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 ensure a controlled and predictable release of metoprolol, allowing for once-daily dosing. Each tablet contains either 23.75 mg or 47.5 mg of metoprolol succinate, which is equivalent to 25 mg and 50 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 it has a molecular weight of 652.8. The structural formula is represented as follows:

Metoprolol succinate appears as a white crystalline powder and exhibits varying solubility characteristics: it is freely soluble in water, soluble in methanol, sparingly soluble in ethanol, and slightly soluble in dichloromethane and 2-propanol. It is practically insoluble in ethyl acetate, acetone, diethyl ether, and heptane.

Inactive ingredients in the formulation include colloidal silicon dioxide, crospovidone, ethylcellulose, ethylene glycol and vinyl alcohol graft copolymer, glycerol monocaprylocaprate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, povidone, talc, titanium dioxide, and triethyl citrate. The product contains no ingredients derived from gluten-containing grains (wheat, barley, or rye) and meets the USP Dissolution Test 7.

Uses and Indications

Metoprolol Succinate Extended-Release Tablets USP, containing metoprolol succinate, are indicated for the treatment of the following conditions:

Hypertension This drug is indicated for the management of hypertension. Lowering blood pressure with metoprolol succinate reduces the risk of both fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions.

Angina Pectoris Metoprolol succinate is also indicated for the treatment of angina pectoris, providing symptomatic relief and improving exercise tolerance.

Heart Failure This medication is indicated for the treatment of heart failure. It has been shown to reduce the risk of cardiovascular mortality and hospitalizations due to heart failure in affected patients.

Limitations of Use There are no teratogenic or nonteratogenic effects associated with metoprolol succinate as per the available data.

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, as these conditions may exacerbate the risks associated with its use.

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 significantly 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 surgical procedures, particularly non-cardiac surgeries, the initiation of high-dose extended-release metoprolol should be avoided. However, it is not routinely necessary to withdraw chronic beta-blocker therapy before surgery, as this could lead to adverse cardiovascular events.

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. Regular monitoring of blood glucose levels is recommended for these individuals.

In cases of thyrotoxicosis, abrupt withdrawal of beta-blockers may precipitate a thyroid storm, a life-threatening condition. Therefore, careful management and gradual dosage 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 consider this when managing anaphylactic events and may need to adjust treatment protocols accordingly.

Side Effects

Patients receiving treatment with 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 have also been observed. 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 the use of beta-blockers due to the potential for 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 recommended to initiate therapy with an alpha-blocker prior to starting beta-blocker treatment. During major surgery, the initiation of high-dose extended-release metoprolol should be avoided, and chronic beta-blocker therapy should not routinely be withdrawn before surgery. Patients with a history of hypoglycemia may experience an increased risk for hypoglycemia and may have masked early warning signs. In those with thyrotoxicosis, abrupt withdrawal of the medication could precipitate a thyroid storm. Furthermore, patients with peripheral vascular disease may experience aggravated 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, nausea, and vomiting.

Contraindications for the use of Metoprolol Succinate Extended-Release Tablets include known hypersensitivity to the product components, severe bradycardia (greater than first-degree heart block), 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) for a duration of 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 the studied population, no clinically relevant differences in the adverse event profile were observed between pediatric patients aged 6 to 16 years and 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 years and older to determine whether these elderly patients respond differently compared to younger individuals. However, other clinical experiences in hypertensive patients have not identified significant differences in responses between elderly and younger patients.

In the MERIT-HF trial, which involved 1,990 patients with heart failure randomized to receive 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, 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, while also increasing the fetal risk for intrauterine growth restriction and intrauterine death. Therefore, pregnant women with hypertension should be carefully monitored and managed accordingly.

It is important to note that metoprolol crosses the placenta, and neonates born to mothers receiving metoprolol during pregnancy may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. Healthcare professionals should observe neonates and manage them accordingly. Although 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

There is no specific information available regarding the use of this medication in lactating mothers or its effects on breastfed infants. Healthcare professionals should consider the lack of data when advising lactating mothers about the use of this medication.

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 may present with a range of severe clinical symptoms. The most notable signs include severe bradycardia, hypotension, and cardiogenic shock. Additional manifestations may encompass atrioventricular block, heart failure, bronchospasm, hypoxia, and varying levels of impairment of consciousness, including coma. Patients may also experience gastrointestinal symptoms such as nausea and vomiting.

In the event of an overdose, it is crucial to consider intensive care management. Patients with underlying conditions such as myocardial infarction or heart failure are particularly susceptible to 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. Hemodialysis is generally not effective for the elimination of metoprolol and is unlikely to provide any significant benefit.

For bradycardia, healthcare professionals should assess the necessity of administering atropine, adrenergic-stimulating drugs, or the placement of a pacemaker to address bradycardia and conduction disorders. In cases of hypotension, it is essential to treat the underlying bradycardia and consider the use of intravenous vasopressor infusions, such as dopamine or norepinephrine.

Heart failure and shock may require appropriate interventions, including volume expansion and the administration of glucagon, which may be followed by an intravenous infusion of glucagon if necessary. Additionally, intravenous adrenergic drugs such as dobutamine may be indicated, with α1 receptor agonists added in the presence of vasodilation.

Bronchospasm resulting from an overdose can typically be managed with bronchodilators, which are effective in reversing this condition.

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

During post-approval use of Metoprolol Succinate Extended-Release Tablets and immediate-release metoprolol, various adverse reactions have been reported voluntarily or through surveillance programs. Due to the nature of these reports, which originate from a population of uncertain size, it is not always feasible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular events include cold extremities, arterial insufficiency (typically of the Raynaud type), palpitations, peripheral edema, syncope, chest pain, and hypotension. Respiratory reactions consist of wheezing (bronchospasm) and dyspnea. Central nervous system effects reported include confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety/nervousness, hallucinations, and paresthesia.

Gastrointestinal adverse reactions encompass nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, and vomiting. Hypersensitivity reactions have included pruritus. Miscellaneous reports involve musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, tinnitus, reversible alopecia, agranulocytosis, dry eyes, worsening of psoriasis, Peyronie’s disease, sweating, photosensitivity, and taste disturbance.

Additionally, there are potential adverse reactions not specifically listed above that have been associated with other beta-adrenergic blocking agents and may also be relevant for Metoprolol Succinate Extended-Release Tablets. These include central nervous system effects such as reversible mental depression progressing to catatonia, and an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, clouded sensorium, and decreased performance on neuropsychometric tests. Hematologic concerns include agranulocytosis, nonthrombocytopenic purpura, and thrombocytopenic purpura. Hypersensitivity reactions may also involve laryngospasm and respiratory distress.

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 to inform patients that they should not interrupt or discontinue Metoprolol Succinate Extended-Release Tablets without first consulting their physician.

Healthcare providers should counsel 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.

Patients or caregivers should be informed about the risk of hypoglycemia associated with Metoprolol Succinate Extended-Release Tablets, particularly in patients who are fasting or vomiting. They should be instructed on how to monitor for signs of hypoglycemia to ensure timely intervention.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. 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. 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 Nivagen Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)