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 to reduce the risk of cardiovascular mortality and heart-failure hospitalization in patients with heart failure.

2.1 Hypertension

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.

2.4 Administration

TOPROL-XL tablets are scored and can be divided; however, do not crush or chew the whole or half tablet.

5.1 Abrupt Cessation of Therapy

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 to 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 Bradycardia

Bradycardia, including sinus pause, heart block, and cardiac arrest have occurred with the use of TOPROL-XL. Patients with first-degree atrioventricular block, sinus node dysfunction, conduction disorders (including Wolff- Parkinson-White) or on concomitant drugs that cause bradycardia [see Drug Interactions (7.3)], may be at increased risk. Monitor heart rate in patients receiving TOPROL-XL. If severe bradycardia develops, reduce or stop TOPROL- XL.

5.5 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.

5.6 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.

5.7 Hypoglycemia

Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment.

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 Peripheral Vascular Disease

Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.

5.10 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.

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.

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, 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.

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 are strong inhibitors of CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone were shown to double metoprolol concentrations. While there is no information about moderate or weak inhibitors, these too are likely to increase metoprolol concentration. Increases in plasma concentration decrease the cardioselectivity of metoprolol [see Clinical Pharmacology (12.3)]. Monitor patients closely when the combination cannot be avoided.

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 co-administered, 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.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

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, 1or 2 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,
• 1 mg/kg vs. placebo for change in SBP, and
• 2 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.

8.5 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.

8.6 Hepatic Impairment

No studies have been performed with TOPROL-XL in patients with hepatic impairment. Because TOPROL-XL is metabolized by the liver, metoprolol blood levels are likely to increase substantially with poor hepatic function. Therefore, initiate therapy at doses lower than those recommended for a given indication; and increase doses gradually in patients with impaired hepatic function.

8.7 Renal Impairment

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. No reduction in dosage is needed in patients with chronic renal failure [see Clinical Pharmacology (12.3)].

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. 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:

Hemodialysis is unlikely to make a useful contribution to metoprolol elimination [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

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.

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.

12.2 Pharmacodynamics

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 relationship between plasma metoprolol levels and reduction in exercise heart rate is independent of the pharmaceutical formulation. Beta1-blocking effects in the range of 30-80% of the maximal effect (approximately 8 to 23% reduction in exercise heart rate) correspond to metoprolol plasma concentrations from 30 to 540 nmol/L. The relative beta1-selectivity of metoprolol diminishes and blockade of beta2-adrenoceptors increases at plasma concentration above 300 nmol/L.

In five controlled studies in normal healthy subjects, extended-release metoprolol succinate 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 to 400 mg. In another controlled study, 50 mg once daily for each product, extended-release metoprolol succinate produced significantly higher total beta1-blockade over 24 hours than immediate-release metoprolol. For extended-release metoprolol succinate, 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.

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., and 100 mg and 200 mg extended-release metoprolol succinate once daily. Extended-release metoprolol succinate 200 mg once daily 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 other studies, treatment with metoprolol succinate produced an improvement in left ventricular ejection fraction. Metoprolol succinate was also shown to delay the increase in left ventricular end-systolic and end-diastolic volumes after 6 months of treatment.

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.

12.3 Pharmacokinetics

12.5 Pharmacogenomics

CYP2D6 is absent in about 8% of Caucasians (poor metabolizers) and about 2% of most other populations. CYP2D6 can be inhibited by several drugs. Poor metabolizers of CYP2D6 will have increased (several-fold) metoprolol blood levels, decreasing metoprolol's cardioselectivity.

13.1 Carcinogenesis, Mutagenesis, 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 three 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 three oral dosage levels of up to 750 mg/kg/day (18 times, on a mg/m2 basis, the daily dose of 200 mg for a 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.

14.1 Hypertension

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.

14.2 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.

14.3 Heart Failure

MERIT-HF was a randomized double-blind, placebo-controlled study of TOPROL-XL in which 3991 patients with ejection fraction ≤0.40 and NYHA Class II-IV heart failure attributable to ischemia, hypertension, or cardiomyopathy were randomized 1:1 to TOPROL XL or placebo. 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. 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

Store at 25°C (77°F). Excursions permitted to 15-30°C (59-86°F). (See USP Controlled Room Temperature.)

Risk of hypoglycemia

Inform patients or caregivers that there is a risk of hypoglycemia when TOPROL-XL is given to patients who are fasting or who are vomiting. Instruct patients or caregivers how to monitor for signs of hypoglycemia. [see Warnings and Precautions (5.7)].