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 designed to reduce the risk of cardiovascular mortality and heart failure hospitalization in patients with heart failure.
Adult:The usual starting dose is 25 to 100 mg per day in a single dose. Adjust dose 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≥ 6 years:The recommended starting dose of metoprolol succinate extended-release tablets is 1 mg/kg once daily, but the maximum starting dose should not exceed 50 mg once daily. Adjust dose according to blood pressure response. Doses greater than 2 mg/kg (or greater than 200 mg) once daily have not been studied in pediatric patients[see Use in Specific Populations (8.4) and clinical pharmacology (12.3)].
Metoprolol succinate extended-release tablets have not been studied in pediatric patients less than 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 to 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 tablet, or temporary discontinuation. The dose of metoprolol succinate extended-release tablets should not be increased until symptoms of worsening heart failure have stabilized.
Metoprolol succinate extended-release tablets are scored and can be divided. However, do not crush or chew all or half of the tablet.
Metoprolol Succinate Extended-Release Tablets, USP, are available as follows:
25 mg – Each white to off-white, capsule-shaped, embossed film-coated tableton one side and A9 on the other side and marked on both sides, contains 23.75 mg Metoprolol Succinate, USP, equivalent to 25 mg Metoprolol Tartrate, USP.
50 mg - Each white to off-white, capsule-shaped film-coated tabletand 676 on one side and notched on the other side contains 47.5 mg Metoprolol Succinate, USP, equivalent to 50 mg Metoprolol Tartrate, USP.
100 mg - Each white to off-white, capsule-shaped film-coated tabletand 677 on one side and notched on the other side contains 95 mg Metoprolol Succinate, USP, equivalent to 100 mg Metoprolol Tartrate, USP.
200 mg - Each white to off-white, capsule-shaped, engraved film-coated tabletand 678 on one side and notched on the other side contains 190 mg Metoprolol Succinate, USP, equivalent to 200 mg Metoprolol Tartrate, USP.
Metoprolol succinate extended-release tablets are contraindicated in severe bradycardia, second- or third-degree heart block, cardiogenic shock, congestive heart failure, weak atrial syndrome (unless a permanent pacemaker is present), and in patients with hypersensitivity to any of the components of this product.
5.1 Abrupt interruption of treatment
Angina pectoris worsened and, in some cases, myocardial infarction occurred after abrupt withdrawal of some beta-blockers. When stopping chronic extended-release metoprolol succinate, particularly in patients with ischemic heart disease, reduce the dose gradually over 1 to 2 weeks and monitor the patient. If angina pectoris worsens markedly or acute coronary ischemia develops, immediately resume extended-release metoprolol succinate and take appropriate measures to treat unstable angina pectoris. Advise patients not to discontinue treatment without physician advice. Because coronary artery disease is common and may remain unrecognized, abrupt withdrawal of extended-release metoprolol succinate should be avoided in patients treated for hypertension alone.
5.2 Heart failure
With increasing dose of extended-release metoprolol succinate, worsening heart failure may occur. If such symptoms appear, increase diuretics and restore clinical stability before increasing dose of extended-release metoprolol succinate[see dosage and application (2)]. The dose of extended-release metoprolol succinate may need to be reduced or temporarily discontinued. Such episodes do not preclude subsequent successful titration of sustained-release metoprolol succinate.
5.3 Bronchospastic disease
Patients with bronchospastic diseases generally should not take beta-blockers. Because of its relative beta1Cardioselectivity, however, extended-release metoprolol succinate may be used in patients with bronchospastic disease who do not respond to or are intolerant of other antihypertensive therapies. because beta1- Selectivity is not absolute. Use the lowest possible dose of extended-release metoprolol succinate. bronchodilators, including beta2-Agonists must be readily available or co-administered[see dosage and application (2)].
Bradycardia, including sinus arrest, heart block and cardiac arrest, has been reported with the use of extended-release metoprolol succinate. Patients with first-degree atrioventricular block, sinus node dysfunction, conduction disorders (including Wolff-Parkinson-White), or concomitant medications that cause bradycardia[see Drug Interactions (7.3)], possibly at increased risk. Monitor heart rate in patients receiving metoprolol extended-release succinate. If severe bradycardia occurs, reduce or discontinue the use of sustained-release metoprolol succinate.
When extended-release metoprolol is used in pheochromocytoma, it should be given in combination with an alpha-blocker and only after initiation of alpha-blocker treatment. 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.
