Metoprolol Succinate

Description

Metoprolol succinate is a beta 1-selective (cardioselective) adrenoceptor blocking agent intended for oral administration, available in the form of extended-release tablets. These tablets are specifically formulated to provide a controlled and predictable release of metoprolol, allowing for once-daily dosing. Each tablet contains metoprolol succinate in a multiple unit system composed of numerous controlled release pellets, with each pellet functioning as an independent drug delivery unit designed to release metoprolol continuously throughout the dosage interval.

The available strengths of metoprolol succinate extended-release tablets, USP include 23.75 mg, 47.5 mg, 95 mg, and 190 mg, which are equivalent to 25 mg, 50 mg, 100 mg, and 200 mg of metoprolol tartrate, USP, respectively. The chemical name of metoprolol succinate is (±)1-(isopropylamino)-3-p-(2-methoxyethyl) phenoxy-2-propanol succinate (2:1) (salt), and its structural formula is represented as follows:

Metoprolol succinate, USP appears as a white or almost white crystalline powder with a molecular weight of 652.8. It is freely soluble in water, soluble in methanol, sparingly soluble in ethanol, slightly soluble in isopropyl alcohol, and practically insoluble in ethyl acetate. The formulation includes inactive ingredients such as microcrystalline cellulose, colloidal silicon dioxide, povidone, ethyl cellulose, hypromellose, methacrylic acid and ethyl acrylate copolymer dispersion, triethyl citrate, talc, silicified microcrystalline cellulose, polyethylene glycol, croscarmellose sodium, sodium stearyl fumarate, and titanium dioxide.

Uses and Indications

Metoprolol succinate is indicated for the treatment of hypertension, angina pectoris, and heart failure. In patients with hypertension, this medication is utilized to lower blood pressure, thereby reducing the risk of both fatal and non-fatal cardiovascular events, including strokes and myocardial infarctions.

In the management of angina pectoris, metoprolol succinate aids in alleviating symptoms associated with this condition. Additionally, it is indicated for patients with heart failure, where it has been shown to reduce the risk of cardiovascular mortality and hospitalizations due to heart failure.

There are no teratogenic or nonteratogenic effects associated with metoprolol succinate.

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 between 25 mg and 100 mg. In the case of angina pectoris, the recommended starting dose is 100 mg. For heart failure, the initial dose may be either 12.5 mg 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 who do not have 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. Therefore, it is crucial for healthcare professionals to consider the potential risks associated with sudden discontinuation of treatment.

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.

For individuals with bronchospastic disease, the use of beta-blockers is contraindicated due to the potential for bronchospasm. Alternative therapies should be considered for these patients.

Concomitant administration of beta-blockers with glycosides, clonidine, diltiazem, or verapamil may increase the risk of bradycardia. Close monitoring of heart rate and rhythm is advised when these medications are used together.

In patients diagnosed with pheochromocytoma, it is essential to initiate therapy with an alpha-blocker prior to starting beta-blocker treatment to prevent hypertensive crises.

During major surgical procedures, particularly non-cardiac surgeries, the initiation of high-dose extended-release metoprolol should be avoided. However, it is not routinely necessary to withdraw chronic beta-blocker therapy prior to surgery, and careful consideration should be given to the patient's overall management plan.

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 recommended, especially in diabetic patients.

In cases of thyrotoxicosis, abrupt withdrawal of beta-blockers may precipitate a thyroid storm, a potentially life-threatening condition. Therefore, gradual tapering of the medication is advised in these patients.

For individuals with peripheral vascular disease, beta-blockers may exacerbate symptoms of arterial insufficiency. Monitoring of peripheral circulation is recommended to assess any worsening of symptoms.

Lastly, patients receiving beta-blockers may exhibit reduced responsiveness to the standard doses of epinephrine used in the treatment of allergic reactions. Healthcare professionals should be aware of this potential interaction and consider alternative dosing strategies in emergency situations.

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 an 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, severe bradycardia, hypotension, and cardiogenic shock may occur. Clinical presentations can also include atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness or coma, nausea, and vomiting.

Contraindications 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, 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.

