Metoprolol succinate

Description

Metoprolol succinate is a beta 1-selective (cardioselective) adrenoceptor blocking agent intended for oral administration, available as extended release tablets. 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 designed to provide continuous release of metoprolol throughout the dosage interval. The tablets are available in strengths of 23.75, 47.5, 95, and 190 mg of metoprolol succinate, which is equivalent to 25, 50, 100, and 200 mg of metoprolol tartrate, USP, respectively. The chemical name of metoprolol succinate is (±)1- (isopropylamino)-3-p-(2-methoxyethyl) phenoxy-2-propanol succinate (2:1) (salt). Metoprolol succinate, USP is a white crystalline powder with a molecular weight of 652.8. It is freely soluble in water, soluble in methanol, sparingly soluble in ethanol, slightly soluble in dichloromethane and 2-propanol, and practically insoluble in ethyl acetate, acetone, diethylether, and heptane. Inactive ingredients include sugar spheres, povidone, ethyl cellulose, polyethylene glycol, hydroxypropyl cellulose, triethyl citrate, magnesium stearate, microcrystalline cellulose, titanium dioxide, polydextrose, hypromellose, and triacetin.

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. For patients experiencing angina pectoris, metoprolol succinate serves to alleviate symptoms associated with this condition. Additionally, in the context of heart failure, this drug is indicated 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 the case 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 metoprolol succinate extended-release tablets, it is essential to use the same total daily dose of metoprolol succinate extended-release tablets as the immediate-release formulation.

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, due to the potential for exacerbating these conditions.

Warnings and Precautions

Abrupt cessation of beta-blocker therapy may lead to exacerbation of myocardial ischemia, necessitating careful consideration when discontinuing treatment.

In patients with heart failure, there is a risk of worsening cardiac function. Therefore, monitoring of cardiac status is essential in this population to ensure that any deterioration is promptly addressed.

For individuals with bronchospastic disease, beta-blockers should be avoided due to the potential for bronchospasm.

Concomitant use of beta-blockers with glycosides, clonidine, diltiazem, or verapamil may increase the risk of bradycardia. Healthcare professionals should monitor heart rate and rhythm closely in patients receiving these combinations.

In cases of pheochromocytoma, it is critical 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. 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 for patients at risk of hypoglycemia.

In patients with thyrotoxicosis, abrupt withdrawal of beta-blockers may precipitate a thyroid storm, which is a life-threatening condition. Therefore, careful management and gradual tapering of the medication are advised.

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

Lastly, patients receiving beta-blockers may be unresponsive to the usual doses of epinephrine used in the treatment of allergic reactions. It is important for healthcare providers to be aware of this potential interaction and to consider alternative treatment strategies in such 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. 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 beta blockers due to the risk of bronchospasm. Additionally, 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. For those undergoing major surgery, the initiation of high-dose extended-release metoprolol should be avoided, and chronic beta blocker therapy should not routinely be withdrawn prior to surgery.

Patients may also experience an increased risk of hypoglycemia, which can mask early warning signs. In individuals with thyrotoxicosis, abrupt withdrawal of treatment may precipitate a thyroid storm. Furthermore, patients with peripheral vascular disease may find that their symptoms of arterial insufficiency are aggravated. 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, symptoms may include severe bradycardia, hypotension, and cardiogenic shock. Other clinical presentations can involve 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, and cardiogenic shock or decompensated heart failure.

Drug Interactions

There are currently no documented drug interactions associated with this medication. Additionally, there are no known interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are necessary at this time.

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

In a clinical study involving 144 hypertensive pediatric patients aged 6 to 16 years, participants were randomized to receive either placebo or one of three dose levels of metoprolol succinate extended-release tablets (0.2, 1.0, or 2.0 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.

For pediatric patients aged 6 to 16 years, no clinically relevant differences in the adverse event profile were observed when compared to adult patients, indicating a similar safety profile within this age group.

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 efficacy and adverse effects is advised to optimize treatment outcomes 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. Notably, no fetal abnormalities were observed when pregnant rats received metoprolol orally at doses up to 200 mg/kg/day. The estimated background risk of major birth defects and miscarriage for the indicated population remains 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 elevating the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Additionally, 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. It is essential to observe neonates and manage them accordingly. While the published literature has reported inconsistent findings regarding intrauterine growth retardation, preterm birth, and perinatal mortality with maternal use of metoprolol, methodological limitations in these studies hinder definitive interpretation.

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.

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

Patients with renal impairment have not been specifically addressed in terms of dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be prudent in this population to ensure safety and efficacy.

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

In cases of overdose with metoprolol succinate extended-release tablets, healthcare professionals should be vigilant for a range of signs and symptoms. These may include severe bradycardia, hypotension, cardiogenic shock, atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness or coma, as well as gastrointestinal symptoms such as nausea and vomiting.

Management of an overdose may necessitate intensive care, particularly for patients with underlying conditions such as myocardial infarction or heart failure, due to the risk of hemodynamic instability. It is important to note that beta-blocker overdose can lead to significant resistance to resuscitation efforts with adrenergic agents, including beta-agonists.

For patients presenting with bradycardia, it is essential to assess the need for atropine, adrenergic-stimulating drugs, or the placement of a pacemaker. In instances of hypotension resulting from the overdose, addressing the underlying bradycardia is crucial, and intravenous vasopressor infusion, such as dopamine or norepinephrine, should be considered.

In cases where heart failure and shock are present, appropriate management may include volume expansion, glucagon injection, and the intravenous administration of adrenergic drugs like dobutamine. Additionally, bronchospasm that occurs as a result of the overdose can typically be reversed with the use of bronchodilators.

Healthcare professionals are advised to monitor the patient closely and provide supportive care as needed, tailoring interventions to the specific symptoms and clinical status of the individual.

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, 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 are available in the extracted data. As such, there are no additional adverse events or rare case reports to summarize at this time.

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 or engaging in other tasks 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, it is crucial to consult their physician if they notice 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 when metoprolol succinate extended-release tablets are administered to patients who are fasting or vomiting. Lastly, healthcare providers should instruct patients or caregivers on how to monitor for signs of hypoglycemia.

Storage and Handling

The product is supplied in tight containers to ensure integrity and stability. It should be stored at a temperature range of 20° to 25°C (68° to 77°F). Temporary excursions are permissible between 15° to 30°C (59° to 86°F), in accordance with USP Controlled Room Temperature guidelines.

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 BluePoint Laboratories. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)