5.6 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.
5.7 Masking symptoms of hypoglycemia
Beta-blockers can mask the tachycardia that occurs with hypoglycemia, but other symptoms such as dizziness and sweating may not be significantly affected.
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 Peripheral vascular disease
Beta-blockers may worsen or exacerbate 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 various allergens may respond better to repeated exposures and may not respond to the usual doses of epinephrine used to treat an allergic reaction.
The following side effects are described elsewhere in the package insert:
- Worsening angina pectoris or myocardial infarction[see Warnings and Precautions (5)].
- Worsening heart failure[see Warnings and Precautions (5)].
- AV block worsening[see contraindications (4)].
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, which compared extended-release metoprolol succinate at daily doses of up to 200 mg (mean dose 159 mg once daily; n=1990) with placebo (n=2001), 10.3% of patients Adverse events were treated with extended-release metoprolol succinate compared with 12.2% of patients on placebo.
The table below 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.
n=1990% two patients
n=2001% two patients
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, treatment with metoprolol succinate 100 mg extended-release tablets for 2 to 4 hours was started. she then continued on 200 mg daily for 30 days before surgery. 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 1.575, CI 1.5%) associated, CI 1.5%, 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 to placebo.
6.2 Post-launch experience
The following side effects have been observed with post-marketing use of extended-release or immediate-release metoprolol succinate. 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.
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:In addition, there are side effects not listed above that have been reported with other β-adrenergic blockers that should be considered as possible side effects of metoprolol succinate extended release.
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.
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 severe bradycardia that may lead to dizziness, syncope, or orthostatic hypotension.
7.2 CYP2D6 inhibitors
Drugs that are strong CYP2D6 inhibitors, such as quinidine, fluoxetine, paroxetine, and propafenone, have been shown to double metoprolol concentrations. Although no information is available on moderate or weak inhibitors, it is likely that they also increase metoprolol concentrations. Increased plasma concentrations reduce the cardioselectivity of metoprolol[see Clinical Pharmacology (12.3)]. Monitor patients carefully if the combination cannot be avoided.
7.3 Digitalis, 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 switching from clonidine to beta-blocker therapy, delay introduction of beta-blockers for several days after stopping clonidine.
Untreated high blood pressure and heart failure during pregnancy can lead to negative consequences for the mother and fetus(see Clinical Considerations). Available data from published observational studies have not demonstrated a drug-related risk of serious congenital abnormalities, miscarriage, or adverse maternal or fetal outcomes from the use of metoprolol during pregnancy. However, there are conflicting reports of intrauterine growth restriction, preterm delivery, and perinatal mortality due to maternal use of beta-blockers, including metoprolol, during pregnancy.(I understandData). In animal reproduction studies, metoprolol has been shown to increase postimplantation loss and survival in rats at oral doses of 500 mg/kg/day, approximately 24 times the daily dose of 200 mg in a 60 kg patient, up to 1 mg /kg day of newborns decreased. M2Base.
The estimated historical risk of major birth defects and miscarriages for the specified population is unknown. With all pregnancies, there is a risk of a birth defect, loss or other undesirable consequences in the past. In the general US population, the estimated historical risk of major birth defects and miscarriage for clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Risk associated with the disease for the mother and/or foetus(ren).
Hypertension during pregnancy increases the mother's risk of preeclampsia, gestational diabetes, preterm delivery, and delivery complications (eg, need for caesarean section and postpartum haemorrhage). Hypertension increases the risk of intrauterine growth retardation and intrauterine fetal death. Pregnant women with hypertension must be carefully monitored and treated accordingly.
During pregnancy, stroke volume and heart rate increase, causing cardiac output to increase, especially in the first trimester. Pregnant women with chronic heart failure in the third trimester of pregnancy are at risk for premature delivery.
Adverse reactions in the fetus/newborn
Metoprolol crosses the placenta. Newborns of mothers taking metoprolol during pregnancy may be at risk of hypotension, hypoglycaemia, bradycardia and respiratory depression. Observe the puppies and act accordingly.
Data from published observational studies have not shown an association between severe birth defects and the use of metoprolol in pregnancy. Conflicting results have been reported in the published literature on intrauterine growth retardation, preterm delivery and perinatal mortality due to maternal use of metoprolol during pregnancy. However, these studies have methodological limitations that make interpretation difficult. Methodological limitations include retrospective design, concomitant use of other medications, and other unadjusted confounders that may explain study results, including underlying maternal conditions. These observational studies cannot conclusively prove or rule out a drug-associated risk during pregnancy.
