TOPROL XL

1 INDICATIONS AND USAGE TOPROL-XL, metoprolol succinate, is a beta 1 -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 (e.g., 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.

2 DOSAGE AND ADMINISTRATION 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 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 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.

4 CONTRAINDICATIONS TOPROL-XL is contraindicated in severe bradycardia, second or third degree heart block, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), and in patients who are hypersensitive to any component of this product. • 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)

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 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) ]. 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.

7 DRUG INTERACTIONS • 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 (e.g., 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) ].

6 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) ]. Most common adverse reactions: tiredness, dizziness, depression, shortness of breath, bradycardia, hypotension, diarrhea, pruritus, rash. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aralez Pharmaceuticals US Inc. at 1-866-207-6592 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 the 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. 6.2 Post-Marketing Experience 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. 6.3 Laboratory Test Findings Clinical laboratory findings may include elevated levels of serum transaminase, alkaline phosphatase, and lactate dehydrogenase.

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/m 2 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.