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. The tablets contain 23.75 mg, 47.5 mg, 95 mg, and 190 mg of metoprolol succinate, which is equivalent to 25 mg, 50 mg, 100 mg, and 200 mg of metoprolol tartrate, respectively. The chemical name of metoprolol succinate is (±)1- (isopropylamino)-3-p-(2-methoxyethyl) phenoxy-2-propanol succinate (2:1) (salt). It appears as a white or almost white crystalline powder with a molecular weight of 652.8 g/mol. Metoprolol succinate is freely soluble in water, soluble in methanol, sparingly soluble in ethanol, slightly soluble in isopropyl alcohol, and practically insoluble in ethyl acetate. The inactive ingredients include 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. For patients experiencing angina pectoris, metoprolol succinate serves to alleviate symptoms associated with this condition. Additionally, in the context of heart failure, this drug is indicated 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 should be administered once daily. Dosing may 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 dose may be either 12.5 mg or 25 mg, depending on clinical judgment.

When transitioning a patient 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. The product is also contraindicated in patients experiencing cardiogenic shock or decompensated heart failure.

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 exacerbating respiratory conditions. 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 before surgical procedures.

Beta-blockers may increase the risk of hypoglycemia and can mask the early warning signs of this condition, necessitating careful blood glucose monitoring in at-risk populations. In patients with thyrotoxicosis, abrupt withdrawal of beta-blockers may precipitate a thyroid storm, highlighting the importance of gradual tapering under medical supervision.

Patients with peripheral vascular disease may experience aggravated symptoms of arterial insufficiency when treated with beta-blockers. It is also critical to note that individuals may be unresponsive to standard doses of epinephrine used for the treatment of allergic reactions, which requires 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. 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 can increase the risk of bradycardia.

In patients with pheochromocytoma, it is recommended to initiate therapy with an alpha-blocker. For those undergoing major surgery, particularly non-cardiac procedures, 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 a history of hypoglycemia may experience an increased risk for hypoglycemia and may have masked early warning signs. Abrupt withdrawal in patients with thyrotoxicosis could precipitate a thyroid storm, and those with peripheral vascular disease may find their symptoms of arterial insufficiency aggravated.

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, 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.

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

There are currently no documented drug interactions associated with the use of this medication. Additionally, there is no information available regarding interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted at this time.

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 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 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 beats per minute, 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 tablets in the treatment of hypertension did not include a sufficient number of subjects aged 65 and older to determine whether these elderly patients respond differently compared to younger individuals. However, other clinical experiences in hypertensive patients have not identified significant differences in responses between elderly and younger patients.

In the MERIT-HF trial, which involved 1,990 patients with heart failure randomized to 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 from this trial 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 generally recommended to initiate treatment with a low starting dose in geriatric patients. Careful monitoring and dose adjustments may be necessary to ensure safety and efficacy in 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, 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, 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 essential to observe neonates and manage them accordingly. While data from published observational studies did not demonstrate an association of major congenital malformations with the use of metoprolol in pregnancy, the inconsistent findings regarding intrauterine growth retardation, preterm birth, and perinatal mortality warrant caution, as these studies have methodological limitations that hinder interpretation.

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 breastfed infants for these potential 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 individuals with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

Hepatic Impairment

There is no information available regarding the use of this medication in patients with hepatic impairment. Consequently, there are no dosage adjustments, special monitoring requirements, or precautions specified for individuals with compromised liver function. Healthcare professionals should exercise caution and consider the overall clinical context when prescribing this medication to patients with liver problems, as the absence of specific guidance necessitates careful evaluation of potential risks and benefits.

Overdosage

In cases of overdose with metoprolol succinate extended-release tablets, a range of signs and symptoms may manifest, including severe bradycardia, hypotension, cardiogenic shock, atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness or coma, as well as gastrointestinal symptoms such as nausea and vomiting.

Management of an overdose may necessitate intensive care, particularly for patients with underlying conditions such as myocardial infarction or heart failure, due to the risk of hemodynamic instability. It is important to note that beta-blocker overdose can result in significant resistance to resuscitation efforts with adrenergic agents, including beta-agonists.

For specific symptoms, the following management strategies are recommended:

Bradycardia

In cases of bradycardia, healthcare professionals should assess the need for atropine administration, the use of adrenergic-stimulating drugs, or the placement of a pacemaker.

Hypotension

Management of hypotension 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

Heart failure and shock may be addressed through volume expansion, glucagon injection followed by intravenous glucagon infusion, and the administration of adrenergic drugs such as dobutamine.

Bronchospasm

Bronchospasm resulting from overdose is typically reversible with the use of bronchodilators.

It is important to recognize that hemodialysis is unlikely to facilitate the elimination of metoprolol in overdose situations. Prompt recognition and appropriate management of these symptoms are critical to improving patient outcomes.

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

Postmarketing experience has revealed reports of various adverse reactions associated with the use of the product. Notable cardiovascular events include bradycardia, hypotension, and exacerbation of heart failure. Additional adverse reactions reported encompass dizziness, fatigue, and depression.

Rare cases of severe allergic reactions, such as anaphylaxis, angioedema, and urticaria, have been documented. Instances of hepatic dysfunction, characterized by elevated liver enzymes, have also been reported. Furthermore, pulmonary complications, including bronchospasm, have been observed in patients with a history of asthma or obstructive airway disease.

Some patients have experienced worsening of psoriasis or new-onset psoriasis. Reports of sexual dysfunction, including erectile dysfunction and decreased libido, have been noted in the postmarketing experience.

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 regarding activities that require alertness. Patients should be advised to avoid operating automobiles and machinery or engaging in other tasks 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 experiencing 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 available in two packaging configurations: 90 units in a plastic bottle and 30 units in a blister pack.

It should be stored at a controlled room temperature of 25°C (77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) as defined by USP guidelines. Proper storage conditions are essential to maintain the integrity of the product.

Additional Clinical Information

Patients should be cautioned against interrupting therapy without consulting their physician. In the event of severe hypoglycemia, it is imperative that patients seek emergency medical treatment. No further information is available regarding laboratory tests, abuse potential, route, method, and frequency of administration, or postmarketing experience.

FDA Insert (PDF)

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

View full prescribing information (PDF)