Metoprolol has been shown to be effective in rats at oral doses of 500 mg/kg/day, i.e. H. 24 times, in mg/m2, increases post-implantation loss and decreases neonatal survival.2The basis is a daily dose of 200 mg for a patient weighing 60 kg.
No fetal abnormalities were observed when pregnant rats received metoprolol up to 200 mg/kg/day orally, ie H. 10 times the daily dose of 200 mg in a 60 kg patient.
Limited data available in the published literature indicate that metoprolol is present in breast milk. The estimated daily dose of metoprolol for infants obtained from breast milk ranges from 0.05 mg to less than 1 mg. The estimated relative dose for infants was 0.5% to 2% of the weight-adjusted maternal dose.(see data). No side effects of metoprolol have been identified in breastfed infants. There is no information on the effects of metoprolol on milk production.
Beware of side effects
Monitor the infant for bradycardia and other beta-blocker symptoms such as B. Atonia (hypoglycemia).
Based on published case reports, the estimated daily dose of metoprolol for infants obtained from breast milk ranges from 0.05 mg to less than 1 mg. The estimated relative dose for infants was 0.5% to 2% of the weight-adjusted maternal dose.
Milk samples were collected from two women who received an unspecified amount of metoprolol after a single dose of metoprolol. The estimated amount of metoprolol and alpha-hydroxy-metoprolol in breast milk has been reported to be less than 2% of the weight-adjusted maternal dose.
In one small study, breast milk was collected every 2 to 3 hours over a dosing interval from three mothers (at least 3 months postpartum) receiving an unspecified amount of metoprolol. The mean amount of metoprolol in breast milk was 71.5 µg/day (range 17.0 to 158.7). The mean relative dose for infants was 0.5% of the weight-adjusted maternal dose.
8.3 Women and men with reproductive potential
Based on published literature, beta-blockers (including metoprolol) can cause erectile dysfunction and inhibit sperm motility.
In rats, no evidence of impaired fertility due to metoprolol was observed.[see Non-clinical toxicology (13.1)].
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 extended-release metoprolol succinate (0.2, 1, or 2 mg/kg once daily) and followed 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,
- 1 mg/kg versus placebo for change in SBP and
- 2 mg/kg versus placebo to change 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 extended-release metoprolol succinate 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 patients with heart failure randomized to metoprolol extended-release succinate in the MERIT-HF study, 50% (990) were 65 years or older and 12% (238) were 75 years 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 extended-release succinate in patients with hepatic impairment. Since extended-release metoprolol is metabolized in the liver, blood levels of metoprolol are likely to increase markedly 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)].
Signs and Symptoms - Overdose with extended-release metoprolol succinate may result in severe bradycardia, hypotension, and cardiogenic shock. Clinical presentations may also include: atrioventricular block, heart failure, bronchospasm, hypoxia, loss of consciousness/coma, nausea and vomiting.
Treatment - Consider treating the patient in the ICU. Patients with myocardial infarction or heart failure may be prone to significant hemodynamic instability. Overdose of beta-blockers can result in significant resistance to resuscitation with adrenergic agents, including beta-agonists. Based on the pharmacological effects of metoprolol, perform the following actions.
Hemodialysis is unlikely to make a significant contribution to the elimination of metoprolol[see Clinical Pharmacology (12.3)].
Bradycardia: Assess the need for atropine, adrenergic stimulating drugs, or pacemakers to treat bradycardia and conduction disorders.
Hypotension: Treat underlying bradycardia. Consider an intravenous vasoconstrictor infusion such as dopamine or norepinephrine.
Heart failure and shock: can be treated as appropriate by appropriate volume expansion, injection of glucagon (if necessary, followed by intravenous infusion of glucagon), intravenous administration of adrenergic drugs such as dobutamine, with a. to be treated1Receptor agonists added in vasodilation.
Bronchospasm: usually reversible with bronchodilators.
