Metoprolol succinate

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 management of angina pectoris, metoprolol succinate aids in alleviating symptoms associated with this condition. Additionally, it is indicated for patients with 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 transitioning from immediate-release metoprolol to extended-release metoprolol succinate, it is essential to use the same total daily dose of metoprolol succinate extended-release tablets.

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 who do not have 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, necessitating careful consideration when discontinuing treatment.

Heart Failure Patients with pre-existing heart failure may experience worsening cardiac function. Continuous monitoring of cardiac status is recommended in these individuals.

Bronchospastic Disease Beta-blockers are contraindicated in patients with bronchospastic diseases, as they may induce bronchospasm.

Drug Interactions Concomitant administration of beta-blockers with glycosides, clonidine, diltiazem, or verapamil can significantly increase the risk of bradycardia. Healthcare professionals should exercise caution and monitor heart rate and rhythm in patients receiving these combinations.

Pheochromocytoma 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.

Major Surgery For patients undergoing non-cardiac surgery, the initiation of high-dose extended-release metoprolol should be avoided. Additionally, chronic beta-blocker therapy should not be routinely withdrawn prior to surgical procedures, as this may lead to adverse cardiovascular events.

Hypoglycemia Beta-blockers may increase the risk of hypoglycemia and can mask the early warning signs of low blood sugar. Patients with diabetes should be closely monitored for changes in glucose levels.

Thyrotoxicosis Abrupt withdrawal of beta-blockers in patients with thyrotoxicosis can precipitate a thyroid storm, a potentially life-threatening condition. Gradual tapering of the medication is advised.

Peripheral Vascular Disease In patients with peripheral vascular disease, beta-blockers may exacerbate symptoms of arterial insufficiency. Monitoring of peripheral circulation is recommended.

Allergic Reactions Patients on beta-blockers may exhibit unresponsiveness to the standard doses of epinephrine used for the treatment of allergic reactions. Alternative treatment strategies should be considered in these cases.

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 pre-existing heart failure. In patients with bronchospastic disease, beta-blockers should be avoided due to the potential for exacerbation of 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 be at increased risk for 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), sick sinus syndrome without a pacemaker, 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 mitigate the risk of adverse effects associated with elevated drug levels.

Additionally, beta-blockers, including metoprolol, have the potential to exacerbate rebound hypertension following the withdrawal of clonidine. It is advisable to monitor blood pressure closely during the transition period when discontinuing clonidine therapy, particularly in patients who are also receiving beta-blockers.

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 mg/kg, 1 mg/kg, 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 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 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 elderly patients. This approach helps to ensure safety and tolerability in this population. Regular monitoring for adverse effects and therapeutic efficacy is advised when treating geriatric patients with metoprolol succinate extended-release tablets.

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 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 inconsistent findings regarding intrauterine growth retardation, preterm birth, and perinatal mortality highlight the need for cautious interpretation of the available literature, which may have methodological limitations.

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. There is no specific data provided 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

Patients with renal impairment have not been specifically addressed in the available prescribing information. There are no dosage adjustments, special monitoring requirements, or safety considerations outlined for individuals with reduced kidney function. Healthcare professionals should exercise caution and consider the lack of data when prescribing to 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 severe clinical manifestations. The most notable 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 imperative to consider intensive care management for the patient. Those 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 may lead to considerable resistance to resuscitation efforts utilizing adrenergic agents, including beta-agonists.

Management Strategies

Bradycardia: The management of bradycardia may necessitate the administration of atropine, adrenergic-stimulating drugs, or the placement of a pacemaker to address bradycardia and conduction disorders.

Hypotension: Treatment should focus on addressing 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 interventions may include volume expansion and the injection of glucagon, which may be followed by an intravenous glucagon infusion. Additionally, intravenous administration of adrenergic drugs such as dobutamine may be warranted, 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 contribute to the elimination of metoprolol from the body. Therefore, the focus should remain on the aforementioned management strategies to mitigate the effects of overdose effectively.

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 evaluated in a Salmonella/mammalian-microsome mutagenicity test, which yielded 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 reactions encompass nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, and vomiting.

Hypersensitive reactions have been noted, including pruritus, laryngospasm, and respiratory distress. Miscellaneous adverse events include musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, tinnitus, reversible alopecia, dry eyes, worsening of psoriasis, Peyronie’s disease, sweating, photosensitivity, and taste disturbance.

Additionally, there are potential adverse reactions that have been reported with other beta-adrenergic blocking agents, which should be considered as potential adverse reactions to metoprolol succinate extended-release tablets. These include central nervous system effects such as reversible mental depression progressing to catatonia, characterized by disorientation for time and place, short-term memory loss, emotional lability, clouded sensorium, and decreased performance on neuropsychometric tests. Hematologic reactions reported include agranulocytosis, nonthrombocytopenic purpura, and thrombocytopenic purpura.

Patient Counseling

Patients should be advised not to interrupt therapy with metoprolol succinate extended-release tablets without consulting their physician, particularly if they have ischemic heart disease. When discontinuing the medication, it is important to gradually reduce the dosage over a period of 1 to 2 weeks while closely monitoring the patient for any adverse effects.

During the up-titration of metoprolol succinate extended-release tablets, healthcare providers should ensure that patients are monitored for signs of worsening cardiac failure. In cases where patients experience symptomatic bradycardia, they should be instructed to reduce the dose of the medication accordingly.

For patients with bronchospastic diseases, it is generally advised to avoid beta-blockers. However, metoprolol succinate extended-release tablets may be considered for use in patients with bronchospastic disease who do not respond to or cannot tolerate other antihypertensive treatments.

Additionally, patients should be monitored for bradycardia and other symptoms of beta-blockade, such as listlessness, particularly when breastfeeding. It is crucial to instruct patients to seek emergency treatment if they experience severe hypoglycemia.

Finally, patients with a history of severe anaphylactic reactions should be made aware that they may be more reactive to repeated challenges and may not respond to the usual doses of epinephrine used to treat allergic reactions while taking beta-blockers.

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 25°C (77°F), with permissible excursions between 15-30°C (59-86°F) as outlined by the United States Pharmacopeia (USP) guidelines for controlled room temperature. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Patients should be advised to administer the medication once daily, with titration occurring at weekly or longer intervals as needed and tolerated. It is important for patients not to interrupt therapy without consulting their physician. Clinicians should monitor breastfed infants for potential adverse effects, including bradycardia and other symptoms of beta-blockade, such as listlessness indicative of hypoglycemia.

Postmarketing experience has revealed various adverse reactions across multiple systems. Cardiovascular effects may include cold extremities, arterial insufficiency (often of the Raynaud type), palpitations, peripheral edema, syncope, chest pain, and hypotension. Respiratory issues can manifest as wheezing (bronchospasm) and dyspnea. Central nervous system effects may involve confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety/nervousness, hallucinations, and paresthesia. Gastrointestinal reactions include nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, and vomiting. Hypersensitivity reactions may present as pruritus. Additional miscellaneous effects reported include 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.

FDA Insert (PDF)

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

View full prescribing information (PDF)