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 it has a molecular weight of 652.8. Metoprolol succinate appears as a white crystalline powder that is freely soluble in water and soluble in methanol.

Inactive ingredients in the formulation 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 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 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, as these conditions may exacerbate the risks associated with its use.

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 surgical procedures, particularly non-cardiac surgeries, 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 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 standard 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 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 conditions. Patients with bronchospastic disease should avoid beta-blockers due to the potential for exacerbation of their condition. 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 prior to starting metoprolol. During 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 diabetes may experience an increased risk of hypoglycemia, and metoprolol may mask the early warning signs of this condition. In individuals with thyrotoxicosis, abrupt withdrawal of metoprolol may precipitate a thyroid storm. Furthermore, patients with peripheral vascular disease may find that their symptoms of arterial insufficiency are aggravated by the use of this medication. It is also important to note that patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

In cases of overdosage, symptoms may include severe bradycardia, hypotension, and cardiogenic shock. Other clinical presentations can involve atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness or coma, as well as nausea and vomiting.

Fetal and neonatal adverse reactions have been observed in neonates born to mothers receiving metoprolol during pregnancy. These neonates may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression, necessitating careful observation and management.

Contraindications for metoprolol include known hypersensitivity to its components, severe bradycardia (greater than first-degree heart block), 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. This interaction could potentially enhance the pharmacological effects of both drug classes, necessitating careful monitoring of blood pressure and heart rate in patients receiving this combination.

CYP2D6 inhibitors are known to increase the concentration of metoprolol. Clinicians should consider dosage adjustments of metoprolol when initiating or discontinuing CYP2D6 inhibitors to avoid potential adverse effects associated with elevated metoprolol levels.

Additionally, beta-blockers, including metoprolol, may exacerbate rebound hypertension following the withdrawal of clonidine. It is advisable to monitor blood pressure closely during the transition period when discontinuing clonidine in patients who are also receiving beta-blockers to mitigate the risk of significant hypertension.

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 a duration of 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 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 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 demonstrate an association of major congenital malformations with the use of metoprolol 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 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 individuals with reduced kidney function, as the lack of information necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in these patients to ensure safety and efficacy.

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 can result in a range of severe clinical manifestations. The most notable signs and symptoms 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:

Bradycardia

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.

Hypotension

Management of hypotension should focus on treating 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 interventions may include volume expansion and the administration of glucagon, if necessary, followed by an intravenous glucagon infusion. Additionally, intravenous adrenergic drugs such as dobutamine may be employed, with α1 receptor agonists added in the presence of vasodilation.

Bronchospasm

Bronchospasm associated with metoprolol overdose can typically be reversed with bronchodilators.

It is important to note that hemodialysis is unlikely to significantly enhance the elimination of metoprolol from the body. Therefore, supportive care and the aforementioned treatment strategies should be prioritized in the management of metoprolol succinate overdosage.

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. Similarly, 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. These include hypoglycemia, bradycardia, exacerbation of heart failure, dizziness, fatigue, and depression. Additionally, allergic reactions such as rash and pruritus, liver enzyme elevations, anaphylactic reactions, and other cardiovascular events have also been documented. It is important to note that these adverse reactions may not be directly related to the drug's use.

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 take only the next scheduled dose and should not double the dose.

It is important to inform patients that they should not interrupt or discontinue metoprolol succinate extended-release tablets without first consulting their physician. Providers should also counsel 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 advise them to consult their physician if they notice signs or symptoms of worsening heart failure, such as weight gain or increasing shortness of breath.

Healthcare providers should inform patients or caregivers about the risk of hypoglycemia when metoprolol succinate extended-release tablets are administered to patients who are fasting or experiencing vomiting. It is also essential to instruct patients or caregivers on how to monitor for signs of hypoglycemia.

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), with permissible excursions between 15°C to 30°C (59°F to 86°F) as outlined by USP guidelines. Proper storage conditions are essential to maintain 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 Cipla USA Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)