These highlights do not contain all of the information necessary for the safe and effective use of metoprolol succinate extended-release tablets. See full prescribing information for metoprolol succinate extended-release tablets. ME (2023)

1.1 Hypertension

Metoprolol succinate extended-release tablets are indicated for the treatment of hypertension to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, particularly stroke and myocardial infarction. These benefits have been observed in controlled studies of antihypertensive drugs from various pharmacological classes, including metoprolol.

Hypertension control should form part of overall cardiovascular risk management, including lipid control, diabetes management, antiplatelet therapy, smoking cessation, exercise, and sodium restriction as appropriate. Many patients need more than one medication to reach their blood pressure goals. For specific advice on goals and management, consult published guidelines, such as those from the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) of the National High Blood Pressure Education Program.

Many antihypertensive drugs from different pharmacological classes and with different mechanisms of action have been shown in randomized controlled studies to reduce cardiovascular morbidity and mortality. It can be concluded that it is the reduction in blood pressure and not another pharmacological property of the drugs that is largely responsible for these benefits. The largest and most consistent benefit for cardiovascular outcome was the reduced risk of stroke, but reductions in myocardial infarction and cardiovascular mortality were also regularly observed.

Elevated systolic or diastolic pressure carries an increased cardiovascular risk, and the absolute increase in risk per mmHg is greater at higher blood pressures, so even small reductions in severe hypertension can provide significant benefits. Relative risk reduction from lowering blood pressure is similar across populations at different levels of absolute risk, so the absolute benefit is greatest in patients at highest risk regardless of their hypertension (e.g., those with diabetes or hyperlipidemia). and these patients would be expected to benefit from more aggressive treatment to lower blood pressure.

Some antihypertensive drugs have less effect on blood pressure in black patients (than monotherapy), and many antihypertensive drugs have approved indications and additional effects (eg, in angina, heart failure, or diabetic kidney disease). These considerations may influence the choice of treatment.

Metoprolol succinate extended-release tablets may be administered along with other antihypertensive agents.

1.2 Angina pectoris

Metoprolol succinate extended-release tablets are indicated for the long-term treatment of angina pectoris to reduce angina pectoris attacks and improve exercise tolerance.

1.3 Heart failure

Metoprolol succinate extended-release tablets are indicated for the treatment of stable and symptomatic heart failure (NYHA class II or III) of ischemic, hypertensive or cardiomyopathic origin. It has been studied in patients already taking ACE inhibitors, diuretics and, in most cases, digitalis. In this population, extended-release metoprolol succinate reduced mortality and hospitalization rates, primarily through reduced cardiovascular mortality and hospitalizations for heart failure.

2.1 Hypertension

Adult: The usual starting dose is 25 to 100 mg per day in a single dose. Dosage may be increased at weekly (or longer) intervals until optimal blood pressure reduction is achieved. In general, the maximum effect of a given dose will be seen after one week of treatment. Doses above 400 mg per day have not been studied.

Pediatric hypertensive patients ≥ 6 years: A clinical trial of pediatric hypertension in patients aged 6 to 16 years did not meet its primary endpoint (dose-response for SBP reduction). However, some other parameters showed efficacy[see use in specific populations (8.4)]. When selected for treatment, the recommended starting dose of metoprolol succinate extended-release tablets is 1.0 mg/kg once daily, but the maximum starting dose should not exceed 50 mg once daily. Dosage should be adjusted according to blood pressure response. Doses greater than 2.0 mg/kg (or greater than 200 mg) once daily have not been studied in pediatric patients[see Clinical Pharmacology (12.3)].

Metoprolol succinate extended-release tablets are not recommended for pediatric patients under 6 years of age[see use in specific populations (8.4)].

2.2 Angina pectoris

Individualize the dose of metoprolol succinate extended-release tablets. The usual starting dose is 100 mg a day in a single dose. Increase the dose gradually at weekly intervals until an optimal clinical response is achieved or a marked deceleration of heart rate occurs. Doses above 400 mg per day have not been studied. If treatment has to be stopped, gradually reduce the dose over 1-2 weeks[see warnings and precautions (5)].