Metoprolol Succinate, USP is Beta1- Selective (cardioselective) blocker of adrenergic receptors for oral administration, available as extended-release tablets. Metoprolol Succinate Extended-Release Tablets (USP) are formulated to provide controlled, predictable release of metoprolol when administered once daily. Tablets consist of a multi-unit system containing metoprolol succinate, USP, in a variety of controlled-release pellets. Each lozenge acts as a separate drug delivery unit and is designed for continuous administration of metoprolol during the dosing interval. Tablets contain 23.75, 47.5, 95, and 190 mg Metoprolol Succinate, USP, corresponding to 25, 50, 100, and 200 mg Metoprolol Tartrate, USP. Its chemical name is (±)1-(isopropylamino)-3-[p-(2-methoxyethyl)phenoxy]-2-propanol succinate (2:1) (salt). Its structural formula is:
Metoprolol Succinate, USP is a white crystalline powder with a molecular weight of 652.8. It is freely soluble in water. soluble in methanol. Slightly soluble in ethanol. Slightly soluble in dichloromethane and 2-propanol. practically insoluble in ethyl acetate, acetone, diethyl ether and heptane. Inactive Ingredients: Acetyl Tributyl Citrate, Caprylic/Capric Triglyceride, Colloidal Silicon Dioxide, Copovidone, Crospovidone, Denatured Alcohol, Ethyl Cellulose, Hydroxypropyl Cellulose, Magnesium Stearate, Microcrystalline Cellulose, Polyethylene Glycol 30050, Polyethylene Glycol, Polyethylene Glycol Dioxide.
USP dissolution test pending.
12.1 Mechanism of Action
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.
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.
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.
Syncope:The exact mechanism for the beneficial effects of beta-blockers in heart failure is unclear.
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.
The association between metoprolol plasma levels and heart rate reduction during exercise is independent of the pharmaceutical formulation. beta1- Unique effects ranging from 30 to 80% of the maximum effect (approximately 8 to 23% reduction in heart rate during exercise) correspond to metoprolol plasma concentrations of 30 to 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.
In five controlled studies in normal healthy volunteers, once daily extended-release metoprolol succinate and immediate-release metoprolol 1-4 times daily provided comparable total beta1- Block for 24 hours (area in beta1blockade time curve) in the dose range of 100 to 400 mg. In another controlled study, 50 mg once daily of each product, extended-release metoprolol succinate, resulted in a significantly higher total beta1- Block immediate-release metoprolol for 24 hours. For extended-release metoprolol succinate, the percent reduction in heart rate during exercise was relatively constant across the dosing range and beta1-Blockade increased with increasing doses from 50 to 300 mg per day.
In a controlled crossover study in patients with heart failure, plasma and beta concentrations were compared1- inhibitory effect of metoprolol 50 mg immediate release administered three times a day. and 100 mg and 200 mg of extended-release metoprolol succinate once daily. Sustained-release electrical metoprolol 200 mg once daily had a greater effect on 24-hour Holter-monitored exercise-induced suppression of heart rate compared to 50 mg three times daily. Immediate-release metoprolol.
In other studies, treatment with metoprolol succinate resulted in improvement in left ventricular ejection fraction. Metoprolol succinate has also been shown to delay post-systolic and end-diastolic left ventricular volume increase after 6 months of treatment.
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.
Peak plasma levels after once-daily administration of extended-release metoprolol succinate range on average from 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 extended-release metoprolol succinate in a dose range of 50 to 400 mg once daily was 77% of the corresponding single or divided doses of conventional metoprolol.
The bioavailability of metoprolol shows a dose-dependent, though not directly proportional, increase with dose and is not significantly affected by food intake following administration of extended-release metoprolol succinate.
However, after oral administration of conventional metoprolol tablets, peak 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. 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%.
Patients with 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.
The prolonged-release pharmacokinetic profile of metoprolol succinate was studied in 120 hypertensive pediatric patients (6 to 17 years of age) who received doses ranging from 12.5 to 200 mg once daily. The pharmacokinetic properties of metoprolol were similar to those previously described in adults. Metoprolol pharmacokinetics have not been studied in patients less than 6 years of age.
body weight, age and race
Metoprolol apparent oral clearance (CL/F) increased linearly with body weight. Age, sex and race had no significant effect on metoprolol pharmacokinetics.
Interactions with other drugs
Metoprolol is primarily metabolised by CYP2D6. In healthy subjects with the CYP2D6 extensive metabolizer phenotype, co-administration of 100 mg of quinidine, a potent CYP2D6 inhibitor, and 200 mg of immediate-release metoprolol tripled the concentration of S-metoprolol and halved the elimination 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 stable metoprolol concentrations that were 2 to 5 times greater than metoprolol alone. Extensive metabolizers, who are also taking CYP2D6 inhibitor drugs, have a (fold) increased blood level of metoprolol, which reduces the cardioselectivity of metoprolol[see Drug Interactions (7.2)].
