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HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to useTOPROL-XL safely and effectively. See full prescribing information forTOPROL-XL.TOPROL-XL (metoprolol succinate) Tablet, Extended-Release for OralUseInitial U.S. Approval: 1992WARNING: 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 haveoccurred. Warn patients against interruption or discontinuation oftherapy without the physician’s advice. (5.1)--------------------------- INDICATIONS AND USAGE ------------------------- TOPROL-XL, metoprolol succinate, is a beta1-selective adrenoceptorblocking agent.TOPROL-XL is indicated for the treatment of: Hypertension, to lower blood pressure. Lowering blood pressure reducesthe risk of fatal and non-fatal cardiovascular events, primarily strokesand myocardial infarctions. (1.1) Angina Pectoris. (1.2) Heart Failure - for the treatment of stable, symptomatic (NYHA Class IIor III) heart failure of ischemic, hypertensive, or cardiomyopathic origin.(1.3)---------------------- DOSAGE AND ADMINISTRATION --------------------- Administer once daily. Dosing of TOPROL-XL should beindividualized. (2) Heart Failure: Recommended starting dose is 12.5 mg or 25 mg doubledevery 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. Thedosage may be increased at weekly (or longer) intervals until optimumblood pressure reduction is achieved. Dosages above 400 mg per dayhave not been studied. (2.1) Angina Pectoris: Usual initial dosage is 100 mg once daily. Graduallyincrease the dosage at weekly intervals until optimum clinical responsehas been obtained or there is an unacceptable bradycardia. Dosagesabove 400 mg per day have not been studied. (2.2) Switching from immediate-release metoprolol to TOPROL-XL: use thesame total daily dose of TOPROL-XL. (2) --------------------- DOSAGE FORMS AND STRENGTHS ------------------- TOPROL-XL Extended-Release Tablets (metoprolol succinate): 25 mg,50 mg, 100 mg and 200 mg. (3)------------------------------ CONTRAINDICATIONS ---------------------------- Known hypersensitivity to product components. (4) Severe bradycardia. (4) Heart block greater than first degree. (4) Cardiogenic shock. (4) Decompensated cardiac failure. (4) Sick sinus syndrome without a pacemaker. (4)FULL PRESCRIBING INFORMATION: CONTENTS*WARNING: ISCHEMIC HEART DISEASE:1 INDICATIONS AND USAGE1.1 Hypertension1.2 Angina Pectoris1.3 Heart Failure2 DOSAGE AND ADMINISTRATION2.1 Hypertension2.2 Angina Pectoris2.3 Heart Failure3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 Ischemic Heart Disease5.2 Heart Failure5.3 Bronchospastic Disease5.4 Pheochromocytoma5.5 Major Surgery5.6 Diabetes and Hypoglycemia5.7 Hepatic ImpairmentReference ID: 3501404----------------------- 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 alphablocker. (5.4) Major Surgery: Avoid initiation of high-dose extended-releasemetoprolol in patients undergoing non-cardiac surgery because it hasbeen associated with bradycardia, hypotension, stroke and death. Do notroutinely withdraw chronic beta blocker therapy prior to surgery. (5.5,6.1) Diabetes and Hypoglycemia: May mask tachycardia occurring withhypoglycemia. (5.6) Patients with Hepatic Impairment: (5.7) Thyrotoxicosis: Abrupt withdrawal in patients with thyrotoxicosis mightprecipitate a thyroid storm. (5.8) Anaphylactic Reactions: Patients may be unresponsive to the usual dosesof epinephrine used to treat allergic reaction. (5.9) Peripheral Vascular Disease: Can aggravate symptoms of arterialinsufficiency. (5.10) Calcium Channel Blockers: Because of significant inotropic andchronotropic effects in patients treated with beta-blockers and calciumchannel blockers of the verapamil and diltiazem type, caution should beexercised in patients treated with these agents concomitantly. (5.11)------------------------------ ADVERSE REACTIONS ---------------------------- Most common adverse reactions: tiredness, dizziness, depression,shortness of breath, bradycardia, hypotension, diarrhea, pruritus, rash.(6.1)To report SUSPECTED ADVERSE REACTIONS, contactAstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 --- DRUG INTERACTIONS ---------------------------- Catecholamine-depleting drugs may have an additive effect when givenwith beta-blocking agents. (7.1) CYP2D6 Inhibitors are likely to increase metoprolol concentration. (7.2) Concomitant use of glycosides, clonidine, and diltiazem and verapamilwith beta-blockers can increase the risk of bradycardia. (7.3) Beta-blockers including metoprolol, may exacerbate the reboundhypertension that can follow the withdrawal of clonidine. (7.3)----------------------- USE IN SPECIFIC POPULATIONS --------------------- Pregnancy: There are no adequate and well-controlled studies inpregnant women. Use this drug during pregnancy only if clearly needed.(8.1) Nursing Mothers: Consider possible infant exposure. (8.3) Pediatrics: Safety and effectiveness have not been established in patients 6 years of age. (8.4) Geriatrics: No notable difference in efficacy or safety vs. youngerpatients. (8.5) Hepatic Impairment: Consider initiating TOPROL-XL therapy at lowdoses and gradually increase dosage to optimize therapy, whilemonitoring closely for adverse events. (8.6)See 17 for PATIENT COUNSELING INFORMATIONRevised: 05/20145.8 Thyrotoxicosis5.9 Anaphylactic Reaction5.10 Peripheral Vascular Disease5.11 Calcium Channel Blockers6 ADVERSE REACTIONS6.1 Clinical Trials Experience6.2 Post-Marketing Experience6.3 Laboratory Test Findings7 DRUG INTERACTIONS7.1 Catecholamine Depleting Drugs7.2 CYP2D6 Inhibitors7.3 Digitalis, Clonidine, and Calcium Channel Blockers8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use8.6 Hepatic Impairment8.7 Renal Impairment