2.3 Heart failure

Dosage must be individualized and carefully monitored during titration. Before starting treatment with metoprolol succinate extended-release tablets, stabilize the dose of other drug therapy for heart failure. The recommended starting dose of metoprolol succinate extended-release tablets 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 maximum tolerated by the patient or up to 200 mg of metoprolol succinate in extended-release tablets. Initial difficulties with titration should not impede later attempts to introduce metoprolol succinate extended-release tablets. If patients experience symptomatic bradycardia, reduce the dose of metoprolol succinate extended-release tablets. If transient worsening of heart failure occurs, consider treatment with increased doses of diuretics, dose reduction of metoprolol succinate extended-release tablets, or temporary discontinuation. The dose of metoprolol succinate extended-release tablets should not be increased until symptoms of worsening heart failure have stabilized.

5.1 Ischemic heart disease

Angina pectoris worsened and, in some cases, myocardial infarction occurred after abrupt withdrawal of some beta-blockers. When stopping chronic metoprolol succinate extended-release tablets, particularly in patients with ischemic heart disease, reduce the dose gradually over 1 to 2 weeks and monitor the patient. If angina pectoris significantly worsens or acute coronary artery ischemia develops, stop taking metoprolol succinate extended-release tablets immediately and take appropriate measures to treat unstable angina pectoris. Advise patients not to discontinue treatment without physician advice. As coronary artery disease is common and may go unnoticed, abrupt withdrawal of metoprolol succinate extended-release tablets should be avoided in patients treated for hypertension alone.

5.2 Heart failure

Worsening heart failure may occur when increasing the dose of metoprolol succinate extended-release tablets. If such symptoms appear, increase diuretics and restore clinical stability before increasing dose of Metoprolol Succinate Extended-Release Tablets[see dosage and administration (2)]. The dose of metoprolol succinate extended-release tablets may need to be temporarily reduced or discontinued. Such episodes do not preclude subsequent successful titration of metoprolol succinate extended-release tablets.

5.3 Bronchospastic disease

PATIENTS WITH BRONCHOSPASTIC DISEASE GENERALLY SHOULD NOT TAKE BETA BLOCKERS. Because of its relative beta1Cardioselectivity: However, metoprolol succinate extended-release tablets may be used in patients with bronchospastic disease who are unresponsive or intolerant of other antihypertensive therapies. because beta1- Selectivity is not absolute. Use the lowest possible dose of metoprolol succinate extended-release tablets. bronchodilators, including beta2-Agonists must be readily available or co-administered[see dosage and administration (2)].

5.4 Pheochromocytoma

When metoprolol succinate extended-release tablets are used in pheochromocytoma, they should be given in combination with an alpha-blocker and only after starting treatment with the alpha-blocker. Administration of beta-blockers alone in pheochromocytoma has been associated with a paradoxical increase in blood pressure due to attenuation of beta-mediated vasodilation in skeletal muscle.

5.5 Major Surgery

Avoid initiating high-dose extended-release metoprolol therapy in patients undergoing noncardiac surgery, as this use has been associated with bradycardia, hypotension, stroke, and death in patients with cardiovascular risk factors.

However, chronic beta-blocker therapy should not be routinely discontinued prior to major surgery because the heart's decreased ability to respond to reflex adrenergic stimuli may increase the risk of general anesthesia and surgical procedures.

5.6 Diabetes and hypoglycemia

Beta-blockers can mask the tachycardia that occurs with hypoglycemia, but other symptoms such as dizziness and sweating may not be significantly affected.

5.7 Liver failure

Consider starting metoprolol succinate extended-release tablets at lower doses than recommended for a specific indication. Increase the dose gradually to optimize treatment, while carefully monitoring for side effects.

5.8 Tireotoxicose

Beta-adrenergic blockade can reduce some clinical signs of hyperthyroidism, such as B. tachycardia, masking. Stopping beta blockers suddenly can lead to a thyroid storm.

5.9 Anaphylactic reaction

While taking beta-blockers, patients with a history of severe anaphylactic reactions to various allergens may respond better to repeated exposures and may not respond to the usual doses of epinephrine used to treat an allergic reaction.

5.10 Peripheral Vascular Disease

Beta-blockers may worsen or exacerbate symptoms of arterial insufficiency in patients with peripheral vascular disease.

5.11 Calcium channel blockers

Due to the significant inotropic and chronotropic effects in patients treated with beta-blockers and calcium channel blockers such as verapamil and diltiazem, caution is advised in patients treated concomitantly with these agents.