Additionally, beta-blockers, including metoprolol, may exacerbate rebound hypertension following the withdrawal of clonidine. Caution is recommended when discontinuing clonidine in patients who are also on beta-blockers, and appropriate monitoring of blood pressure should be conducted during this transition to prevent significant hypertensive episodes.

Packaging & NDC

The table below lists all NDC Code configurations of Metoprolol Succinate (metoprolol succinate er tablets), 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 tablets (0.2 mg/kg, 1 mg/kg, 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 reduction in systolic blood pressure (SBP). However, some pre-specified secondary endpoints indicated effectiveness, including a dose-response for reduction in diastolic blood pressure (DBP) and significant changes in SBP when comparing the 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 between pediatric patients aged 6 to 16 years and 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 tablets in the treatment of hypertension did not include a sufficient number of subjects aged 65 and over to ascertain whether these elderly patients respond differently compared to younger individuals. However, other clinical experiences involving hypertensive patients have not revealed 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 tablets, 50% of the participants were aged 65 years and older, and 12% were aged 75 years and older. The findings indicated no notable differences in efficacy or the rate of adverse reactions between older and younger patients.

Given the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies, it is recommended to initiate treatment with a low starting dose in geriatric patients. This approach allows for careful monitoring and adjustment based on individual patient response and tolerability.

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.

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.

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 elevates the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

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.

In summary, while metoprolol has not been conclusively associated with major congenital malformations, careful consideration and monitoring are warranted for pregnant patients receiving this medication.

Lactation

Metoprolol crosses into breast milk. Although specific data on the effects of metoprolol on breastfed infants are not available, caution is advised when administering this medication to lactating mothers.

Neonates born to mothers receiving metoprolol during pregnancy may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. Therefore, it is recommended that healthcare professionals observe breastfed infants for any potential adverse effects and manage them accordingly.

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.

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 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 utilizing adrenergic agents, including beta-agonists.

Management Strategies

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

Hypotension: Treatment should focus on addressing the underlying bradycardia. Consideration should be given to intravenous vasopressor infusion, utilizing agents such as dopamine or norepinephrine.

Heart Failure and Shock: In cases of heart failure and shock, appropriate management may include volume expansion and the injection of glucagon, if necessary, followed by an intravenous glucagon infusion. Additionally, intravenous administration of adrenergic drugs such as dobutamine may be warranted, with α1 receptor agonistic drugs added in the presence of vasodilation.

Bronchospasm: Bronchospasm associated with overdose 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

No specific postmarketing experience details are available. As such, there are no additional adverse events or rare case reports to summarize at this time.

Patient Counseling

Healthcare providers should advise patients to take metoprolol succinate extended-release tablets regularly and continuously, as directed, preferably with or immediately following meals. In the event that a dose is missed, patients should be instructed to take only the next scheduled dose and not to double up on doses.

It is important for patients to understand that they should not interrupt or discontinue metoprolol succinate extended-release tablets without first consulting their physician. Providers should emphasize the need for caution, advising patients to avoid operating automobiles and machinery or engaging in other tasks that require alertness until their response to therapy with metoprolol succinate extended-release tablets has been determined.

Patients should be instructed to contact their physician if they experience any difficulty in breathing. Additionally, they should inform their physician or dentist prior to any type of surgery that they are taking metoprolol succinate extended-release tablets.

For patients with heart failure, it is crucial to consult their physician if they notice signs or symptoms of worsening heart failure, such as weight gain or increasing shortness of breath. Providers should also inform patients or caregivers about the risk of hypoglycemia, particularly when metoprolol succinate extended-release tablets are administered to patients who are fasting or vomiting.

Finally, healthcare providers should instruct patients or caregivers on how to monitor for signs of hypoglycemia to ensure timely recognition and management.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. It should be stored at a controlled room temperature of 25°C (77°F). Temporary excursions are permissible within the range of 15° to 30°C (59° to 86°F). Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Patients should be advised not to interrupt therapy without consulting their physician. In the event of severe hypoglycemia, it is crucial for patients to seek emergency treatment promptly. No further information is available regarding laboratory tests, abuse potential, route, method, frequency of administration, or postmarketing experience.

FDA Insert (PDF)

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

View full prescribing information (PDF)