Metoprolol succinate

Description

Metoprolol succinate is a beta 1-selective (cardioselective) adrenoceptor blocking agent formulated for oral administration as extended-release tablets. These tablets are designed to provide a controlled and predictable release of metoprolol, allowing for once-daily dosing. Each tablet comprises a multiple unit system containing metoprolol succinate in a multitude of controlled release pellets, with each pellet functioning as a separate drug delivery unit to ensure continuous delivery of metoprolol throughout the dosage interval.

The tablets are available in strengths of 23.75 mg, 47.5 mg, 95 mg, and 190 mg of metoprolol succinate, which correspond to 25 mg, 50 mg, 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), and its structural formula is represented accordingly. Metoprolol succinate, USP, appears as a white to off-white powder with a molecular weight of 652.8. It is freely soluble in water, soluble in methanol, sparingly soluble in alcohol, and slightly soluble in isopropyl alcohol.

Each metoprolol succinate extended-release tablet contains inactive ingredients including colloidal silicon dioxide, croscarmellose sodium, ethyl cellulose, glycerin, hypromellose, magnesium stearate, methyl cellulose, microcrystalline cellulose, polyethylene glycol, povidone, and talc. Additionally, the tablets contain Opadry II white 03B28796, which includes hypromellose, polyethylene glycol, and titanium dioxide. The formulation meets USP Dissolution Test 4 standards.

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 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 bradycardic 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 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 advised, especially in diabetic patients.

In individuals with thyrotoxicosis, abrupt withdrawal of beta-blockers may precipitate a thyroid storm. Caution is warranted when managing these patients, and any changes in therapy should be approached gradually.

For patients with peripheral vascular disease, beta-blockers may exacerbate symptoms of arterial insufficiency. Careful assessment of vascular status is recommended to ensure that treatment does not worsen the patient's condition.

Lastly, it is important to note that patients receiving beta-blockers may be unresponsive to the usual doses of epinephrine used for the treatment of allergic reactions. Healthcare providers should consider this when managing anaphylactic events in these patients, and alternative dosing strategies may be necessary.

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. In cases of thyrotoxicosis, abrupt withdrawal of treatment might precipitate a thyroid storm. Furthermore, patients with peripheral vascular disease may find that their symptoms of arterial insufficiency are aggravated. It is also important to note that patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

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.

Contraindications for this treatment 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.

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 the patient's response and blood pressure.

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 drug levels.

Beta-blockers, including metoprolol, may worsen rebound hypertension following the withdrawal of clonidine. It is advisable to monitor blood pressure closely in patients transitioning off clonidine, particularly if they are concurrently receiving beta-blockers, to manage any potential increases in blood pressure 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 (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 evaluating metoprolol succinate for hypertension did not include a sufficient number of subjects aged 65 years and older to ascertain whether these elderly patients respond differently compared to younger individuals. However, other clinical experiences in hypertensive patients have not revealed significant differences in responses between elderly and younger populations.

In the MERIT-HF trial, which involved 1,990 patients with heart failure randomized to metoprolol succinate, 50% (990 patients) were aged 65 years and older, and 12% (238 patients) were aged 75 years and older. The findings indicated no notable differences in efficacy or the incidence 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 geriatric patients. This approach helps to mitigate potential risks and ensures careful monitoring of the patient's response to therapy.

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 recommended that healthcare professionals observe these neonates closely and manage any potential adverse effects accordingly. There is no specific data provided regarding the excretion of metoprolol in breast milk or its effects on breastfed infants. Therefore, caution is advised when administering metoprolol to lactating mothers.

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 and consider individual patient factors when prescribing to patients with reduced kidney function, as the absence of specific guidance necessitates careful clinical judgment.

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 considered as part of standard clinical practice.

Overdosage

Overdosage of metoprolol succinate extended-release tablets can result in a range of serious clinical manifestations. The most common signs and symptoms associated with overdose include severe bradycardia, hypotension, and cardiogenic shock. Additional clinical presentations may encompass atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness or coma, as well as gastrointestinal symptoms such as nausea and vomiting.

In the event of an overdose, it is imperative to consider intensive care management for the patient. Those with underlying conditions such as myocardial infarction or heart failure may experience significant hemodynamic instability, necessitating close monitoring and intervention. 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

Bradycardia: The management of bradycardia may require the administration of atropine, adrenergic-stimulating drugs, or the placement of a pacemaker to address conduction disorders.

Hypotension: Treatment should focus on addressing the underlying bradycardia. Intravenous vasopressor infusion, such as dopamine or norepinephrine, may be warranted to stabilize blood pressure.

Heart Failure and Shock: In cases of heart failure and shock, appropriate interventions may include volume expansion and the administration of glucagon. If necessary, an intravenous infusion of glucagon can be initiated. Additionally, intravenous adrenergic drugs such as dobutamine may be employed, with α1 receptor agonists considered in the presence of vasodilation.

Bronchospasm: Bronchospasm associated with overdose can typically be reversed using bronchodilators.

It is important to recognize that hemodialysis is unlikely to significantly enhance the elimination of metoprolol from the body. Therefore, supportive care and the aforementioned management strategies should be prioritized in the treatment of 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, as well as tests on metoprolol succinate, were negative. 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 a risk of hypoglycemia associated with the use of metoprolol succinate extended-release tablets, particularly in patients who are fasting or experiencing vomiting. It is recommended that patients and caregivers be informed of this risk and provided with instructions on how to monitor for signs of hypoglycemia. For further details, please refer to the Warnings and Precautions section (5.7).

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 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 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 Zydus Lifesciences Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)