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 based on patient response and tolerability.

For the management of hypertension, the recommended starting dose ranges from 25 mg to 100 mg. In cases of angina pectoris, the starting dose is established at 100 mg. For patients with heart failure, the initial dosing should be either 12.5 mg or 25 mg, depending on clinical judgment and patient-specific factors.

Healthcare professionals are advised to monitor the patient's response to therapy and adjust the dosage accordingly to achieve optimal therapeutic outcomes.

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 without a pacemaker. The product is also contraindicated in cases of 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, necessitating careful consideration of discontinuation protocols. Healthcare professionals should be vigilant for signs of worsening cardiac failure, which may occur during treatment.

In patients with bronchospastic disease, the use of beta-blockers is contraindicated due to the potential for bronchospasm. Additionally, the concomitant administration of glycosides, clonidine, diltiazem, or verapamil with beta-blockers can significantly increase the risk of bradycardia, warranting close monitoring of heart rate and rhythm.

For patients diagnosed with pheochromocytoma, it is imperative to initiate therapy with an alpha blocker prior to the introduction of beta-blockers to mitigate the risk of hypertensive crises. Furthermore, in the context of non-cardiac surgery, high-dose extended-release metoprolol should not be initiated, and chronic beta-blocker therapy should not be routinely withdrawn prior to surgical procedures.

Healthcare providers should be aware that beta-blockers may mask tachycardia associated with hypoglycemia in diabetic patients, potentially complicating the management of hypoglycemic episodes. In patients with thyrotoxicosis, abrupt withdrawal of beta-blockers may precipitate a thyroid storm, necessitating a gradual tapering of the medication.

Patients with peripheral vascular disease may experience aggravated symptoms of arterial insufficiency when treated with beta-blockers, requiring careful assessment of vascular status. Lastly, it is important to note that patients may exhibit unresponsiveness to standard doses of epinephrine used for the treatment of allergic reactions, highlighting the need for alternative management strategies in such cases. Regular monitoring and individualized patient assessment are essential to ensure safe and effective use of beta-blockers in these populations.

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 may occur, including worsening cardiac failure and exacerbation of myocardial ischemia following abrupt cessation of therapy. Patients with bronchospastic disease should avoid beta-blockers due to the risk of bronchospasm. The concomitant use of glycosides, clonidine, diltiazem, and verapamil with beta-blockers can increase the risk of bradycardia. In patients with pheochromocytoma, therapy should be initiated with an alpha blocker.

It is important to note that high-dose extended-release metoprolol should not be initiated in patients undergoing non-cardiac surgery, and chronic beta-blocker therapy should not be routinely withdrawn prior to surgery. Additionally, beta-blockers may mask tachycardia associated with hypoglycemia in diabetic patients. Abrupt withdrawal in patients with thyrotoxicosis may precipitate a thyroid storm, and symptoms of arterial insufficiency may be aggravated in patients with peripheral vascular disease. Furthermore, patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

In cases of overdosage, patients may present with severe bradycardia, hypotension, and cardiogenic shock. Other clinical manifestations can include atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness or coma, as well as nausea and vomiting.

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

Drug Interactions

Catecholamine-depleting drugs may exhibit an additive effect when administered concurrently with beta-blocking agents. This interaction necessitates careful monitoring of blood pressure and heart rate, as the combined effects could lead to significant cardiovascular changes.

CYP2D6 inhibitors are known to increase the concentration of metoprolol. Clinicians should consider dosage adjustments of metoprolol when initiating or discontinuing CYP2D6 inhibitors to avoid potential adverse effects associated with elevated drug levels.

Beta-blockers, including metoprolol, may exacerbate rebound hypertension following the withdrawal of clonidine. It is advisable to monitor patients closely for signs of increased blood pressure during the transition off clonidine, and to manage the tapering of clonidine carefully to mitigate this risk.

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

Pediatric patients aged 6 years and older with hypertension may be initiated on metoprolol succinate extended-release at a starting dose of 1 mg/kg once daily, with a maximum initial dose not exceeding 50 mg once daily. Dosage adjustments should be made based on the individual blood pressure response. It is important to note that doses exceeding 2 mg/kg (or 200 mg) once daily have not been evaluated in this population.

Metoprolol succinate extended-release has not been studied in pediatric patients younger than 6 years of age, and therefore, its safety and efficacy in this age group remain undetermined.

Geriatric Use

There is no specific geriatric use information provided for metoprolol succinate extended-release tablets. The prescribing information does not include recommended age considerations, dosage adjustments, safety concerns, or special precautions for elderly patients.

Healthcare providers should exercise clinical judgment when prescribing this medication to geriatric patients, as individual responses may vary. Monitoring for efficacy and safety is advised, particularly in the absence of specific guidelines for this population.

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.

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, 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.

It is important to note that stroke volume and heart rate increase during pregnancy, leading to increased cardiac output, particularly during the first trimester. There is also a risk for preterm birth in pregnant women with chronic heart failure during the third trimester. 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.

