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. These tablets are specifically formulated to provide a controlled and predictable release of metoprolol, allowing for once-daily dosing. Each tablet contains a multiple unit system comprising metoprolol succinate in numerous controlled release pellets, with each pellet functioning as an independent drug delivery unit designed to release metoprolol continuously throughout the dosage interval.

The extended-release tablets are available in two strengths: 95 mg and 190 mg of metoprolol succinate, which are equivalent to 100 mg and 200 mg of metoprolol tartrate, USP, respectively. The chemical name of metoprolol succinate is (±) 1-(isopropylamino)-3-p-(2-methoxyethyl) phenoxy-2-propanol succinate (2:1) (salt), and its structural formula is provided in the accompanying documentation. Metoprolol succinate USP appears as a white to off-white powder with a molecular weight of 652.8. It is freely soluble in water and soluble in methanol.

Inactive ingredients in the formulation include acetyl tributyl citrate, colloidal silicon dioxide, croscarmellose sodium, ethyl cellulose, hydrogenated vegetable oil, hydroxypropyl cellulose, hypromellose, methylene chloride, microcrystalline cellulose, polyethylene glycol 6000, prosolv, 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 mg to 100 mg. In cases of angina pectoris, the recommended starting dose is 100 mg. For heart failure, the initial dosing should 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 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 therapy may lead to exacerbation of myocardial ischemia, necessitating careful consideration of discontinuation protocols.

Heart Failure Patients with pre-existing heart failure may experience worsening cardiac function. Continuous monitoring of cardiac status is recommended for these individuals.

Bronchospastic Disease In patients with bronchospastic diseases, the use of beta-blockers is contraindicated due to the potential for exacerbating respiratory conditions.

Drug Interactions Concomitant administration of glycosides, clonidine, diltiazem, or verapamil with beta-blockers may heighten the risk of bradycardia. Healthcare professionals should monitor heart rate and rhythm closely in patients receiving these combinations.

Pheochromocytoma For patients diagnosed with pheochromocytoma, it is imperative to initiate therapy with an alpha blocker prior to the introduction of beta-blockers to mitigate the risk of hypertensive crisis.

Major Surgery In the context of major noncardiac surgery, the initiation of high-dose extended-release metoprolol should be avoided. However, chronic beta-blocker therapy should not be routinely withdrawn prior to surgical procedures, as this may lead to adverse cardiovascular events.

Diabetes and Hypoglycemia Patients with diabetes should be informed that beta-blockers may mask the typical tachycardic response associated with hypoglycemia, which could delay recognition and treatment of low blood sugar episodes.

Thyrotoxicosis Abrupt withdrawal of beta-blockers in patients with thyrotoxicosis can precipitate a thyroid storm, a potentially life-threatening condition. Gradual tapering is advised.

Peripheral Vascular Disease In individuals with peripheral vascular disease, beta-blockers may exacerbate symptoms of arterial insufficiency. Monitoring of peripheral circulation is recommended.

Allergic Reactions Patients on beta-blockers may exhibit reduced responsiveness to standard doses of epinephrine used in the treatment of allergic reactions. Alternative treatment strategies should be considered in these cases.

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. Abrupt cessation of therapy may exacerbate myocardial ischemia, and worsening cardiac failure may occur in patients with heart failure. In individuals with bronchospastic disease, beta-blockers should be avoided due to the potential for exacerbation of symptoms. The concomitant use of glycosides, clonidine, diltiazem, and verapamil with beta-blockers can increase the risk of bradycardia. For patients with pheochromocytoma, it is recommended to initiate therapy with an alpha blocker.

In the context of major surgery, it is advised to avoid the initiation of high-dose extended-release metoprolol in patients undergoing noncardiac procedures. Additionally, chronic beta-blocker therapy should not routinely be withdrawn prior to surgery. Patients with diabetes may experience masking of tachycardia associated with hypoglycemia, while those with thyrotoxicosis may be at risk for precipitating a thyroid storm if therapy is abruptly withdrawn. Furthermore, peripheral vascular disease may be aggravated, leading to worsened symptoms of arterial insufficiency. It is important to note that patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

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, as well as nausea and vomiting.

Drug Interactions

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

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 exacerbate rebound hypertension following the withdrawal of clonidine. It is advisable to monitor patients closely for signs of increased blood pressure during the period following clonidine discontinuation, and to manage the tapering of clonidine carefully to mitigate this risk.

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 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 randomized 1,990 patients with heart failure 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 geriatric 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 elderly patients.

