Metoprolol succinate

Uses and Indications

Metoprolol succinate extended-release tablets are indicated for the treatment of hypertension, angina pectoris, and heart failure.

This drug is indicated for hypertension to lower blood pressure, thereby reducing the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. It is also indicated for the management of angina pectoris. In patients with heart failure, metoprolol succinate extended-release tablets are indicated to reduce the risk of cardiovascular mortality and hospitalizations due to heart failure.

There are no teratogenic or nonteratogenic effects associated with this medication.

Dosage and Administration

The medication is to be administered once daily. Dosing should be titrated at weekly or longer intervals as needed and tolerated.

For the management of hypertension, the starting dose is 25 to 100 mg. In cases of angina pectoris, the recommended starting dose is 100 mg. For heart failure, the initial dosing should be either 12.5 or 25 mg.

When transitioning from immediate-release metoprolol to metoprolol succinate extended-release tablets, it is essential to use the same total daily dose of metoprolol succinate extended-release tablets as the immediate-release formulation.

Contraindications

Use of this product is contraindicated in patients with known hypersensitivity to any of its components.

Additionally, it should not be administered to individuals with severe bradycardia, including those with greater than first-degree heart block or sick sinus syndrome in the absence of a pacemaker.

The product is also contraindicated in patients experiencing cardiogenic shock or decompensated heart failure, due to the potential for exacerbating these conditions.

Warnings and Precautions

Abrupt cessation of beta-blocker therapy may lead to exacerbation of myocardial ischemia. Therefore, healthcare professionals should exercise caution when discontinuing treatment, particularly in patients with a history of ischemic heart disease.

In patients with heart failure, there is a risk of worsening cardiac function. Continuous monitoring of cardiac status is recommended to identify any deterioration in heart failure symptoms.

Beta-blockers are contraindicated in individuals with bronchospastic disease, as they may induce bronchospasm. Alternative therapies should be considered for these patients to avoid respiratory complications.

Concomitant use of beta-blockers with glycosides, clonidine, diltiazem, or verapamil can significantly increase the risk of bradycardia. It is essential to monitor heart rate and rhythm closely in patients receiving these combinations to prevent severe bradycardic events.

For patients diagnosed with pheochromocytoma, therapy should be initiated with an alpha-blocker prior to the introduction of beta-blockers to mitigate the risk of hypertensive crises.

In the context of major surgery, particularly non-cardiac procedures, the initiation of high-dose extended-release metoprolol should be avoided. However, it is not routinely necessary to withdraw chronic beta-blocker therapy before surgery, as this may lead to adverse cardiovascular events.

Patients on beta-blockers may experience an increased risk of hypoglycemia, and these medications can mask the early warning signs of low blood sugar. Regular monitoring of blood glucose levels is advised, especially in diabetic patients.

In individuals with thyrotoxicosis, abrupt withdrawal of beta-blockers may precipitate a thyroid storm, a life-threatening condition. Caution is warranted when considering discontinuation in these patients.

For those with peripheral vascular disease, beta-blockers may exacerbate symptoms of arterial insufficiency. Careful assessment of vascular status is recommended to ensure that treatment does not worsen the patient's condition.

Lastly, patients receiving beta-blockers may exhibit unresponsiveness to the standard doses of epinephrine used in the treatment of allergic reactions. Healthcare providers should be aware of this potential interaction and consider alternative management strategies in such cases.

Side Effects

Patients receiving treatment may experience a range of adverse reactions. The most common adverse reactions reported include tiredness, dizziness, depression, shortness of breath, bradycardia, hypotension, diarrhea, pruritus, and rash.

Serious adverse reactions have also been noted. Abrupt cessation of therapy may exacerbate myocardial ischemia, and worsening cardiac failure may occur in patients with heart failure. In individuals with bronchospastic disease, beta-blockers should be avoided due to the potential for exacerbation of symptoms. The concomitant use of glycosides, clonidine, diltiazem, and verapamil with beta-blockers can increase the risk of bradycardia.

In patients with pheochromocytoma, it is recommended to initiate therapy with an alpha-blocker. During major surgery, the initiation of high-dose extended-release metoprolol should be avoided in patients undergoing non-cardiac procedures, and chronic beta-blocker therapy should not routinely be withdrawn prior to surgery.

Patients may also be at increased risk for hypoglycemia, which may mask early warning signs. In those with thyrotoxicosis, abrupt withdrawal of treatment might precipitate a thyroid storm. Additionally, peripheral vascular disease can be aggravated, leading to worsened symptoms of arterial insufficiency. It is important to note that patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

In cases of overdosage, symptoms may include severe bradycardia, hypotension, and cardiogenic shock. Other clinical presentations can involve atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness or coma, nausea, and vomiting.

Contraindications for this treatment include known hypersensitivity to the product components, severe bradycardia (greater than first-degree heart block), sick sinus syndrome without a pacemaker, cardiogenic shock, or decompensated heart failure.

Drug Interactions

Catecholamine-depleting drugs may exhibit an additive effect when administered concurrently with beta-blocking agents, potentially leading to enhanced pharmacological effects. Clinicians should monitor patients closely for signs of increased hypotension or bradycardia when these drug classes are used together.

