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 are formulated to contain 23.75, 47.5, 95, and 190 mg of metoprolol succinate, which is equivalent to 25, 50, 100, and 200 mg of metoprolol tartrate, respectively. The chemical name of metoprolol succinate is (±)1- (isopropyl amino)-3-p-(2-methoxyethyl) phenoxy-2-propanol succinate (2:1) (salt).

Metoprolol succinate, USP appears as a white to off-white powder with a molecular weight of 652.8 g/mol. It is freely soluble in water, soluble in methanol, sparingly soluble in alcohol, and slightly soluble in isopropyl alcohol. Each extended-release tablet contains metoprolol succinate equivalent to 25 mg, 50 mg, 100 mg, or 200 mg of metoprolol tartrate. The tablets also include inactive ingredients such as colloidal silicon dioxide, croscarmellose sodium, ethyl cellulose, glycerin, hypromellose, magnesium stearate, methyl cellulose, microcrystalline cellulose, polyethylene glycol, povidone, and talc. Additionally, each tablet contains Opadry II white 03B28796, which consists of hypromellose, polyethylene glycol, and titanium dioxide.

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 between 25 mg and 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 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 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, necessitating careful consideration when discontinuing treatment. In patients with heart failure, there is a risk of worsening cardiac function, which should be monitored closely.

In individuals with bronchospastic disease, the use of beta-blockers is contraindicated due to the potential for bronchospasm. Additionally, the concomitant administration of beta-blockers with glycosides, clonidine, diltiazem, or verapamil may significantly increase the risk of bradycardia, warranting vigilant 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 avoid hypertensive crises. During major surgical procedures, particularly non-cardiac surgeries, the initiation of high-dose extended-release metoprolol should be avoided. Furthermore, chronic beta-blocker therapy should not be routinely withdrawn before surgery, as this may lead to adverse cardiovascular events.

Patients receiving beta-blockers may experience an increased risk of hypoglycemia, and these medications can mask the early warning signs of low blood sugar, necessitating careful blood glucose monitoring in at-risk populations. In cases of thyrotoxicosis, abrupt withdrawal of beta-blockers may precipitate a thyroid storm, which is a life-threatening condition requiring immediate medical attention.

In patients with peripheral vascular disease, beta-blockers can exacerbate symptoms of arterial insufficiency, and caution should be exercised in this population. Lastly, it is important to note that patients on beta-blockers may exhibit reduced responsiveness to the standard doses of epinephrine used in the treatment of allergic reactions, which may complicate emergency management. Regular assessment and appropriate adjustments in treatment protocols are essential to ensure patient safety.

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, the initiation of high-dose extended-release metoprolol should be avoided, and chronic beta-blocker therapy should not routinely be 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 individuals with peripheral vascular disease may find that symptoms of arterial insufficiency are aggravated.

It is important to note that patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. Contraindications 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.

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.

Drug Interactions

There are currently no documented drug interactions associated with 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, 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 (0.2, 1, or 2 mg/kg once daily) and were followed for 4 weeks. The safety and effectiveness of metoprolol succinate extended-release tablets have not been established in patients younger than 6 years of age. In pediatric patients aged 6 to 16 years, no clinically relevant differences in the adverse event profile were observed when compared to adult patients.

Geriatric Use

Elderly patients may exhibit different pharmacokinetic and pharmacodynamic responses to medications due to age-related physiological changes. Clinical studies of metoprolol succinate in hypertension did not include a sufficient number of subjects aged 65 and over to definitively determine whether these patients respond differently from 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, 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 elderly 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, 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. Notably, 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.

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. Furthermore, there is a risk for preterm birth among pregnant women with chronic heart failure in 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 essential to observe neonates and manage them 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 any drug-associated risk 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 important to 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 prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to 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

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 metoprolol 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 lead to significant resistance to resuscitation efforts with adrenergic agents, including beta-agonists.

For specific symptoms, the following interventions 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 the intravenous infusion of vasopressors, such as dopamine or norepinephrine, to stabilize blood pressure.

Heart Failure and Shock

Heart failure and shock may be managed through appropriate volume expansion, glucagon injection, and the intravenous administration of adrenergic drugs, such as dobutamine, to support cardiac function.

Bronchospasm

Bronchospasm resulting from overdose can typically be reversed with the administration of bronchodilators.

It is important to recognize that hemodialysis is unlikely to facilitate the elimination of metoprolol in overdose situations. Therefore, comprehensive supportive care and monitoring are essential in the management of patients experiencing 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

Postmarketing experience has identified several adverse reactions associated with the use of the product. These include bradycardia, heart failure, hypotension, dizziness, fatigue, depression, shortness of breath, peripheral edema, syncope, and allergic reactions such as rash, pruritus, and urticaria. Additionally, liver enzyme elevations, pancreatitis, thrombocytopenia, and anaphylaxis have been reported.

Further safety information derived from postmarketing experience indicates occurrences of increased blood glucose levels in diabetic patients, exacerbation of asthma or bronchospasm in individuals with a history of asthma, and withdrawal symptoms following abrupt discontinuation of therapy.

These adverse reactions and safety updates are based on voluntary reports and surveillance programs and may not reflect the actual frequency of these events in the general population.

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 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 a tight container, in accordance with USP standards. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), as defined by USP Controlled Room Temperature guidelines. 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, 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)