FDA label 44ac9bcd-df33-4b4c-e054-00144ff8d46c

Boxed Warning section 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).

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) 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. 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. PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of its relative beta 1 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 beta 1 -selectivity is not absolute, use the lowest possible dose of TOPROL-XL. Bronchodilators, including beta 2 -agonists, should be readily available or administered concomitantly [see Dosage and Administration (2) ]. 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. 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. Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected. 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. Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may precipitate a thyroid storm. 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. Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. 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.

ADVERSE REACTIONS The following adverse reactions are described elsewhere in labeling: •Worsening angina or myocardial infarction. [see Warnings and Precautions (5) ] •Worsening heart failure. [see Warnings and Precautions (5) ] •Worsening AV block. [see Contraindications (4) ] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Hypertension and Angina: Most adverse reactions have been mild and transient. The most common (>2%) adverse reactions are tiredness, dizziness, depression, diarrhea, shortness of breath, bradycardia, and rash. Heart Failure: 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 reactions vs. 12.2% of placebo patients. The table below lists adverse reactions in the MERIT-HF study that occurred at an incidence of ≥ 1% in the TOPROL-XL group and greater than placebo by more than 0.5%, regardless of the assessment of causality. Adverse Reactions Occurring in the MERIT-HF Study at an Incidence ≥1% in TOPROL-XL Group and Greater Than Placebo by More than 0.5% TOPROL-XL n=1990 % of patients Placebo n=2001 % of patients Dizziness/vertigo 1.8 1.0 Bradycardia 1.5 0.4 Accident and/or injury 1.4 0.8 Post-operative Adverse Events: In a randomized, double-blind, placebo-controlled trial of 8351 patients with or at risk for atherosclerotic disease undergoing non-vascular surgery and who were not taking beta–blocker therapy, TOPROL-XL 100 mg was started 2 to 4 hours prior to surgery then continued for 30 days at 200 mg per day. TOPROL-XL use was associated with a higher incidence of bradycardia (6.6% vs 2.4%; HR, 2.74; 95% CI 2.19, 3.43), hypotension (15% vs. 9.7%; HR 1.55; 95% CI 1.37, 1.74), stroke (1.0% vs 0.5%; HR 2.17; 95% CI 1.26, 3.74) and death (3.1% vs 2.3%; HR 1.33; 95% CI 1,03, 1.74) compared to placebo. The following adverse reactions have been identified during post-approval use of TOPROL-XL or immediate-release metoprolol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular: Cold extremities, arterial insufficiency (usually of the Raynaud type), palpitations, peripheral edema, syncope, chest pain and hypotension. Respiratory: Wheezing (bronchospasm), dyspnea. Central Nervous System: Confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety/nervousness, hallucinations, paresthesia. Gastrointestinal: Nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, vomiting. Hypersensitive Reactions: Pruritus. Miscellaneous: Musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, tinnitus, reversible alopecia, agranulocytosis, dry eyes, worsening of psoriasis, Peyronie’s disease, sweating, photosensitivity, taste disturbance. Potential Adverse Reactions: In addition, there are adverse reactions not listed above that have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to TOPROL-XL. Central Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, clouded sensorium, and decreased performance on neuropsychometrics. Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura. Hypersensitive Reactions: Laryngospasm, respiratory distress. Clinical laboratory findings may include elevated levels of serum transaminase, alkaline phosphatase, and lactate dehydrogenase.

<table> <caption>Adverse Reactions Occurring in the MERIT-HF Study at an Incidence &#x2265;1% in TOPROL-XL Group and Greater Than Placebo by More than 0.5%</caption> <col span="1" width="23%"/> <col span="1" width="23%"/> <col span="1" width="23%"/> <tbody> <tr> <td/> <td> <paragraph>TOPROL-XL</paragraph> <paragraph> n=1990 % of patients</paragraph> </td> <td> <paragraph>Placebo</paragraph> <paragraph> n=2001 % of patients</paragraph> </td> </tr> <tr> <td> <paragraph>Dizziness/vertigo</paragraph> </td> <td> <paragraph>1.8</paragraph> </td> <td> <paragraph>1.0</paragraph> </td> </tr> <tr> <td> <paragraph>Bradycardia</paragraph> </td> <td> <paragraph>1.5</paragraph> </td> <td> <paragraph>0.4</paragraph> </td> </tr> <tr> <td> <paragraph>Accident and/or injury</paragraph> </td> <td> <paragraph>1.4</paragraph> </td> <td> <paragraph>0.8</paragraph> </td> </tr> </tbody> </table>