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 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 available strengths of metoprolol succinate extended-release tablets, USP include 23.75 mg, 47.5 mg, and 95 mg, which are equivalent to 25 mg, 50 mg, and 100 mg of metoprolol tartrate, USP, 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 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, 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 between 25 mg and 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, due to the potential for exacerbating these conditions.

The product is also contraindicated in patients experiencing cardiogenic shock or decompensated heart failure, as its use may worsen hemodynamic stability in these populations.

Warnings and Precautions

Abrupt cessation of beta-blocker therapy may exacerbate myocardial ischemia, necessitating careful consideration when discontinuing treatment. Patients with heart failure may experience worsening cardiac function; therefore, monitoring is essential in this population.

In individuals with bronchospastic disease, beta-blockers should be avoided due to the potential for exacerbating respiratory symptoms. Caution is advised when beta-blockers are used concomitantly with glycosides, clonidine, diltiazem, or verapamil, as this combination can increase the risk of bradycardia.

For patients diagnosed with pheochromocytoma, it is critical to initiate therapy with an alpha blocker prior to starting beta-blockers to prevent hypertensive crises. During major surgical procedures, particularly non-cardiac surgeries, the initiation of high-dose extended-release metoprolol should be avoided. It is not routinely necessary to withdraw chronic beta-blocker therapy before surgery.

Patients with diabetes should be aware that beta-blockers may increase the risk of hypoglycemia and can mask the early warning signs of low blood sugar. In cases of thyrotoxicosis, abrupt withdrawal of beta-blockers may precipitate a thyroid storm, which requires careful management.

Peripheral vascular disease patients may experience aggravated symptoms of arterial insufficiency when treated with beta-blockers. Additionally, it is important to note that patients may be unresponsive to the usual doses of epinephrine used for treating allergic reactions, which could complicate emergency interventions.

Healthcare professionals should remain vigilant in monitoring these conditions and consider the implications of beta-blocker therapy in their management plans.

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 can increase the risk of bradycardia.

In patients with pheochromocytoma, it is recommended to initiate therapy with an alpha blocker. 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 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. Furthermore, 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, 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, such as metoprolol. This interaction may enhance the pharmacological effects of both drug classes, necessitating careful monitoring of blood pressure and heart rate.

Inhibitors of the CYP2D6 enzyme are likely to increase the concentration of metoprolol. Clinicians should consider dosage adjustments of metoprolol when prescribing CYP2D6 inhibitors to mitigate the risk of adverse effects associated with elevated drug levels.

Additionally, 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 transition off clonidine therapy, and to consider alternative strategies for managing hypertension in these patients.

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 reduction in systolic blood pressure (SBP). However, some pre-specified secondary endpoints indicated effectiveness, including a dose-response for 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 beats per minute, 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 extended-release in the treatment of hypertension did not include a sufficient number of subjects aged 65 and older to ascertain whether these elderly patients respond differently compared to younger individuals. However, other clinical experiences involving hypertensive patients have not revealed any significant differences in responses between elderly and younger populations.

In the MERIT-HF trial, which involved 1,990 patients with heart failure randomized to receive metoprolol succinate extended-release, 50% of the participants were aged 65 years and older, with 12% being 75 years of age and older. The findings from this trial indicated no notable differences in efficacy or the incidence of adverse reactions between older and younger patients.

Given the increased likelihood of diminished 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 and consideration of dose adjustments may be necessary 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, 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. 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, the methodological limitations of these studies—including retrospective design, concomitant use of other medications, and unadjusted confounders—hinder definitive conclusions regarding 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 that healthcare professionals monitor the breastfed infant for bradycardia and other symptoms of beta blockade, such as listlessness or 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 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 alpha-hydroxy metoprolol in breast milk was less than 2% of the mother's weight-adjusted dosage.

Renal Impairment

There is no specific information available 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 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

Overdosage of metoprolol succinate extended-release tablets can result in a range of serious clinical manifestations. The most common signs and symptoms 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. 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

The need for atropine, adrenergic-stimulating drugs, or a pacemaker should be evaluated 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 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 employed, with α1 receptor agonists added in the presence of vasodilation.

Bronchospasm

Bronchospasm associated with overdose can typically be reversed using 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 two-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

No specific postmarketing experience details are available. As such, there are no additional adverse events or rare case reports to summarize at this time.

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 be instructed to contact their physician if they experience any difficulty in breathing. Additionally, patients should be reminded to 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 a blister pack configuration. It should be stored at a temperature range of 20°-25°C (68°-77°F), in accordance with USP Controlled Room Temperature guidelines. It is imperative that the product is not used if the blister is torn or broken, as this may compromise the integrity of the medication.

Additional Clinical Information

Patients should be advised not to interrupt therapy without consulting their physician. It is important for patients to have bronchodilators, including beta-agonists, readily available or to administer them concomitantly as needed.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Metoprolol Succinate as submitted by Cardinal Health 107, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)