CYP2D6 inhibitors are known to increase the concentration of metoprolol. It is advisable to consider dosage adjustments of metoprolol in patients receiving CYP2D6 inhibitors to mitigate the risk of adverse effects associated with elevated drug levels.

Beta-blockers, including metoprolol, may exacerbate rebound hypertension following the withdrawal of clonidine. Caution is recommended when discontinuing clonidine in patients who are also receiving beta-blockers, and appropriate monitoring of blood pressure should be implemented during this transition.

Packaging & NDC

The table below lists all NDC Code configurations of Metoprolol Succinate, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

One hundred forty-four hypertensive pediatric patients aged 6 to 16 years were randomized to receive either placebo or one of three dose levels of metoprolol succinate extended-release (0.2, 1, or 2 mg/kg once daily) over a 4-week period. The study did not achieve its primary endpoint of demonstrating a dose response for the reduction in systolic blood pressure (SBP). However, some pre-specified secondary endpoints indicated effectiveness, including a dose-response for the reduction in diastolic blood pressure (DBP) and significant changes in SBP when comparing 1 mg/kg and 2 mg/kg doses to placebo.

The mean placebo-corrected reductions in SBP ranged from 3 to 6 mmHg, while reductions in DBP ranged from 1 to 5 mmHg. Additionally, the mean reduction in heart rate was between 5 to 7 bpm, with some individuals experiencing considerably greater reductions.

No clinically relevant differences in the adverse event profile were observed in pediatric patients aged 6 to 16 years compared to adult patients. It is important to note that the safety and effectiveness of metoprolol succinate extended-release tablets have not been established in patients younger than 6 years of age.

Geriatric Use

Clinical studies of metoprolol succinate extended-release in hypertension did not include a sufficient number of subjects aged 65 and over to determine whether these elderly patients respond differently from younger individuals. However, other reported clinical experiences in hypertensive patients have not identified significant differences in responses between elderly and younger patients.

In the MERIT-HF trial, which randomized 1,990 patients with heart failure to metoprolol succinate extended-release, 50% of the participants were aged 65 years and older, and 12% were aged 75 years and older. The findings from this trial indicated no notable differences in efficacy or the rate of adverse reactions between older and younger patients.

Given the greater frequency of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies in elderly patients, it is generally recommended to initiate treatment with a low starting dose in this population. Careful monitoring is advised to ensure safety and efficacy in geriatric patients.

Pregnancy

Untreated hypertension and heart failure during pregnancy can lead to adverse outcomes for both the mother and the fetus. Available data from published observational studies have not demonstrated a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes with the use of metoprolol during pregnancy. However, there are inconsistent reports regarding intrauterine growth restriction, preterm birth, and perinatal mortality associated with maternal use of beta-blockers, including metoprolol, during pregnancy.

In animal reproduction studies, metoprolol has been shown to increase post-implantation loss and decrease neonatal survival in rats at oral dosages of 500 mg/kg/day, which is approximately 24 times the daily dose of 200 mg in a 60 kg patient on a mg/m² basis. Conversely, no fetal abnormalities were observed when pregnant rats received metoprolol orally at doses up to 200 mg/kg/day, equivalent to 10 times the daily dose of 200 mg in a 60 kg patient.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown; however, all pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications, such as the need for cesarean section and post-partum hemorrhage. Additionally, hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death, necessitating careful monitoring and management of pregnant women with hypertension.

Metoprolol crosses the placenta, and neonates born to mothers receiving metoprolol during pregnancy may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. Therefore, it is recommended that neonates be observed and managed accordingly. While the published literature has reported inconsistent findings regarding intrauterine growth retardation, preterm birth, and perinatal mortality with maternal use of metoprolol, methodological limitations in these studies, such as retrospective design and concomitant use of other medications, hinder definitive conclusions about drug-associated risks during pregnancy.

Lactation

Metoprolol crosses the placenta. Lactating mothers receiving metoprolol should be aware that neonates born to them may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. It is recommended that healthcare professionals observe these neonates closely and manage any adverse effects accordingly. There is no specific data provided regarding the excretion of metoprolol in breast milk or its effects on breastfed infants. Therefore, caution is advised when administering metoprolol to lactating mothers.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in these patients to ensure safety and efficacy.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Overdosage of metoprolol succinate extended-release tablets can result in a range of serious clinical manifestations. The most common signs and symptoms include severe bradycardia, hypotension, and cardiogenic shock. Additional clinical presentations may encompass atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness or coma, as well as gastrointestinal symptoms such as nausea and vomiting.

In the event of an overdose, it is crucial to consider intensive care management for the patient, particularly for those with underlying conditions such as myocardial infarction or heart failure, as they may experience significant hemodynamic instability. It is important to note that beta-blocker overdose can lead to considerable resistance to resuscitation efforts with adrenergic agents, including beta-agonists.

Management Strategies

Bradycardia: The management of bradycardia may require the administration of atropine, adrenergic-stimulating drugs, or the placement of a pacemaker to address conduction disorders.

