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 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-(isopropyl amino)-3-p-(2-methoxyethyl)phenoxy-2-propanol succinate (2:1) (salt), and its structural formula is provided in the relevant documentation. Metoprolol succinate, USP is characterized as a white crystalline powder with a molecular weight of 652.8. It exhibits solubility properties that include being freely soluble in water, soluble in methanol, sparingly soluble in ethanol, and slightly soluble in dichloromethane and 2-propanol, while being practically insoluble in ethyl acetate, acetone, diethyl ether, and heptane.

Inactive ingredients in the formulation include colloidal silicon dioxide, crospovidone, ethylcellulose, hypromellose, lactose monohydrate (25 mg and 50 mg), magnesium stearate, microcrystalline cellulose, polyethylene glycol, partially hydrolyzed polyvinyl alcohol, sugar spheres (composed of corn starch and sucrose), talc, titanium dioxide, and triethyl citrate. It is important to note that FDA-approved dissolution test specifications may differ from those established by the USP.

Uses and Indications

Metoprolol succinate is indicated for the treatment of hypertension, angina pectoris, and heart failure. In patients with hypertension, this medication is utilized to lower blood pressure, thereby reducing the risk of both fatal and non-fatal cardiovascular events, including strokes and myocardial infarctions.

In the context of angina pectoris, metoprolol succinate serves to alleviate symptoms associated with this condition. Additionally, it is indicated for the management of heart failure, where it has been shown to reduce the risk of cardiovascular mortality and hospitalizations due to heart failure.

There are no teratogenic or nonteratogenic effects associated with metoprolol succinate.

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 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 or 25 mg.

When switching 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. Therefore, healthcare professionals should exercise caution when discontinuing treatment, particularly in patients with underlying cardiovascular conditions.

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.

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

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.

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 surgery, particularly non-cardiac procedures, the initiation of high-dose extended-release metoprolol should be avoided. Additionally, 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 recommended, especially in diabetic patients.

In cases of thyrotoxicosis, abrupt withdrawal of beta-blockers may precipitate a thyroid storm. Caution is advised when managing patients with this condition.

For patients with peripheral vascular disease, beta-blockers may aggravate symptoms of arterial insufficiency. Monitoring of peripheral circulation is recommended to assess for any worsening of symptoms.

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 professionals should consider alternative treatment strategies in these cases.

Side Effects

Patients receiving metoprolol succinate extended-release tablets 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 may occur, including worsening heart failure and exacerbation of myocardial ischemia following abrupt cessation of therapy. Patients with bronchospastic disease should avoid beta-blockers due to the potential for bronchospasm. 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 in patients undergoing non-cardiac procedures, and chronic beta-blocker therapy should not routinely be withdrawn prior to surgery. Additionally, metoprolol may increase the risk of hypoglycemia and mask early warning signs of this condition. In patients with thyrotoxicosis, abrupt withdrawal of metoprolol may precipitate a thyroid storm. Patients with peripheral vascular disease may experience aggravated symptoms of arterial insufficiency. It is also 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, cardiogenic shock, atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness or coma, as well as nausea and vomiting.

Fetal and neonatal adverse reactions have been observed in neonates born to mothers receiving metoprolol during pregnancy, which may include hypotension, hypoglycemia, bradycardia, and respiratory depression.

Contraindications for the use of metoprolol include known hypersensitivity to the product components, severe bradycardia (greater than first-degree heart block or sick sinus syndrome without a pacemaker), and cardiogenic shock or decompensated heart failure.

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 in patients receiving CYP2D6 inhibitors to avoid potential 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 blood pressure closely during the withdrawal of clonidine in patients who are also receiving beta-blockers to manage any potential hypertensive episodes 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 extended-release tablets (0.2, 1, or 2 mg/kg once daily) and were followed for 4 weeks. The safety and effectiveness of metoprolol succinate extended-release tablets have not been established in patients younger than 6 years of age. In pediatric patients aged 6 to 16 years, no clinically relevant differences in the adverse event profile were observed when compared to adult patients.

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 over 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 greater frequency of decreased 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 is advised 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.

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 increases 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, methodological limitations in these studies, such as retrospective design and concomitant use of other medications, hinder definitive conclusions regarding 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 adverse effects accordingly. There is no specific data available 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

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 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, 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.

Given the pharmacologic profile of metoprolol, the following management strategies are recommended:

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 employed, with α1 receptor agonists added in the presence of vasodilation.

Bronchospasm

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

It is important to note that hemodialysis is unlikely to significantly enhance the elimination of metoprolol from the body. Therefore, supportive care and the aforementioned interventions should be prioritized in the management 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 have been reported. 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 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 experience signs or symptoms of worsening heart failure, such as weight gain or increasing shortness of breath. Patients or caregivers should also be informed about the risk of hypoglycemia when metoprolol succinate extended-release tablets are administered to patients who are fasting or vomiting. It is essential to instruct patients or caregivers on how to monitor for signs of hypoglycemia.

Storage and Handling

The product is supplied in accordance with the following specifications: it should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as defined by USP Controlled Room Temperature guidelines.

It is essential to keep this medication out of the reach of children to ensure safety.

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 Slate Run Pharmaceuticals, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)