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. This formulation is designed to provide a controlled and predictable release of metoprolol, allowing for once-daily dosing. The tablets consist 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, USP, 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 represented accordingly. Metoprolol succinate appears as a white crystalline powder with a molecular weight of 652.8 g/mol. 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 include silicon dioxide, cellulose compounds, sodium stearyl fumarate, polyethylene glycol, titanium dioxide, and paraffin.

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 succinate to extended-release metoprolol succinate, the same total daily dose of metoprolol succinate extended release 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 who do not have a pacemaker.

The product is also contraindicated in patients experiencing cardiogenic shock or decompensated heart failure, due to the potential for exacerbating these conditions.

Warnings and Precautions

Abrupt cessation of therapy may lead to exacerbation of myocardial ischemia; therefore, it is crucial to taper the dosage under medical supervision to mitigate this risk (5.1).

In patients with heart failure, there is a potential for worsening cardiac function. Continuous monitoring of cardiac status is recommended to identify any deterioration promptly (5.2).

For individuals with bronchospastic disease, the use of beta blockers is contraindicated due to the risk of bronchospasm (5.3).

Concomitant administration of beta blockers with glycosides, clonidine, diltiazem, or verapamil may heighten the risk of bradycardia. Healthcare professionals should monitor heart rate and rhythm closely in patients receiving these combinations (5.4).

In cases of pheochromocytoma, it is essential to initiate therapy with an alpha blocker prior to starting beta blocker treatment to prevent hypertensive crises (5.5).

During major surgical procedures, particularly non-cardiac surgeries, the initiation of high-dose extended-release metoprolol should be avoided. Additionally, chronic beta blocker therapy should not be routinely withdrawn before surgery, as this may lead to adverse cardiovascular events (5.6, 6.1).

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 advised, especially in diabetic patients (5.7).

In patients with thyrotoxicosis, abrupt withdrawal of beta blockers can precipitate a thyroid storm, necessitating careful management of therapy in this population (5.8).

For individuals with peripheral vascular disease, beta blockers may exacerbate symptoms of arterial insufficiency. Monitoring of peripheral circulation is recommended to assess for any worsening of symptoms (5.9).

It is important to note that patients receiving beta blockers may be unresponsive to the standard doses of epinephrine used in the treatment of allergic reactions. Healthcare providers should consider alternative treatment strategies in these cases (5.10).

Side Effects

Patients receiving treatment may experience a range of adverse reactions. The most common adverse reactions reported include tiredness, dizziness, depression, diarrhea, shortness of breath, bradycardia, and rash.

Serious adverse reactions have also been observed. 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 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 cases of thyrotoxicosis, abrupt withdrawal of treatment might precipitate a thyroid storm. Additionally, 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, and known hypersensitivity to product components should be considered.

Severe bradycardia, defined as greater than first-degree heart block or sick sinus syndrome without a pacemaker, may occur, as well as cardiogenic shock or decompensated heart failure.

In the event 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, as well as nausea and vomiting.

Drug Interactions

Catecholamine-depleting drugs may exhibit an additive effect when administered concurrently with beta-blocking agents, such as metoprolol. This interaction may enhance the pharmacological effects of both drug classes, necessitating careful monitoring of blood pressure and heart rate.

Inhibitors of the CYP2D6 enzyme are likely 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 exacerbate rebound hypertension following the withdrawal of clonidine. It is advisable to monitor patients closely for signs of increased blood pressure during the transition off clonidine therapy, and to consider a gradual tapering of clonidine to minimize this risk.

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 study demonstrated that there were no clinically relevant differences in the adverse event profile between pediatric patients in this age group 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 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 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 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 establish an association between major congenital malformations and the use of metoprolol in pregnancy, these studies have methodological limitations that hinder definitive conclusions regarding any drug-associated risk during pregnancy.

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.

There is no information regarding the effects of metoprolol on milk production. In a small study involving three mothers (at least 3 months postpartum) who took metoprolol of unspecified amounts, breast milk was collected every 2 to 3 hours over one dosage interval. 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. Additionally, in two women taking unspecified amounts of metoprolol, milk samples taken 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.

Renal Impairment

In patients with renal impairment, the systemic availability and half-life of metoprolol do not differ to a clinically significant degree compared to individuals with normal renal function. Therefore, no reduction in dosage is necessary for patients with chronic renal failure. Monitoring of renal function is advised, but dosing adjustments are not required based on the available clinical data.

Hepatic Impairment

Patients with hepatic impairment may experience increased blood levels of metoprolol succinate due to its hepatic metabolism. As no studies have been conducted specifically in this population, caution is advised.

It is recommended to initiate therapy at doses lower than those typically recommended for the specific indication. Doses should be increased gradually, taking into account the patient's liver function and response to treatment. Close monitoring of the patient's clinical status and any potential adverse effects is essential to ensure safe and effective use of metoprolol succinate in individuals with compromised liver function.

Overdosage

Overdosage of metoprolol succinate extended-release tablets can result in a range of serious clinical manifestations. The most common signs and symptoms associated with overdose 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, particularly for those with underlying conditions such as myocardial infarction or heart failure, as they may experience 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

Bradycardia: The management of bradycardia may require 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. Intravenous vasopressor infusion, such as dopamine or norepinephrine, may be necessary to manage hypotension effectively.

Heart Failure and Shock: In cases of heart failure and shock, appropriate interventions may include volume expansion and the administration of glucagon, which may be followed by an intravenous infusion of glucagon if indicated. Additionally, intravenous administration of adrenergic drugs such as dobutamine may be warranted, with α1 receptor agonistic drugs considered 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, 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 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 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

Postmarketing experience has identified a risk of hypoglycemia associated with the use of metoprolol succinate extended-release tablets. Reports indicate that this risk is particularly relevant for patients who are not feeding regularly or who are experiencing vomiting. It is recommended that parents or caregivers be informed about the potential for hypoglycemia and be instructed on how to recognize its signs. Additionally, monitoring for signs and symptoms of hypoglycemia in patients is advised to ensure timely intervention.

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 to inform patients 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 instructed to contact their physician if they experience any difficulty in breathing. Additionally, they 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, healthcare providers should advise them to consult their physician if they notice signs or symptoms of worsening heart failure, such as weight gain or increasing shortness of breath.

Parents or caregivers of patients should be informed about the risk of hypoglycemia when metoprolol succinate extended-release tablets are administered to patients who are not feeding regularly or who are vomiting. Providers should instruct them on how to recognize the signs of hypoglycemia and emphasize the importance of monitoring for these signs and symptoms in patients.

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 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 New American Therapeutics. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)