Metoprolol succinate

Description

Metoprolol succinate is a beta 1-selective (cardioselective) adrenoceptor blocking agent formulated for oral administration as extended-release tablets. These tablets are designed to provide a controlled and predictable release of metoprolol, allowing for once-daily dosing. Each tablet comprises a multiple unit system containing metoprolol succinate in a multitude of 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 correspond 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 it has a molecular weight of 652.8. Metoprolol succinate, USP appears as a white to off-white powder that is freely soluble in water, soluble in methanol, sparingly soluble in alcohol, and slightly soluble in isopropyl alcohol.

Each metoprolol succinate extended-release tablet contains inactive ingredients including colloidal silicon dioxide, croscarmellose sodium, ethyl cellulose, glycerin, hypromellose, magnesium stearate, methyl cellulose, microcrystalline cellulose, polyethylene glycol, povidone, and talc. Additionally, the tablets contain Opadry II white 03B28796, which includes hypromellose, polyethylene glycol, and titanium dioxide. The formulation meets the USP Dissolution Test 4.

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.

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 previously administered.

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 these conditions may lead to serious complications.

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 a history of ischemic heart disease.

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 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 prior to surgery, and careful consideration should be given to the individual patient's circumstances.

Patients receiving 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. Therefore, gradual tapering of the medication is advised in these patients.

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

Lastly, patients treated with beta-blockers may exhibit unresponsiveness to the standard doses of epinephrine used for the management of allergic reactions. Healthcare professionals should be aware of this potential interaction and consider alternative treatment strategies in such scenarios.

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. Abrupt cessation of therapy may exacerbate myocardial ischemia, and worsening cardiac failure may occur in patients with heart failure. In individuals with bronchospastic disease, beta-blockers should be avoided 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, 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.

Patients may also experience an increased risk of hypoglycemia, which may mask early warning signs. In those with thyrotoxicosis, abrupt withdrawal of treatment might precipitate a thyroid storm. Additionally, peripheral vascular disease may be aggravated, leading to worsened 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 this treatment include known hypersensitivity to the product components, severe bradycardia (greater than first-degree heart block or sick sinus syndrome without a pacemaker), and conditions such as 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 combination could potentially enhance the pharmacological effects of both drug classes, necessitating careful monitoring of the patient's response and blood pressure.

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 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 in patients transitioning off clonidine, particularly if they are concurrently 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 (0.2, 1, or 2 mg/kg once daily) for a duration of 4 weeks. The study demonstrated no clinically relevant differences in the adverse event profile between pediatric patients in this age range and adult patients. However, 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 the use of metoprolol succinate in the treatment of hypertension did not include a sufficient number of subjects aged 65 years and older to ascertain whether this population responds differently compared to younger individuals. However, other clinical experiences with hypertensive patients have not indicated 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 receive metoprolol succinate, 50% of the participants were aged 65 years and older, and 12% were aged 75 years and older. The findings from this trial revealed 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 geriatric patients, it is advisable to initiate treatment with a lower starting dose in this population. Careful monitoring is recommended to ensure safety and efficacy in elderly patients receiving metoprolol succinate.

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. Notably, 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.

Pregnant women with hypertension should be carefully monitored and managed accordingly. Stroke volume and heart rate increase during pregnancy, leading to increased cardiac output, particularly during the first trimester. There is also a risk for preterm birth in pregnant women with chronic heart failure during the third trimester. 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 essential to observe neonates and manage them accordingly.

While data from published observational studies did not establish 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

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 potential adverse effects accordingly.

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 severe clinical manifestations. The most notable signs and symptoms include severe bradycardia, hypotension, and cardiogenic shock. Additionally, patients may present with 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, complicating treatment. 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

• Bradycardia: The need for atropine, adrenergic-stimulating drugs, or a pacemaker should be evaluated to address bradycardia and associated conduction disorders.

• Hypotension: Treatment should focus on the underlying bradycardia. Intravenous vasopressor infusion, such as dopamine or norepinephrine, may be necessary to manage hypotension effectively.

• Heart Failure and Shock: Appropriate management may include volume expansion and the administration of glucagon, if indicated, followed by an intravenous glucagon infusion. Additionally, intravenous adrenergic drugs such as dobutamine may be utilized, with α1 receptor agonists considered in cases of vasodilation.

• Bronchospasm: This condition can typically be reversed with the use of 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 management strategies should be prioritized in the treatment of metoprolol overdose.

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. However, 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, as well as tests on metoprolol succinate, were negative. 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 a range of adverse reactions reported voluntarily or through surveillance programs. These include bradycardia, heart failure, hypotension, dizziness, fatigue, depression, shortness of breath, peripheral edema, rash, pruritus, nausea, vomiting, diarrhea, dry mouth, insomnia, nightmares, sexual dysfunction, and allergic reactions, including anaphylaxis. Additionally, hepatic enzyme elevations, thrombocytopenia, agranulocytosis, psoriasis exacerbation, alopecia, hyperglycemia, and hypoglycemia have also been reported. It is important to note that these adverse reactions may not be directly related to the drug.

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 up on doses.

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 regarding activities that require alertness. Patients should be advised to avoid operating automobiles and machinery until their response to therapy with metoprolol succinate extended-release tablets has been established.

Patients should be instructed to contact their physician if they experience any difficulty in breathing. Additionally, they should inform their physician or dentist prior to any surgical procedures that they are taking metoprolol succinate extended-release tablets.

For patients with heart failure, it is crucial to consult their physician if they notice any signs or symptoms of worsening heart failure, such as weight gain or increasing shortness of breath. Providers should also inform patients or caregivers about the risk of hypoglycemia, particularly in those 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 a tight container, in accordance with USP guidelines. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), consistent with USP Controlled Room Temperature requirements. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

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. No further information is available regarding laboratory tests, abuse potential, route, method, frequency of administration, or postmarketing experience.

FDA Insert (PDF)

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

View full prescribing information (PDF)