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 dose may be either 12.5 or 25 mg, depending on the patient's condition and response.

When transitioning from immediate-release metoprolol to metoprolol succinate extended-release tablets, it is essential to maintain the same total daily dose of metoprolol succinate extended-release tablets as the patient was receiving with 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 without a pacemaker, due to the potential for exacerbating cardiac conduction issues.

The product is also contraindicated in patients experiencing cardiogenic shock or decompensated heart failure, as these conditions may lead to further deterioration of cardiac function.

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 may increase the risk of bradycardia. It is essential to monitor heart rate and rhythm closely in patients receiving these combinations to prevent significant 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, chronic beta-blocker therapy should not be routinely withdrawn prior to 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. Careful management and gradual tapering of the medication are recommended in these cases.

For patients with peripheral vascular disease, beta-blockers may exacerbate symptoms of arterial insufficiency. Clinicians should assess the risk versus benefit of beta-blocker therapy in this population and consider alternative treatments if necessary.

Lastly, patients receiving beta-blockers may be unresponsive to the usual doses of epinephrine used for the treatment of allergic reactions. It is crucial for healthcare providers to be aware of this potential interaction and to adjust treatment protocols accordingly in the event of anaphylaxis.

Side Effects

Patients may experience a range of adverse reactions while receiving treatment. 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. Worsening cardiac failure may occur in patients with pre-existing heart conditions. Abrupt cessation of therapy can exacerbate myocardial ischemia, and patients with bronchospastic disease should avoid beta-blockers due to the risk of bronchospasm. Additionally, the concomitant use of glycosides, clonidine, diltiazem, and verapamil with beta-blockers may increase the risk of bradycardia.

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

Patients with diabetes may experience an increased risk of hypoglycemia, and beta-blockers can mask the early warning signs of this condition. In individuals with thyrotoxicosis, abrupt withdrawal of treatment may precipitate a thyroid storm. Furthermore, patients with peripheral vascular disease may find that their symptoms of arterial insufficiency are aggravated.

In the event 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, nausea, and vomiting. It is important to note that patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

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.

Inhibitors of the CYP2D6 enzyme are likely to elevate 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 increased drug levels.

Beta-blockers, including metoprolol, may worsen rebound hypertension following the discontinuation of clonidine. Caution is recommended when transitioning patients off clonidine, and monitoring of blood pressure is essential to manage potential rebound effects effectively.

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 evaluating the efficacy of metoprolol succinate extended-release in the treatment of hypertension did not include a sufficient number of subjects aged 65 years and older to ascertain whether this population responds differently compared to younger individuals. However, other clinical experiences with hypertensive patients have not indicated any significant differences in responses between elderly and younger patients.

In the MERIT-HF trial, which involved 1,990 patients with heart failure randomized to receive 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 revealed no notable differences in efficacy or the incidence of adverse reactions between older and younger patients.

Given the increased likelihood of diminished hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies in geriatric patients, it is recommended to initiate treatment with a low starting dose in this population. Careful monitoring and dose adjustments may be necessary to ensure safety and efficacy in elderly patients.

Pregnancy

Available data indicate that untreated hypertension and heart failure during pregnancy can lead to adverse outcomes for both the mother and the fetus. While observational studies have not demonstrated a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes with metoprolol use during pregnancy, 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. However, 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 remains unknown, although 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 is associated with increased maternal risks, including pre-eclampsia, gestational diabetes, premature delivery, and delivery complications such as the need for cesarean section and post-partum hemorrhage. Additionally, hypertension elevates the fetal risk for intrauterine growth restriction and intrauterine death. Therefore, pregnant women with hypertension should be carefully monitored and managed accordingly.

Metoprolol crosses the placenta, and neonates born to mothers receiving metoprolol during pregnancy may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. It is recommended that neonates be observed and managed appropriately. Overall, while the available data do not support a strong association between metoprolol use and major congenital malformations, the inconsistent findings regarding intrauterine growth retardation, preterm birth, and perinatal mortality necessitate careful consideration and monitoring in pregnant patients.

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 important to observe breastfed infants for these potential effects and manage them accordingly.

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 this patient population.

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 severe 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 imperative to consider intensive care management for the patient. Those with underlying conditions such as myocardial infarction or heart failure are particularly susceptible to significant hemodynamic instability. It is important to note that beta-blocker overdose may lead to considerable resistance to resuscitation efforts with adrenergic agents, including beta-agonists.

Management Strategies

• Bradycardia: The need for atropine, adrenergic-stimulating drugs, or a pacemaker should be evaluated to address bradycardia and associated conduction disorders.