6.1 Experience in Clinical Trials

Because clinical trials are conducted under very different conditions, adverse event rates observed in clinical trials of one drug cannot be directly compared with rates in clinical trials of another drug and may not reflect rates observed in real-world settings. However, information on adverse events from clinical trials provides a basis for identifying adverse events that appear to be related to drug use and for approximate frequencies.

Hypertension and angina pectoris:Most side effects were mild and transient. The most common side effects (>2%) are fatigue, dizziness, depression, diarrhea, dyspnea, bradycardia, and rash.

Syncope:In the MERIT-HF study comparing extended-release metoprolol succinate at daily doses up to 200 mg (mean dose 159 mg once daily; n=1990) with placebo (n=2001), 10.3% of the release tablets Prolonged treatment was metoprolol succinate Patients who discontinued treatment due to adverse events compared with 12.2% of patients who received placebo.

The following table lists adverse reactions in the MERIT-HF study that occurred with an incidence of ≥1% in the metoprolol succinate extended-release group and were greater than 0.5% greater than placebo, regardless of causality assessment.

Postoperative side effects:In a randomized, double-blind, placebo-controlled study in 8351 patients with or at risk of atherosclerotic disease undergoing nonvascular surgery and not receiving beta-blocker therapy, metoprolol succinate 100 mg extended-release tablets was administered 2 to 4 hours before surgery started with 200 mg daily for 30 days. The use of extended-release metoprolol succinate was associated with a higher incidence of bradycardia (6.6% vs 2.4%; HR 2.74; 95% CI 2.19, 3.43) and hypotension (15% vs. 9.7%; HR 1.3% CI; HR) Associated CI 1.5%; , 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 with placebo.

6.2 Post-launch experience

The following side effects have been identified with post-marketing use of metoprolol succinate extended-release or metoprolol immediate-release tablets. 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 Raynaud's syndrome), palpitations, peripheral edema, syncope, chest pain, and hypotension.

Respiratory tract:wheezing (bronchospasm), shortness of breath.

Central nervous system:Confusion, short-term memory loss, headache, drowsiness, nightmares, insomnia, anxiety/nervousness, hallucinations, paraesthesia.

Gastrointestinal:Nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, vomiting.

Hypersensitivity reactions:Itch.

Difference:Musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, tinnitus, reversible alopecia, agranulocytosis, dry eye, worsening psoriasis, Peyronie's disease, sweating, photosensitivity, taste disturbances.

Possible side effects:Additionally, there are side effects not listed above that have been reported with other β-blockers and should be considered as possible side effects of metoprolol succinate extended release tablets.

Central nervous system:Reversible mental depression leading to catatonia. an acute reversible syndrome characterized by disorientation to time and place, short-term memory loss, emotional lability, sensory numbness, and impaired neuropsychometric performance.

Hematological:Agranulocytosis, non-thrombocytopenic purpura, thrombocytopenic purpura.

Hypersensitivity reactions:Laryngospasm, shortness of breath.

6.3 Laboratory Test Results

Clinical laboratory findings may include elevations in serum transaminase, alkaline phosphatase, and lactate dehydrogenase.

7.1 Drugs that destroy catecholamines

Drugs that destroy catecholamines (eg reserpine, monoamine oxidase (MAO) inhibitors) may have an additive effect when given concomitantly with beta-blockers. Monitor patients treated with extended-release metoprolol succinate plus a catecholamine-lowering agent for signs of hypotension or marked bradycardia that may lead to dizziness, syncope, or orthostatic hypotension.

7.2 CYP2D6 inhibitors

Drugs that inhibit CYP2D6, such as quinidine, fluoxetine, paroxetine, and propafenone, are likely to increase metoprolol concentrations. In healthy subjects with the CYP2D6 extensive metabolizer phenotype, co-administration of quinidine 100 mg and immediate-release metoprolol 200 mg resulted in a tripling of S-metoprolol concentrations and a doubling of the elimination half-life of metoprolol. Four patients with cardiovascular disease required co-administration of propafenone 150 mg three times a day. with immediate-release metoprolol 50 mg t.i.d. resulted in a two- to five-fold increase in steady-state metoprolol concentrations. These increases in plasma concentration would decrease the cardioselectivity of metoprolol.

7.3 Dactylitis, clonidine and calcium channel blockers

Digitalis glycosides, clonidine, diltiazem, and verapamil slow AV conduction and decrease heart rate. Concomitant use with beta-blockers may increase the risk of bradycardia.

