Metoprolol succinate

Description

Metoprolol succinate is a beta1-selective (cardioselective) adrenoceptor blocking agent intended for oral administration, available as extended-release tablets. These tablets are 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 controlled release pellets, with each pellet functioning as an independent drug delivery unit designed to release metoprolol continuously throughout the dosage interval.

The tablets are available in strengths of 47.5 mg, 95 mg, and 190 mg of metoprolol succinate, which are equivalent to 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, and its structural formula is represented as follows:

Metoprolol succinate, USP is a white crystalline powder with a molecular weight of 652.8 g/mol. It is freely soluble in water and soluble in methanol. The inactive ingredients include acetyl tributyl citrate, colloidal silicon dioxide, crosspovidone, ethyl cellulose, hydroxypropyl cellulose, hypromellose, isopropyl alcohol, methylene chloride, microcrystalline cellulose, microcrystalline cellulose sphere, polyethylene glycol, sodium stearyl fumarate, and talc. The tablets are film-coated with Opadry white 04F58804, which contains 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 heart failure hospitalization.

There are no teratogenic or nonteratogenic effects associated with this medication.

Dosage and Administration

The medication should be administered once daily. Dosing may be titrated at weekly or longer intervals based on patient response and tolerance.

For the management of hypertension, the recommended starting dose is between 25 mg and 100 mg. In cases of angina pectoris, the starting dose is set at 100 mg. For patients with heart failure, the initial dosing should be either 12.5 mg or 25 mg.

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. 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, 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 cardiovascular 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 outcomes.

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. Caution is warranted when considering discontinuation in these patients.

For those with peripheral vascular disease, beta-blockers may exacerbate symptoms of arterial insufficiency. Clinicians should evaluate the risk versus benefit of beta-blocker therapy in this population.

Lastly, patients receiving beta-blockers may exhibit unresponsiveness to the usual doses of epinephrine used for the treatment of allergic reactions. It is crucial to consider this potential interaction when managing anaphylactic events in these patients.

Side Effects

Patients receiving metoprolol may experience a range of adverse reactions, which can be categorized by frequency and seriousness.

The most common adverse reactions reported include tiredness, dizziness, depression, shortness of breath, bradycardia, hypotension, diarrhea, pruritus, and rash. These reactions were observed in clinical trials and may vary in incidence among different patient populations.

Serious adverse reactions have also been noted. Abrupt cessation of metoprolol may exacerbate myocardial ischemia, and worsening cardiac failure can occur in patients with pre-existing heart failure. In patients with bronchospastic disease, beta-blockers should be avoided due to the potential for exacerbating respiratory symptoms. Additionally, the concomitant use of glycosides, clonidine, diltiazem, and verapamil with beta-blockers can increase the risk of bradycardia.

Specific patient populations may require careful management. For instance, in patients with pheochromocytoma, therapy should be initiated with an alpha-blocker. During major surgery, it is advised to avoid the initiation of high-dose extended-release metoprolol in patients undergoing non-cardiac procedures, 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. In cases of thyrotoxicosis, abrupt withdrawal of metoprolol could precipitate a thyroid storm. Furthermore, patients with peripheral vascular disease may experience aggravated symptoms of arterial insufficiency.

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, as well as gastrointestinal symptoms such as nausea and vomiting.

Neonates born to mothers who received metoprolol during pregnancy may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. Close observation and appropriate management of these neonates are recommended.

Contraindications for metoprolol include known hypersensitivity to its 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.

Patients should be monitored closely for these adverse reactions to ensure timely intervention and management.

Drug Interactions

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

Inhibitors of the CYP2D6 enzyme are known to increase the concentration of metoprolol. Clinicians should consider dosage adjustments of metoprolol in patients receiving CYP2D6 inhibitors to avoid potential adverse effects associated with elevated drug levels.

Additionally, beta-blockers, including metoprolol, may worsen rebound hypertension following the discontinuation of clonidine. It is advisable to monitor blood pressure closely during the withdrawal of clonidine in patients who are also receiving beta-blockers to manage any potential hypertensive episodes 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 tablets (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.

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 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 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 greater frequency of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies in elderly patients, it is generally recommended to initiate treatment with a low starting dose in this population. Careful monitoring is advised to ensure safety and efficacy in geriatric patients.

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 metoprolol use during pregnancy. However, there are inconsistent reports of 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. 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 increases 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 recommended that neonates be observed and managed accordingly. While data from published observational studies did not demonstrate an association of major congenital malformations with metoprolol use in pregnancy, methodological limitations in these studies, such as retrospective design and concomitant use of other medications, hinder definitive conclusions regarding 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 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 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 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 can result in a range of serious clinical manifestations. The signs and symptoms associated with an overdose may include severe bradycardia, hypotension, and cardiogenic shock. Additionally, patients may present with atrioventricular block, heart failure, bronchospasm, hypoxia, and varying levels of consciousness, including coma. Gastrointestinal symptoms such as nausea and vomiting may also occur.

In the event of an overdose, it is crucial to consider intensive care management, particularly for patients with underlying conditions such as myocardial infarction or heart failure, as they may experience significant hemodynamic instability. 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. Hemodialysis is generally not effective for the elimination of metoprolol.

For bradycardia, healthcare professionals should assess the need for atropine, adrenergic-stimulating drugs, or the placement of a pacemaker to address bradycardia and conduction disorders. In cases of hypotension, it is essential to treat the underlying bradycardia and consider the administration of intravenous vasopressors, such as dopamine or norepinephrine.

Heart failure and shock may require appropriate interventions, including volume expansion and the administration of glucagon, which may be followed by an intravenous infusion of glucagon if necessary. Additionally, intravenous adrenergic drugs such as dobutamine may be indicated, with α1 receptor agonists considered in the presence of vasodilation.

Bronchospasm resulting from an overdose can typically be managed with bronchodilators, which are effective in reversing this condition.

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 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 reported voluntarily or through surveillance programs. Notable adverse reactions include bradycardia, hypotension, and exacerbation of heart failure. Additional reactions reported encompass dizziness, fatigue, and depression.

Severe allergic reactions, such as anaphylaxis and angioedema, have also been documented. Instances of hepatic dysfunction, characterized by elevated liver enzymes, have been observed. Furthermore, pulmonary complications, including bronchospasm, have been reported, particularly in patients with a history of asthma or chronic obstructive pulmonary disease (COPD).

Hypoglycemia has been noted, especially among diabetic patients. There are rare reports of skin reactions, including rash and pruritus. Postmarketing surveillance has indicated that some patients may experience withdrawal symptoms upon abrupt discontinuation of therapy.

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 informed to contact their physician if they experience any difficulty in breathing. Additionally, they should notify 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 two packaging configurations: a blister pack containing 30 units and a plastic bottle containing 90 units.

Storage conditions require the product to be maintained at a temperature of 25°C (77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F), in accordance with USP Controlled Room Temperature guidelines. Proper handling and storage are essential to ensure 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 REMEDYREPACK INC.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)