Metoprolol succinate

Description

Metoprolol succinate is a beta1-selective (cardioselective) adrenoceptor blocking agent intended for oral administration, available as extended-release tablets. These tablets consist of a multiple unit system containing metoprolol succinate in numerous controlled release pellets, with each pellet functioning as an independent drug delivery unit designed to provide continuous release of metoprolol throughout the dosage interval. The tablets are formulated to contain 95 mg and 190 mg of metoprolol succinate, which is equivalent to 100 mg 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 and soluble in methanol. The inactive ingredients include acetyl tributyl citrate, colloidal silicon dioxide, croscarmellose sodium, ethyl cellulose, hydrogenated vegetable oil, hydroxypropyl cellulose, hypromellose, methylene chloride, microcrystalline cellulose, polyethylene glycol, sodium stearyl fumarate, talc, 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 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 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. 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.

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 surgery, particularly non-cardiac procedures, the initiation of high-dose extended-release metoprolol should be avoided. Additionally, 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 recommended, especially in diabetic patients.

In cases of thyrotoxicosis, abrupt withdrawal of beta-blockers may precipitate a thyroid storm. Therefore, careful management and gradual tapering of the medication are 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 unresponsiveness to the usual doses of epinephrine used for the treatment of allergic reactions. Healthcare providers should be aware of this potential interaction and consider alternative treatment strategies in such scenarios.

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 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 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 those with peripheral vascular disease may find their symptoms of arterial insufficiency 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

There are currently no documented drug interactions associated with this medication. Additionally, there are no known interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are necessary 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 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 of metoprolol succinate extended-release in hypertension did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, other reported 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, 50% (990) of the participants were aged 65 years and older, and 12% (238) 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 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 recommended to initiate treatment with a low initial starting dose for 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 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 recommended that neonates be observed and managed accordingly. While data from published observational studies did not establish an association of major congenital malformations with the use of metoprolol in pregnancy, these studies have methodological limitations that hinder definitive conclusions regarding any drug-associated risk during pregnancy.

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

There is no specific information 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 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

Signs and symptoms of overdose may manifest as severe bradycardia, hypotension, cardiogenic shock, atrioventricular block, heart failure, bronchospasm, hypoxia, and impairment of consciousness, which may progress to coma. Additionally, gastrointestinal symptoms such as nausea and vomiting may occur.

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 recognize that beta-blocker overdose can result in significant resistance to resuscitation efforts with adrenergic agents, including beta-agonists.

In cases of bradycardia and conduction disorders, the need for atropine, adrenergic-stimulating drugs, or the placement of a pacemaker should be evaluated. For hypotension, addressing the underlying bradycardia is crucial, and intravenous vasopressor infusion, such as dopamine or norepinephrine, may be warranted.

Heart failure and shock resulting from an overdose may be managed through volume expansion, glucagon injection, and the intravenous administration of adrenergic drugs like dobutamine. Bronchospasm, a potential complication of overdose, can typically be reversed with bronchodilators.

It is important to note that hemodialysis is unlikely to significantly enhance the elimination of metoprolol in overdose situations, and therefore may not be a preferred treatment option.

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 identified the following adverse reactions reported voluntarily or through surveillance programs: hypoglycemia, difficulty in breathing, and signs or symptoms of worsening heart failure, which may include weight gain or increasing shortness of breath.

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 the dose.

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 a plastic bottle containing 90 tablets. It should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), in accordance with 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, patients are instructed 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 REMEDYREPACK INC.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)