Hypotension: Treatment should focus on addressing the underlying bradycardia. Intravenous vasopressor infusion, such as dopamine or norepinephrine, may be necessary to stabilize blood pressure.

Heart Failure and Shock: In cases of heart failure and shock, appropriate interventions may include volume expansion and the administration of glucagon, which can be followed by an intravenous infusion if required. Additionally, intravenous adrenergic drugs such as dobutamine may be utilized, with α1 receptor agonists considered in the presence of vasodilation.

Bronchospasm: Bronchospasm associated with overdose can typically be managed with bronchodilators, which are effective in reversing the bronchoconstriction.

It is important to note that hemodialysis is unlikely to significantly enhance the elimination of metoprolol from the body. Therefore, supportive care and the aforementioned management strategies should be prioritized in the treatment of metoprolol overdose.

Nonclinical Toxicology

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. However, 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, including 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, were negative. Additionally, metoprolol succinate was also tested in a Salmonella/mammalian-microsome mutagenicity test, yielding negative results.

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.

Postmarketing Experience

During post-approval use of metoprolol succinate extended-release and immediate-release metoprolol, various adverse reactions have been reported voluntarily or through surveillance programs. Due to the nature of these reports, which originate from a population of uncertain size, it is not always feasible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular events include cold extremities, arterial insufficiency (typically of the Raynaud type), palpitations, peripheral edema, syncope, chest pain, and hypotension. Respiratory reactions consist of wheezing (bronchospasm) and dyspnea.

Central nervous system effects reported include confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety/nervousness, hallucinations, and paresthesia. Gastrointestinal reactions encompass nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, and vomiting.

Hypersensitive reactions have been noted, including pruritus, laryngospasm, and respiratory distress. Miscellaneous adverse events include musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, tinnitus, reversible alopecia, dry eyes, worsening of psoriasis, Peyronie’s disease, sweating, photosensitivity, and taste disturbance.

Additionally, there are potential adverse reactions that have been reported with other beta-adrenergic blocking agents, which should be considered as potential reactions to metoprolol succinate extended-release. These include central nervous system effects such as reversible mental depression progressing to catatonia, characterized by disorientation for time and place, short-term memory loss, emotional lability, clouded sensorium, and decreased performance on neuropsychometric tests. Hematologic reactions reported include agranulocytosis, nonthrombocytopenic purpura, and thrombocytopenic purpura.

Patient Counseling

Patients should be cautioned against interrupting therapy with metoprolol succinate extended-release tablets without consulting their physician, as abrupt cessation may lead to exacerbations of angina pectoris and, in some cases, myocardial infarction. When discontinuing metoprolol succinate extended-release tablets, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1 to 2 weeks, and the patient should be closely monitored during this process.

Patients should be advised to seek emergency treatment if they experience severe hypoglycemia, as beta-blockers may mask early warning signs of hypoglycemia, such as tachycardia. It is important to inform patients with bronchospastic diseases that they should generally avoid beta-blockers; however, metoprolol succinate extended-release tablets may be considered for those who do not respond to or cannot tolerate other antihypertensive treatments, with the recommendation to use the lowest effective dose.

Monitoring for bradycardia and other symptoms of beta-blockade, such as listlessness, particularly in breastfed infants, is essential. Patients should also be informed that metoprolol crosses the placenta, and neonates born to mothers receiving metoprolol during pregnancy may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. Additionally, patients should be encouraged to monitor their heart rate and report any significant changes while taking metoprolol succinate extended-release tablets.

Storage and Handling

This product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a temperature range of 20°-25°C (68°-77°F), in compliance with USP Controlled Room Temperature guidelines.

It is essential to keep this product, along with all medications, out of the reach of children to ensure safety.

Additional Clinical Information

Metoprolol succinate extended-release tablets are scored and can be divided; however, they should not be crushed or chewed. Clinicians should advise patients against abruptly discontinuing therapy, as this may lead to exacerbations of angina pectoris or myocardial infarction, particularly in those with ischemic heart disease. A gradual dosage reduction over 1 to 2 weeks is recommended, with close monitoring. If symptoms worsen, metoprolol should be reinstated promptly, and appropriate measures for unstable angina should be taken. Patients should be cautioned not to interrupt therapy without consulting their physician.

In patients with bronchospastic diseases, beta-blockers are generally contraindicated. However, due to its relative beta1-cardio-selectivity, metoprolol may be considered for those who do not respond to or cannot tolerate other antihypertensive treatments, with the lowest effective dose being used. Bronchodilators should be readily available. Additionally, breastfeeding infants should be monitored for signs of bradycardia and other symptoms of beta-blockade.

Postmarketing experience has revealed various adverse effects, including cardiovascular issues such as cold extremities and hypotension, respiratory symptoms like wheezing, and central nervous system effects including confusion and insomnia. Gastrointestinal disturbances, hypersensitive reactions, and miscellaneous effects such as musculoskeletal pain and decreased libido have also been reported.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Metoprolol Succinate as submitted by Cardinal Health 107, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)