10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility14 CLINICAL STUDIES14.1 Angina Pectoris14.2 Heart Failure15 REFERENCES16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION*Sections or subsections omitted from the full prescribing information are not listed.FULL PRESCRIBING INFORMATIONWARNING: ISCHEMIC HEART DISEASE:Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of anginapectoris and, in some cases, myocardial infarction have occurred. When discontinuing chronicallyadministered TOPROL-XL, particularly in patients with ischemic heart disease, the dosage should begradually reduced over a period of 1 - 2 weeks and the patient should be carefully monitored. If anginamarkedly worsens or acute coronary insufficiency develops, TOPROL-XL administration should bereinstated promptly, at least temporarily, and other measures appropriate for the management ofunstable angina should be taken. Warn patients against interruption or discontinuation of therapywithout 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 forhypertension (5.1).1 INDICATIONS AND USAGE1.1 HypertensionTOPROL-XL is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers therisk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have beenseen 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, asappropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodiumintake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals andmanagement, see published guidelines, such as those of the National High Blood Pressure Education Program’s JointNational 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, havebeen shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded thatit is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible forthose 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 isgreater 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 theabsolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients withdiabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lowerblood pressure goal.Reference ID: 3501404

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and manyantihypertensive drugs have additional approved indications and effects (eg, on angina, heart failure, or diabetic kidneydisease). These considerations may guide selection of therapy.TOPROL-XL may be administered with other antihypertensive agents.1.2 Angina PectorisTOPROL-XL is indicated in the long-term treatment of angina pectoris, to reduce angina attacks and to improve exercisetolerance.1.3 Heart FailureTOPROL-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 themajority of cases, digitalis. In this population, TOPROL-XL decreased the rate of mortality plus hospitalization, largelythrough a reduction in cardiovascular mortality and hospitalizations for heart failure.2 DOSAGE AND ADMINISTRATIONTOPROL-XL is an extended-release tablet intended for once daily administration. For treatment of hypertension andangina, 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.2.1 HypertensionAdults: 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 levelwill 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 agedid not meet its primary endpoint (dose response for reduction in SBP); however some other endpoints demonstratedeffectiveness [see Use in Specific Populations (8.4)]. If selected for treatment, the recommended starting dose ofTOPROL-XL is 1.0 mg/kg once daily, but the maximum initial dose should not exceed 50 mg once daily. Dosage shouldbe adjusted according to blood pressure response. Doses above 2.0 mg/kg (or in excess of 200 mg) once daily have notbeen 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 PectorisIndividualize the dosage of TOPROL-XL. The usual initial dosage is 100 mg daily, given in a single dose. Graduallyincrease the dosage at weekly intervals until optimum clinical response has been obtained or there is a pronouncedslowing of the heart rate. Dosages above 400 mg per day have not been studied. If treatment is to be discontinued, reducethe dosage gradually over a period of 1 - 2 weeks [see Warnings and Precautions (5)].2.3 Heart FailureDosage must be individualized and closely monitored during up-titration. Prior to initiation of TOPROL-XL, stabilize thedose of other heart failure drug therapy. The recommended starting dose of TOPROL-XL is 25 mg once daily for twoweeks 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 experienceReference ID: 3501404

symptomatic bradycardia, reduce the dose of TOPROL-XL. If transient worsening of heart failure occurs, considertreating with increased doses of diuretics, lowering the dose of TOPROL-XL or temporarily discontinuing it. The dose ofTOPROL-XL should not be increased until symptoms of worsening heart failure have been stabilized.3 DOSAGE FORMS AND STRENGTHS25 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