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 designed to provide a controlled and predictable release of metoprolol, allowing for once-daily dosing. Each tablet consists of a multiple unit system containing metoprolol succinate in numerous controlled release pellets, with each pellet functioning as an independent drug delivery unit that continuously releases 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 are equivalent to 25 mg, 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 (2:1) (salt). Metoprolol succinate, USP is characterized as a white to off-white powder with a molecular weight of 652.81. It exhibits solubility properties as follows: freely soluble in water, soluble in methanol, sparingly soluble in ethanol, slightly soluble in dichloromethane and 2-propanol, and practically insoluble in ethyl acetate, acetone, diethyl ether, and heptane.

Inactive ingredients in the formulation include colloidal silicon dioxide, ethyl cellulose, hypromellose, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, sodium stearyl fumarate, titanium dioxide, and triacetin.

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 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. Therefore, it is crucial to taper the dosage gradually under medical supervision to mitigate this risk.

In patients with heart failure, there is a potential for worsening cardiac function. Continuous monitoring of cardiac status is recommended to ensure that any deterioration is promptly addressed.

For individuals with bronchospastic disease, the use of beta-blockers is contraindicated due to the risk of bronchospasm. Healthcare professionals should consider alternative therapies for these patients.

Concomitant administration of beta-blockers with glycosides, clonidine, diltiazem, or verapamil may heighten 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, it is not necessary to routinely withdraw chronic beta-blocker therapy before surgery, as this could 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, a life-threatening condition. Therefore, careful management and gradual dose adjustments are critical in these patients.

For individuals with peripheral vascular disease, beta-blockers may exacerbate symptoms of arterial insufficiency. Monitoring of peripheral circulation is advised to assess any worsening of symptoms.

Lastly, patients receiving beta-blockers may exhibit reduced responsiveness to the standard doses of epinephrine used in the treatment of allergic reactions. Healthcare providers should be aware of this potential interaction and consider alternative dosing strategies in emergency situations.

Side Effects

Patients may experience a range of adverse reactions while receiving treatment. 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 essential to initiate therapy with an alpha-blocker. During major surgery, the initiation of high-dose extended-release metoprolol should be avoided in patients undergoing non-cardiac procedures, and chronic beta-blocker therapy should not routinely be withdrawn prior to surgery.

Patients with a history of hypoglycemia may have an increased risk for hypoglycemic events, and beta-blockers can mask the early warning signs of hypoglycemia. In individuals with thyrotoxicosis, abrupt withdrawal of treatment may precipitate a thyroid storm. Furthermore, patients with peripheral vascular disease may experience aggravated symptoms of arterial insufficiency.

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. It is also important to note that patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

Drug Interactions

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

Inhibitors of the CYP2D6 enzyme are known 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 worsen rebound hypertension following the discontinuation of clonidine. It is advisable to monitor patients closely for signs of increased blood pressure during the withdrawal period of clonidine, particularly in those who are also receiving beta-blocker therapy.

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) 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 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 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 any 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 increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies, it is generally recommended to initiate treatment with a low starting dose in geriatric patients. This approach helps to ensure safety and tolerability in this population. Regular monitoring for efficacy and adverse effects is advised to optimize treatment outcomes in elderly 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 of 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. 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 increases the fetal risk for intrauterine growth restriction and intrauterine death. Therefore, pregnant women with hypertension should be carefully monitored and managed accordingly.

Metoprolol crosses the placenta, and neonates born to mothers receiving metoprolol during pregnancy may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. It is recommended that neonates be observed and managed appropriately. While data from published observational studies did not demonstrate an association of major congenital malformations with the use of metoprolol in pregnancy, the inconsistent findings regarding intrauterine growth retardation, preterm birth, and perinatal mortality necessitate caution, as these studies have methodological limitations that hinder interpretation.

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.

In two women taking unspecified amounts of metoprolol, milk samples collected 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. Additionally, a small study involving three mothers (at least 3 months postpartum) who took metoprolol of unspecified amount found that 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.

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 patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

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 serious clinical manifestations, including severe bradycardia, hypotension, and cardiogenic shock. Patients may also present with atrioventricular block, heart failure, bronchospasm, hypoxia, and varying levels of consciousness, including coma. Symptoms such as nausea and vomiting may also occur.

Given the potential for significant hemodynamic instability, particularly in patients with underlying conditions such as myocardial infarction or heart failure, it is advisable to consider intensive care management. It is important to note that beta-blocker overdose may lead to considerable resistance to resuscitation efforts with adrenergic agents, including beta-agonists.

In managing an overdose, the following measures should be employed based on the pharmacologic actions of metoprolol:

• Bradycardia and Conduction Disorders: Evaluate the necessity for atropine, adrenergic-stimulating drugs, or the placement of a pacemaker to address bradycardia and conduction abnormalities. Treatment of underlying bradycardia may involve intravenous vasopressor infusion, utilizing agents such as dopamine or norepinephrine.

• Heart Failure and Shock: When appropriate, heart failure and shock should be managed with suitable volume expansion. The injection of glucagon may be necessary, followed by an intravenous infusion of glucagon. Additionally, intravenous administration of adrenergic drugs such as dobutamine may be indicated, with α1 receptor agonists considered in the presence of vasodilation.

• Bronchospasm: Bronchospasm associated with 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 symptomatic management remain the cornerstone of treatment in cases of metoprolol overdose.

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

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 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 be instructed 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.

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° to 25°C (68° to 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 Mylan Institutional Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)