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

• Heart Failure and Shock: Appropriate treatment may include volume expansion and the administration of glucagon, if indicated, followed by an intravenous glucagon infusion. Additionally, intravenous adrenergic drugs such as dobutamine may be utilized, with α1 receptor agonists considered in the presence of vasodilation.

• Bronchospasm: This condition can typically be reversed with the use of bronchodilators.

It is important to note that hemodialysis is unlikely to significantly contribute to 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. 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 evaluated in a Salmonella/mammalian-microsome mutagenicity test, which yielded 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 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

Healthcare providers should advise patients about the potential risks associated with the abrupt cessation of therapy with metoprolol succinate extended-release tablets. It is important to inform patients that stopping the medication suddenly may lead to exacerbations of angina pectoris and, in some cases, myocardial infarction. When discontinuing the medication, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1 to 2 weeks, with close monitoring for any worsening of angina or signs of acute coronary ischemia. Patients should be cautioned against interrupting therapy without consulting their physician, especially since coronary artery disease may be unrecognized in those treated solely for hypertension.

During the up-titration of metoprolol succinate extended-release tablets, healthcare providers should inform patients that worsening cardiac failure may occur. If patients experience such symptoms, they should increase diuretics and restore clinical stability before advancing the dose. It may be necessary to lower the dose or temporarily discontinue the medication, but such episodes do not preclude successful titration in the future.

Patients with bronchospastic diseases 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, due to its relative beta1-cardio-selectivity. Providers should emphasize the importance of using the lowest effective dose and ensuring that bronchodilators, including beta2-agonists, are readily available or administered concurrently.

Healthcare providers should monitor heart rate in patients receiving metoprolol succinate extended-release tablets, as bradycardia, including sinus pause, heart block, and cardiac arrest, has been reported. Patients with first-degree atrioventricular block, sinus node dysfunction, or those on concomitant medications that may cause bradycardia are at increased risk. If severe bradycardia develops, the dosage should be reduced or the medication stopped.

In cases of pheochromocytoma, metoprolol succinate extended-release tablets should only be administered in conjunction with an alpha-blocker, and only after the alpha-blocker has been initiated, to avoid a paradoxical increase in blood pressure.

Providers should advise against initiating a high-dose regimen of metoprolol in patients undergoing non-cardiac surgery, as this has been associated with serious complications, including bradycardia, hypotension, stroke, and death. While chronic beta-blocking therapy should not be routinely withdrawn prior to major surgery, it is important to note that the heart's impaired ability to respond to reflex adrenergic stimuli may increase the risks associated with general anesthesia and surgical procedures.

Patients should be informed that beta-blockers may mask early warning signs of hypoglycemia, such as tachycardia, and can increase the risk of severe or prolonged hypoglycemia, particularly in individuals with diabetes mellitus, children, or those who are fasting. In the event of severe hypoglycemia, patients should seek emergency treatment.

Additionally, beta-adrenergic blockade may obscure certain clinical signs of hyperthyroidism, such as tachycardia, and abrupt withdrawal may precipitate a thyroid storm. Patients with peripheral vascular disease should be made aware that beta-blockers can precipitate or worsen symptoms of arterial insufficiency.

Finally, healthcare providers should counsel patients with a history of severe anaphylactic reactions that they may be more reactive to repeated allergen challenges while taking beta-blockers and may not respond to the usual doses of epinephrine used for treating allergic reactions.

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 that abrupt cessation of therapy with beta-blocking agents may lead to exacerbations of angina pectoris and, in some cases, myocardial infarction. It is recommended to gradually reduce the dosage over a period of 1 to 2 weeks when discontinuing metoprolol succinate, especially in patients with ischemic heart disease. Patients should be monitored closely, and if angina worsens or acute coronary ischemia occurs, metoprolol should be reinstated promptly, along with appropriate management for unstable angina. Patients should be cautioned against interrupting therapy without consulting their physician, particularly since coronary artery disease may be unrecognized in those treated solely for hypertension.

Postmarketing experience has revealed various adverse effects associated with metoprolol succinate. Cardiovascular effects include cold extremities, arterial insufficiency, palpitations, peripheral edema, syncope, chest pain, and hypotension. Respiratory issues may manifest as wheezing and dyspnea. Central nervous system effects can include confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety, hallucinations, and paresthesia. Gastrointestinal side effects may involve nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, and vomiting. Hypersensitivity reactions such as pruritus have also been reported. Additional miscellaneous effects 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.

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)