CYP2D6 is absent in about 8% of Caucasians (poor metabolisers) and about 2% of most other populations. CYP2D6 can be inhibited by several drugs. CYP2D6 poor metabolisers increased (fold) blood levels of metoprolol, thereby reducing the cardioselectivity of metoprolol.
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.
In a double-blind study, 1092 patients with mild to moderate hypertension were randomized to once-daily treatment with extended-release metoprolol (25, 100, or 400 mg), PLENDIL®(felodipine extended-release tablets), the combination, or placebo. At 9 weeks, extended-release metoprolol succinate alone reduced sitting blood pressure by 6 to 8/4 to 7 mmHg (placebo-corrected change from baseline) 24 hours after administration. The combination of extended-release metoprolol succinate and PLENDIL®has greater effects on blood pressure.
In controlled clinical trials, an immediate-release pharmaceutical form of metoprolol has been shown to be an effective antihypertensive agent when used alone or as concomitant therapy with thiazide-type diuretics in doses ranging from 100 to 450 mg per day. Extended-release metoprolol succinate at doses of 100 to 400 mg once daily produces similar b1- Exclusion, as conventional metoprolol tablets are administered two to four times a day. In addition, metoprolol extended-release succinate at a dose of 50 mg once daily reduced blood pressure 24 hours after administration in placebo-controlled studies. In comparative controlled clinical trials, immediate-release metoprolol appeared to be an antihypertensive agent comparable to propranolol, methyldopa, and thiazide diuretics, affecting blood pressure in the supine and standing position. Due to the variable plasma levels achieved with a given dose and the lack of a consistent relationship between the antihypertensive effect and plasma drug concentration, selection of the appropriate dose 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 dose used in these studies ranged from 100 to 400 mg per day. Extended-release metoprolol succinate at doses of 100 to 400 mg once daily has been shown to produce beta-blockers similar to conventional metoprolol tablets given two to four times daily.
14.3 Heart failure
MERIT-HF was a randomized, double-blind, placebo-controlled, sustained-release study of metoprolol succinate in which 3991 patients with an ejection fraction ≤ 0.40 and NYHA class II-IV heart failure due to ischemia, hypertension or cardiomyopathy were randomized11: on metoprolol-extended-release tablets or placebo. 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 average daily dose of extended-release metoprolol succinate 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 effects across the study population and subgroups. However, subgroup analyzes can be difficult to interpret and it is not known whether these are true differences or random effects.
|Clinical Endpoint||number of patients|
risk mitigation with
All-cause mortality plus all-cause hospitalizations1
0,81 (0,73 a 0,90)
0,66 (0,53 a 0,81)
All-cause mortality plus hospitalization for heart failure1
0,69 (0,60 a 0,80)
0,62 (0,50 a 0,78)
0,59 (0,45 a 0,78)
Death due to worsening heart failure
0,51 (0,33 a 0,79)
Hospitalization for worsening heart failure2
N / D
N / D
N / D
N / D
1.Time to first event
2.When comparing treatment groups, the number of admissions is examined (Wilcoxon test). relative risk and risk mitigation do not apply.
Metoprolol Succinate Extended-Release Tablets, USP, are as follows:
25mg -Each white to off-white, capsule-shaped, film-coated tablet engravedon one side and A9 on the other side and marked on both sides, contains 23.75 mg Metoprolol Succinate, USP, equivalent to 25 mg Metoprolol Tartrate, USP. Tablets are available in bottles of 30 (NDC 51655-934-52).
Store at 25°C (77°F). Tours are allowed between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature].
Supplied in a sealed, light-resistant USP container.
Advise patients to take metoprolol succinate extended-release tablets regularly and continuously as directed, preferably with or immediately after meals. If a dose is missed, the patient should only take the next scheduled dose (no doubling up). Patients should not stop or stop taking Metoprolol Succinate Extended Release Tablets without consulting a doctor.
Advise the patient (1) to avoid operating cars and machines or other tasks that require attention until the patient's response to treatment with metoprolol succinate extended-release tablets has been established. (2) Consult physician if breathing difficulty occurs. (3) Before any type of surgery, inform the doctor or dentist that he is taking metoprolol succinate extended-release tablets.
Heart failure patients should be instructed to see their physician if they notice signs or symptoms of worsening heart failure, such as weight gain or increased shortness of breath.
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Engine rotation. D 10/2022