If clonidine and a beta-blocker such as metoprolol are given concomitantly, discontinue the beta-blocker a few days before tapering clonidine, as beta-blockers may worsen the rebound hypertension that can occur after clonidine is discontinued. If replacing clonidine with beta-blocker therapy, delay introduction of beta-blockers for several days after stopping clonidine[see Warnings and Precautions (5.11)].

8.1 Pregnancy

pregnancy category C

Metoprolol tartrate has been shown to increase postimplantation loss and reduce neonatal survival in rats at doses up to 22 times (in mg/m2).2The basis is a daily dose of 200 mg for a patient weighing 60 kg. Distribution studies in mice confirm fetal exposure when metoprolol tartrate is administered to the pregnant animal. These studies revealed no evidence of impaired fertility or teratogenicity. There are no adequate and well-controlled studies in pregnant women. As animal reproduction studies are not always indicative of human response, you should not use this medication during pregnancy unless clearly necessary.

8.3 Mothers who breastfeed

Metoprolol passes into breast milk in very small amounts. A child who drinks 1 liter of breast milk per day receives a dose of less than 1 mg of the drug. Consider possible childhood exposure when administering metoprolol succinate extended-release tablets to a nursing woman.

8.4 Use in children

One hundred and forty-four hypertensive pediatric patients aged 6 to 16 years were randomized to receive either placebo or one of three doses of metoprolol succinate extended-release tablets (0.2, 1.0, or 2.0 mg/kg once once a day) and were followed up for 4 weeks. The study did not meet its primary endpoint (dose-response in SBP reduction). Several pre-specified secondary endpoints have demonstrated efficacy, including:

• dose-response relationship to decrease DBP,
• mg/kg versus placebo for change in SBP and
• mg/kg versus placebo for change in SBP and DBP.

Mean placebo-corrected reductions in SBP ranged from 3 to 6 mmHg and in DBP from 1 to 5 mmHg. The mean reduction in heart rate was between 5 and 7 beats per minute, but significantly greater reductions were seen in some subjects.[see dosage and application (2.1)].

No clinically relevant differences in the adverse reaction profile were observed in pediatric patients aged 6 to 16 years compared to adult patients.

The safety and efficacy of metoprolol succinate extended-release tablets in patients younger than 6 years of age have not been established.

8.5 Geriatric use

Clinical trials of extended-release metoprolol succinate in hypertension did not include sufficient numbers of subjects aged 65 years and older to determine whether they responded differently from younger subjects. Other reported clinical experiences in hypertensive patients have not identified differences in responses between elderly and younger patients.

Of the 1990 heart failure patients randomized to receive extended-release metoprolol succinate in the MERIT-HF study, 50% (990) were 65 years of age or older and 12% (238) were 75 years of age or older. There were no notable differences in efficacy or the incidence of adverse events between elderly and younger patients.

In general, a low starting dose should be used in elderly patients because reduced liver, kidney, or heart function is more common and concomitant illnesses or other drug therapies are more common.

8.6 Liver failure

No studies have been conducted with Metoprolol Succinate extended-release tablets in patients with hepatic impairment. Because extended-release metoprolol succinate tablets are metabolized in the liver, it is likely that blood levels of metoprolol will increase significantly in liver failure. Therefore, start treatment with doses lower than those recommended for each indication. In patients with hepatic impairment, the dose should be increased gradually.

8.7 Kidney failure

The systemic availability and half-life of metoprolol in patients with renal impairment are not clinically significantly different from those in healthy subjects. No dose reduction is required in patients with chronic renal failure[see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

hypertension: The mechanism of the antihypertensive effect of β-blockers is unclear. However, several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (particularly cardiac) sites of adrenergic neurons, resulting in decreased cardiac output; (2) a central effect leading to decreased sympathetic outflow to the periphery; and (3) suppression of renin activity.

Syncope: The exact mechanism for the beneficial effects of β-blockers in heart failure is unclear.

12.2 Pharmacodynamics

Clinical pharmacological studies have confirmed the beta-blocking effect of metoprolol in humans, as evidenced by (1) reduction in heart rate and cardiac output at rest and during exercise, (2) reduction in systolic blood pressure during exercise (3). inhibition of isoproterenol-induced tachycardia and (4) reduction of postural reflex tachycardia.

