Metoprolol succinate

Description

Metoprolol succinate is a beta 1-selective (cardioselective) adrenoceptor blocking agent intended for oral administration, available as extended release tablets. The tablets contain 23.75 mg and 47.5 mg of metoprolol succinate, which is equivalent to 25 mg and 50 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). 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. 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 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 the management of hypertension to lower blood pressure, thereby reducing the risk of both fatal and non-fatal cardiovascular events, including strokes and myocardial infarctions.

In addition, metoprolol succinate is indicated for the treatment of angina pectoris.

Furthermore, it is indicated for patients with heart failure, where it serves 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 the case 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.

When transitioning from immediate-release metoprolol to metoprolol succinate extended-release tablets, the same total daily dose of metoprolol succinate extended-release tablets should be utilized.

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, including increased risk of angina pectoris and myocardial infarction. Healthcare professionals should advise patients against discontinuing therapy without prior consultation, as this can result in serious cardiovascular events (5.1).

Heart failure may worsen in patients receiving beta-blockers. Continuous monitoring of cardiac function is recommended to assess any deterioration in heart failure symptoms (5.2).

In patients with bronchospastic disease, the use of beta-blockers is contraindicated due to the potential for bronchospasm. Alternative therapies should be considered for these patients (5.3).

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 (5.4).

For patients diagnosed with pheochromocytoma, it is essential to initiate therapy with an alpha blocker prior to starting beta-blocker treatment to prevent hypertensive crises (5.5).

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 (5.6, 6.1).

Beta-blockers may increase the risk of hypoglycemia and can mask the early warning signs of low blood sugar. Patients with diabetes should be monitored closely for hypoglycemic episodes (5.7).

Patients with thyrotoxicosis are at risk of precipitating a thyroid storm if beta-blocker therapy is abruptly withdrawn. Caution is advised in managing these patients to prevent severe complications (5.8).

In individuals with peripheral vascular disease, beta-blockers may exacerbate symptoms of arterial insufficiency. Monitoring of peripheral circulation is recommended (5.9).

Patients receiving beta-blockers may exhibit reduced responsiveness to standard doses of epinephrine used in the treatment of allergic reactions. Healthcare providers should consider this when managing anaphylactic events (5.10).

Side Effects

Patients may experience a range of adverse reactions while undergoing treatment. The most common adverse reactions reported include tiredness, dizziness, depression, shortness of breath, bradycardia, hypotension, diarrhea, pruritus, and rash.

Serious adverse reactions may occur, particularly in specific patient populations or under certain conditions. Abrupt cessation of therapy with beta-blocking agents has been associated with exacerbations of angina pectoris and myocardial infarction; therefore, patients should be warned against discontinuing therapy without consulting their physician. Additionally, abrupt withdrawal may exacerbate myocardial ischemia and worsen cardiac failure in patients with heart failure.

Patients with bronchospastic disease should avoid beta-blockers due to the potential for exacerbating respiratory symptoms. The concomitant use of glycosides, clonidine, diltiazem, and verapamil with beta-blockers can increase the risk of bradycardia. 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 be routinely 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 experience aggravated symptoms of arterial insufficiency.

Known hypersensitivity to the product components is a contraindication for use. Severe bradycardia, defined as greater than first-degree heart block or sick sinus syndrome without a pacemaker, as well as cardiogenic shock or decompensated heart failure, are also serious concerns.

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 for healthcare providers to monitor for these potential adverse reactions and manage them appropriately.

Drug Interactions

There are currently no documented drug interactions associated with this medication. Additionally, there is no information available regarding interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted 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

There is no pediatric use information available for this medication. Therefore, the safety and efficacy in pediatric patients have not been established. Healthcare professionals should exercise caution when considering this medication for children, infants, or adolescents, as there are no specific dosage recommendations or study outcomes to guide its use in these populations.

Geriatric Use

Elderly patients may not have specific information regarding the use of this medication, including dosage adjustments, safety concerns, or special precautions. Therefore, healthcare providers should exercise caution when prescribing this medication to geriatric patients. It is advisable to monitor these patients closely for any potential adverse effects or changes in efficacy, given the lack of targeted data for this population.

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/m 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 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

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.

No adverse reactions of metoprolol on the breastfed infant have been identified. However, it is recommended to 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.

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), with an average relative infant dosage of 0.5% of the mother's weight-adjusted dosage. Additionally, in two women taking unspecified amounts of metoprolol, milk samples taken after one dose indicated that the estimated amount of metoprolol and alphahydroxy metoprolol in breast milk was less than 2% of the mother's weight-adjusted dosage.

Renal Impairment

There is no information available regarding renal impairment, dosage adjustments, special monitoring, or safety considerations for patients with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of specific guidance when prescribing to patients with renal impairment.

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

In cases of metoprolol succinate extended-release overdose, a range of signs and symptoms may manifest, including severe bradycardia, hypotension, cardiogenic shock, atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness or coma, as well as gastrointestinal symptoms such as nausea and vomiting.

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 note that beta-blocker overdose can lead to significant resistance to resuscitation efforts with adrenergic agents, including beta-agonists.

In addressing bradycardia and conduction disorders, healthcare professionals should evaluate the need for atropine, adrenergic-stimulating drugs, or the placement of a pacemaker. For hypotension associated with overdose, it is crucial to treat the underlying bradycardia and consider the administration of intravenous vasopressors, such as dopamine or norepinephrine.

Heart failure and shock resulting from an overdose may be managed through appropriate volume expansion, glucagon injection, and the intravenous administration of adrenergic drugs like dobutamine. Additionally, bronchospasm that occurs as a result of overdose can typically be reversed with bronchodilators.

It is important to recognize that hemodialysis is unlikely to facilitate the elimination of metoprolol in overdose situations, underscoring the need for careful monitoring and supportive care in affected patients.

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 several adverse reactions associated with the use of the medication. Reports have included dizziness, fatigue, and bradycardia. Additional adverse reactions noted are hypotension, syncope, and exacerbation of heart failure.

Severe allergic reactions, such as anaphylaxis and angioedema, have also been reported. Instances of liver enzyme elevations have been documented in postmarketing surveillance. Furthermore, there is an observed risk of depression and mood changes linked to the use of metoprolol succinate extended-release tablets. Some patients have experienced sleep disturbances, including insomnia and nightmares.

Rare cases of pulmonary complications, such as bronchospasm, have been reported in patients with a history of asthma or chronic obstructive pulmonary disease (COPD).

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 requiring 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 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 also inform patients or caregivers about the risk of hypoglycemia associated with metoprolol succinate extended-release tablets, particularly in patients who are fasting or experiencing vomiting. It is essential to instruct patients or caregivers on how to monitor for signs of hypoglycemia effectively.

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

View full prescribing information (PDF)