In summary, while the available data do not support a significant risk of major congenital malformations with metoprolol use during pregnancy, the potential for adverse fetal outcomes necessitates careful consideration and monitoring of pregnant patients receiving this medication.

Lactation

Limited available data from published literature report that metoprolol is present in human milk. The estimated daily infant dose of metoprolol received from breast milk ranges from 0.05 mg to less than 1 mg, with an estimated relative infant dosage of 0.5% to 2% of the mother's weight-adjusted dosage.

No adverse reactions of metoprolol on the breastfed infant have been identified. However, it is recommended that healthcare professionals monitor the breastfed infant for bradycardia and other symptoms of beta-blockade, such as listlessness or hypoglycemia.

There is no information regarding the effects of metoprolol on milk production. In studies involving lactating mothers, the average amount of metoprolol present in breast milk was reported to be 71.5 mcg/day, with a range of 17 to 158.7 mcg/day. In two women taking unspecified amounts of metoprolol, the estimated amount of metoprolol and alpha-hydroxy metoprolol in breast milk was found to be less than 2% of the mother's weight-adjusted dosage.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring of these patients.

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 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 can result in a range of serious clinical manifestations. The most notable 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. Those with underlying conditions such as myocardial infarction or heart failure may experience significant hemodynamic instability, necessitating close monitoring and intervention. Consultation with a regional poison control center and a medical toxicologist is recommended to guide treatment decisions. 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 should be tailored based on the pharmacologic actions of metoprolol.

Bradycardia

For bradycardia, the need for atropine, adrenergic-stimulating drugs, or a pacemaker should be evaluated to address bradycardia and conduction disorders effectively.

Hypotension

In cases of hypotension, it is essential to treat the underlying bradycardia. Consideration should be given to intravenous vasopressor infusion, utilizing agents such as dopamine or norepinephrine.

Heart Failure and Shock

Heart failure and shock may be managed with appropriate volume expansion. If necessary, glucagon can be administered as an injection, followed by an intravenous infusion. Additionally, intravenous administration of adrenergic drugs such as dobutamine may be warranted, with α1 receptor agonistic drugs introduced in the presence of vasodilation.

Bronchospasm

Bronchospasm, a potential complication of overdose, can typically be reversed with the use of bronchodilators.

While there is limited experience with hemodialysis for the removal of metoprolol, it is noteworthy that metoprolol is not highly protein-bound, which may influence the decision to utilize this method in overdose scenarios.

Nonclinical Toxicology

Long-term studies in animals have been conducted to evaluate the carcinogenic potential of metoprolol tartrate. In two-year studies in rats at three oral dosage levels of up to 800 mg/kg/day (41 times, on a mg/m² basis, the daily dose of 200 mg for a 60 kg patient), there was no increase in the development of spontaneously occurring benign or malignant neoplasms of any type. The only histologic changes that appeared to be drug-related were an increased incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia.

In a 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg/day (18 times, on a mg/m² basis, the daily dose of 200 mg for a 60 kg patient), benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (benign plus malignant) lung tumors, nor in the overall incidence of tumors or malignant tumors. This 21-month study was repeated in CD-1 mice, and no statistically or biologically significant differences were observed between treated and control mice of either sex for any type of tumor.

All genotoxicity tests performed on metoprolol tartrate, 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, agranulocytosis, dry eyes, worsening of psoriasis, Peyronie’s disease, sweating, photosensitivity, and taste disturbance.

Additionally, there are potential adverse reactions not explicitly listed above that have been associated with other beta-adrenergic blocking agents, which should be considered as potential adverse 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 advised not to abruptly discontinue metoprolol succinate extended-release therapy, as this may exacerbate myocardial ischemia. If therapy is to be discontinued, the dosage should be gradually reduced over a period of 1 to 2 weeks, particularly in patients with ischemic heart disease. During the discontinuation process, patients should be monitored for worsening angina or acute coronary ischemia.

Patients should be informed that metoprolol may mask the usual signs of hypoglycemia, such as tachycardia, and they should exercise caution if they have diabetes. Additionally, patients with bronchospastic diseases should generally avoid beta-blockers; however, metoprolol may be used with caution in those who do not respond to or cannot tolerate other antihypertensive treatments.

Monitoring for bradycardia and other symptoms of beta-blockade, such as listlessness or hypoglycemia, is particularly important in breastfed infants. Patients should also be advised that metoprolol crosses the placenta and may pose risks to neonates, including hypotension, hypoglycemia, bradycardia, and respiratory depression.

Patients should be instructed to seek emergency treatment if severe hypoglycemia occurs. Furthermore, it is important to inform patients that beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Lastly, patients with a history of severe anaphylactic reactions may be more reactive to allergens while taking beta-blockers and may not respond to usual doses of epinephrine.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a controlled room temperature of 20°-25°C (68°-77°F), as defined by the United States Pharmacopeia (USP) guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)