Metoprolol is beta1- selective (cardioselective) blocker of adrenergic receptors. However, this preferential effect is not absolute and at higher plasma concentrations, metoprolol also inhibits beta2-Adrenoceptors located mainly in bronchial and vascular muscles. Metoprolol has no intrinsic sympathomimetic activity and its membrane-stabilizing effect is only detectable at plasma concentrations well above those required for beta-blockade. Animal and human studies indicate that metoprolol decreases heart rate and decreases AV conduction.

Of the relative Beta1-The selectivity of metoprolol has been confirmed by the following: (1) In normal subjects, metoprolol cannot reverse beta2- Adrenaline-mediated vasodilator action. This contrasts with the action of non-selective β-blockers, which completely reverse the vasodilator effects of adrenaline. (2) In asthmatics, metoprolol decreases FEV1and significantly lower FVC than a non-selective β-blocker, propranolol, at equivalent beta1-two receptor blockers.

The association between metoprolol plasma levels and heart rate reduction during exercise is independent of the pharmaceutical formulation. with an EmaximumIn the model, the maximum effect is a 30% reduction in exercise heart rate attributable to beta1- clogged up. beta1- Unique effects in the range of 30-80% of the maximum effect (about 8-23% reduction in heart rate during exercise) correspond to metoprolol plasma concentrations of 30-540 nmol/l. The relative beta1-The selectivity of metoprolol is reduced and beta blockade occurs2-Adrenoceptors are increased at plasma concentrations above 300 nmol/L.

While beta-adrenergic receptor blockade is useful in the treatment of angina, hypertension, and heart failure, there are conditions where sympathetic stimulation is critical. In patients with severely damaged hearts, adequate ventricular function may depend on sympathetic stimulation. In the presence of AV block, β block may prevent the necessary supportive effect of sympathetic activity on conduction. beta2- Adrenergic blockade leads to passive bronchoconstriction by impairing endogenous adrenergic bronchodilator activity in patients with bronchospasm and possibly also by impairing the action of exogenous bronchodilators in these patients.

In other studies, treatment with extended-release metoprolol succinate tablets resulted in improvement in left ventricular ejection fraction. Extended-release metoprolol succinate tablets have also been shown to delay post-systolic and end-diastolic left ventricular volume increase after 6 months of treatment.

12.3 Pharmacokinetics

Adult: In humans, the absorption of metoprolol is rapid and complete. However, after oral administration of conventional metoprolol tablets, plasma levels reach about 50% of those after intravenous administration, indicating a first-pass metabolism of about 50%. Metoprolol crosses the blood-brain barrier and has been observed in the CSF at a concentration of 78% of the concomitant plasma concentration.

The plasma levels achieved vary greatly after oral administration. Only a small part of the drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of R and S enantiomers and is primarily metabolized by CYP2D6. When administered orally, it presents a stereoselective metabolism depending on the oxidation phenotype. Elimination occurs primarily by biotransformation in the liver and the plasma half-life is approximately 3 to 7 hours. Less than 5% of an oral metoprolol dose is recovered unchanged in the urine. The remainder is excreted by the kidneys as metabolites that do not appear to have beta-blocking activity.

After intravenous administration of metoprolol, recovery of unchanged drug in urine is about 10%. The systemic availability and half-life of metoprolol in patients with renal impairment are not clinically significantly different from those in healthy subjects. Therefore, dose reduction of metoprolol succinate is generally not necessary in patients with chronic renal failure.

Metoprolol is primarily metabolized by CYP2D6, an enzyme absent in approximately 8% of Caucasians (poor metabolisers) and approximately 2% of most other populations. CYP2D6 can be inhibited by several drugs. Poor metabolisers and heavy metabolisers concomitantly taking drugs that inhibit CYP2D6 have increased (more than one fold) blood levels of metoprolol, thereby reducing the cardioselectivity of metoprolol[see Drug Interactions (7.2)].

