosis Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may precipitate a thyroid storm. 5.9 Anaphylactic Reaction 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. 5.10 Peripheral Vascular Disease Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. 5.11 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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise patients to take TOPROL-XL 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 TOPROL-XL 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 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. TOPROL-XL and PLENDIL are trademarks of the AstraZeneca group of companies. © AstraZeneca 2012 Distributed by: AstraZeneca LP Wilmington, DE 19850 Rev. 10/2012
DOSAGE AND ADMINISTRATION
2 TOPROL-XL is an extended-release tablet intended for once daily administration. For treatment of hypertension and angina, when switching from immediate-release metoprolol to TOPROL-XL, use the same total daily dose of TOPROL-XL. Individualize the dosage of TOPROL-XL. Titration may be needed in some patients. TOPROL-XL tablets are scored and can be divided; however, do not crush or chew the whole or half tablet. •Administer once daily. Dosing of TOPROL-XL should be individualized. (2) •Heart Failure: Recommended starting dose is 12.5 mg or 25 mg doubled every two weeks to the highest dose tolerated or up to 200 mg. (2.3) •Hypertension: Usual initial dosage is 25 to 100 mg once daily. The dosage may be increased at weekly (or longer) intervals until optimum blood pressure reduction is achieved. Dosages above 400 mg per day have not been studied. (2.1) •Angina Pectoris: Usual initial dosage is 100 mg once daily. Gradually increase the dosage at weekly intervals until optimum clinical response has been obtained or there is an unacceptable bradycardia. Dosages above 400 mg per day have not been studied. (2.2) •Switching from immediate-release metoprolol to TOPROL-XL: use the same total daily dose of TOPROL-XL. (2) 2.1 Hypertension Adults: The usual initial dosage is 25 to 100 mg daily in a single dose. 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 per day have not been studied. Pediatric Hypertensive Patients ≥ 6 Years of age: A pediatric clinical hypertension study in patients 6 to 16 years of age did not meet its primary endpoint (dose response for reduction in SBP); however some other endpoints demonstrated effectiveness [see Use in Specific Populations (8.4)]. If selected for treatment, the recommended starting dose of TOPROL-XL is 1.0 mg/kg once daily, but the maximum initial dose should not exceed 50 mg once daily. Dosage should be adjusted according to blood pressure response. Doses above 2.0 mg/kg (or in excess of 200 mg) once daily have not been studied in pediatric patients [see Clinical Pharmacology (12.3)]. TOPROL-XL is not recommended in pediatric patients < 6 years of age [see Use in Specific Populations (8.4)]. 2.2 Angina Pectoris Individualize the dosage of TOPROL-XL. The usual initial dosage is 100 mg daily, given in a single dose. Gradually increase the dosage at weekly intervals until optimum clinical response has been obtained or there is a pronounced slowing of the heart rate. 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 (5)]. 2.3 Heart Failure Dosage must be individualized and closely monitored during up-titration. Prior to initiation of TOPROL-XL, stabilize the dose of other heart failure drug therapy. The recommended starting dose of TOPROL-XL is 25 mg once daily for two weeks in patients with NYHA Class II heart failure and 12.5 mg once daily in patients with more severe heart failure. Double the dose every two weeks to the highest dosage level tolerated by the patient or up to 200 mg of TOPROL-XL. Initial difficulty with titration should not preclude later attempts to introduce TOPROL-XL. If patients experience symptomatic bradycardia, reduce the dose of TOPROL-XL. If transient worsening of heart failure occurs, consider treating with increased doses of diuretics, lowering the dose of TOPROL-XL or temporarily discontinuing it. The dose of TOPROL-XL should not be increased until symptoms of worsening heart failure have been stabilized.