Pregnancy

Available data indicate that untreated hypertension and heart failure during pregnancy can lead to adverse outcomes for both the mother and the fetus. While 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, there are inconsistent reports regarding intrauterine growth restriction, preterm birth, and perinatal mortality associated with maternal use of beta blockers, including metoprolol.

The estimated background risk of major birth defects and miscarriage in the U.S. general population is approximately 2 to 4% and 15 to 20%, respectively; however, the background risk for the indicated population remains unknown. Hypertension in pregnancy is associated with increased maternal risks, including pre-eclampsia, gestational diabetes, premature delivery, and delivery complications such as the need for cesarean section and post-partum hemorrhage. Additionally, hypertension poses fetal risks, including 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, close observation and appropriate management of neonates are recommended. Although data from published observational studies did not show an association with major congenital malformations, the literature presents inconsistent findings regarding intrauterine growth retardation, preterm birth, and perinatal mortality, with methodological limitations affecting interpretation.

Animal studies have shown that metoprolol can increase post-implantation loss and decrease neonatal survival in rats at high dosages (500 mg/kg/day), which is significantly above the human equivalent dose. However, no fetal abnormalities were observed in pregnant rats receiving metoprolol orally at doses up to 200 mg/kg/day, which is ten times the daily dose of 200 mg in a 60 kg patient. Given these findings, healthcare professionals should weigh the potential risks and benefits of metoprolol use in pregnant patients and ensure appropriate monitoring throughout pregnancy.

Lactation

Limited available data from published literature report that metoprolol is present in human milk. The estimated daily infant dose of metoprolol received from breast milk ranges from 0.05 mg to less than 1 mg, with an estimated relative infant dosage of 0.5% to 2% of the mother's weight-adjusted dosage.

In a small study involving three mothers (at least 3 months postpartum) who took metoprolol of unspecified amount, breast milk was collected every 2 to 3 hours over one dosage interval. The average amount of metoprolol present in breast milk was 71.5 mcg/day (range 17.0 to 158.7), corresponding to an average relative infant dosage of 0.5% of the mother's weight-adjusted dosage.

No adverse reactions of metoprolol on the breastfed infant have been identified. However, it is recommended that lactating mothers monitor the breastfed infant for bradycardia and other symptoms of beta blockade, such as listlessness (hypoglycemia). There is no information regarding the effects of metoprolol on milk production.

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 and monitoring of these patients.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there is no information available regarding 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.

Overdosage

Overdosage of metoprolol succinate extended-release 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. 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 crucial to consider intensive care management for the patient. Those with underlying conditions such as myocardial infarction or heart failure may experience significant hemodynamic instability. Consultation with a regional poison control center and a medical toxicologist is recommended to guide treatment decisions. It is important to note that beta-blocker overdose can lead to considerable resistance to resuscitation efforts with adrenergic agents, including beta-agonists.

Given the pharmacologic profile of metoprolol, specific management strategies should be employed:

Bradycardia

The need for atropine, adrenergic-stimulating drugs, or a pacemaker should be evaluated to address bradycardia and associated 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 treatment 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 indicated, with α1 receptor agonists added in the presence of vasodilation.

Bronchospasm

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

It is important to note that hemodialysis is unlikely to significantly contribute to the elimination of metoprolol from the body. Therefore, supportive care and the aforementioned interventions are critical in managing metoprolol overdose effectively.

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. These include bradycardia, heart block, hypotension, dizziness, and fatigue. Additional reported events encompass depression, shortness of breath, peripheral edema, rash, pruritus, nausea, vomiting, diarrhea, dry mouth, insomnia, and nightmares.

Furthermore, sexual dysfunction, anaphylactic reactions, hepatic enzyme elevations, thrombocytopenia, alopecia, and exacerbation of psoriasis have also been documented. There have been reports of drug interactions that lead to increased effects of metoprolol.

Patient Counseling

Patients should be advised 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 for patients to understand that they should not interrupt or discontinue the use of metoprolol succinate extended-release tablets without first consulting their physician.

Healthcare providers should inform 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 also be instructed to contact their physician if they experience any difficulty in breathing. Additionally, patients 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 any signs or symptoms of worsening heart failure, such as weight gain or increasing shortness of breath.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a controlled room temperature of 20°-25°C (68°-77°F), as defined by the United States Pharmacopeia (USP) guidelines for controlled room temperature.

Care should be taken to ensure that the product is kept in its original container to maintain its integrity and efficacy. Special handling requirements should be observed to prevent exposure to extreme temperatures or conditions that may compromise the product's quality.

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 Legacy Pharmaceutical Packaging, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)