Compared to conventional metoprolol, plasma levels of metoprolol following administration of extended-release metoprolol succinate tablets are characterized by lower peak values, a longer time to peak value, and significantly smaller fluctuations from peak to trough . Peak plasma levels after once-daily administration of metoprolol succinate extended-release tablets averaged one-quarter to one-half of the peak plasma levels obtained after an equivalent daily or multiple-dose dose of conventional metoprolol. At steady state, the mean bioavailability of metoprolol after administration of once-daily metoprolol succinate extended-release tablets in a dose range of 50 to 400 mg once-daily was 77% of the corresponding single or divided dose of conventional metoprolol. During the 24-hour dosing interval b1-Block is comparable and dose-dependent[see Clinical Pharmacology (12)]. The bioavailability of metoprolol shows a dose-dependent, although not directly proportional, increase with dose and is not significantly influenced by food intake following ingestion of metoprolol succinate extended-release tablets.

pediatrics: The pharmacokinetic profile of metoprolol succinate extended-release tablets was studied in 120 pediatric hypertensive subjects (aged 6 to 17 years) receiving doses ranging from 12.5 to 200 mg once daily. The pharmacokinetic properties of metoprolol were similar to those previously described in adults. Age, gender, race, and ideal body weight had no significant effect on metoprolol pharmacokinetics. Metoprolol apparent oral clearance (CL/F) increased linearly with body weight. Metoprolol pharmacokinetics have not been studied in patients less than 6 years of age.

13.1 Carcinogenesis, mutagenesis, impaired fertility

Long-term animal studies were performed to evaluate the carcinogenic potential of metoprolol tartrate. In 2-year studies in rats with three oral doses of up to 800 mg/kg/day (41 times, with mg/m²).2Based on a daily dose of 200 mg for a 60 kg patient, there was no increase in the development of spontaneous neoplasms of any type, benign or malignant. slight general focal accumulation of foamy macrophages in the alveoli and a slight increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three oral doses of up to 750 mg/kg/day (18 times, with mg/m²).2Based on a daily dose of 200 mg for a patient weighing 60 kg, benign lung tumors (small adenomas) occurred more frequently in female mice at the highest dose than in untreated controls. There was no increase in malignant or complete lung tumors (benign plus malignant), 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, chromosomal studies in somatic cells,salmonellamammalian microsomal mutagenesis assay and nuclear abnormality assay in interphase somatic nuclei) and metoprolol succinate (asalmonella/mammalian microsomal mutagenesis assay) were negative.

In a study in rats at doses up to 22 times (in mg/m), no evidence of impaired fertility due to metoprolol tartrate was seen.2The basis is a daily dose of 200 mg for a patient weighing 60 kg.

14.1 Angina pectoris

By inhibiting catecholamine-induced increases in heart rate, rate and extent of myocardial contraction, and blood pressure, metoprolol reduces the oxygen demand of the heart at any level of exercise, making it useful in the long-term treatment 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 dose used in these studies ranged from 100 to 400 mg per day. Metoprolol succinate extended-release tablets at doses of 100 to 400 mg once daily have been shown to provide beta-blockers similar to conventional metoprolol tablets given two to four times daily.

14.2 Heart failure

MERIT-HF was a double-blind, placebo-controlled study of metoprolol succinate extended-release tablets conducted in 14 countries, including the United States. They randomized 3,991 patients (1,990 using extended-release metoprolol succinate) with an ejection fraction ≤ 0.40 and NYHA class II-IV heart failure secondary to ischemia, hypertension, or cardiomyopathy. The protocol excluded patients with a contraindication to the use of β-blockers, patients awaiting cardiac surgery and patients with 28 days of myocardial infarction or unstable angina. The study's primary endpoints were (1) all-cause mortality plus all-cause hospitalization (time to first event) and (2) all-cause mortality. Patients were stabilized with 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 due to ischemic heart disease. 44% had a history of hypertension. 25% had diabetes mellitus. 48% had a history of myocardial infarction. Of the study patients, 90% received diuretics, 89% ACE inhibitors, 64% digitalis, 27% lipid-lowering agents, 37% oral anticoagulants, and the mean ejection fraction was 0.28. The average follow-up period was one year. At the end of the study, the mean daily dose of metoprolol succinate extended-release tablets was 159 mg.

The study was terminated early due to 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 study also showed improvements in heart failure-related mortality and heart failure-related hospitalizations and NYHA functional class.

The following table shows the main results for the entire study population. The figure below shows key results for a variety of subgroup comparisons, including US and non-US populations (the latter was not prespecified). The composite endpoints of all-cause mortality plus hospitalization and all-cause mortality plus hospitalization for heart failure showed consistent results across the study population and subgroups including women and the US population. However, in the US subgroup (n=1071) and in women (n=898), cardiovascular and all-cause mortality appears to be less affected. Analyzes were performed on women and US patients, as each represented approximately 25% of the total population. However, subgroup analyzes can be difficult to interpret and it is not known whether these are true differences or random effects.