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. The tablets contain 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- (isopropyl amino)-3-p-(2-methoxyethyl) phenoxy-2-propanol succinate (2:1) (salt). It is classified as a white crystalline powder with a molecular weight of 652.8 g/mol. Metoprolol succinate 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. The inactive ingredients in the formulation 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 the management of angina pectoris, metoprolol succinate aids in alleviating symptoms associated with this condition. Additionally, in patients diagnosed with 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 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 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 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 patient's clinical status.

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 ensure patient safety and to adjust treatment as necessary (5.2).

For individuals with bronchospastic disease, the use of beta-blockers is contraindicated due to the risk of bronchospasm. Alternative therapies should be considered for these patients (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. However, chronic beta-blocker therapy should not be routinely withdrawn prior to 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, a life-threatening condition. Caution is advised when discontinuing therapy in this population (5.8).

For individuals with peripheral vascular disease, beta-blockers may exacerbate symptoms of arterial insufficiency. Careful assessment and monitoring of peripheral circulation are recommended (5.9).

Lastly, patients receiving beta-blockers may exhibit reduced responsiveness to standard doses of epinephrine used in the treatment of allergic reactions. Healthcare providers should be aware of this potential interaction and consider alternative management strategies in such 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, 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. Additionally, patients may 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. Peripheral vascular disease may be aggravated, leading to worsened symptoms of arterial insufficiency. It is also 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, 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

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 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 hypertension did not include a sufficient number of subjects aged 65 and over to determine whether these patients respond differently compared to younger individuals. However, other reported 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% (990) of the participants were aged 65 years and older, and 12% (238) were aged 75 years and older. The findings 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 geriatric patients, it is recommended to initiate treatment with a low starting dose in this population. Careful monitoring is advised to ensure safety and efficacy 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 of 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. Therefore, pregnant women with hypertension should be carefully monitored and managed accordingly.

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 appropriately. 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 necessitate careful consideration and monitoring in pregnant patients.

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 amount, 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 may still be warranted as part of routine clinical practice, but specific dosing adjustments are not required based on renal status.

Hepatic Impairment

Patients with hepatic impairment may experience increased blood levels of metoprolol succinate extended-release tablets due to the drug's metabolism by the liver. No studies have been conducted specifically in this population, and as such, caution is advised when prescribing this medication.

It is recommended that therapy be initiated at doses lower than those typically recommended for the intended indication. Additionally, any dose adjustments should be made gradually to monitor the patient's response and tolerance. Regular assessment of liver function may be necessary to ensure safe and effective use of metoprolol succinate extended-release tablets in patients with compromised hepatic function.

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 Overdose

The management of metoprolol overdose may necessitate intensive care, particularly in 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 result in significant resistance to resuscitation efforts with adrenergic agents, including beta-agonists.

In addressing bradycardia, healthcare providers should assess the need for atropine, adrenergic-stimulating drugs, or the placement of a pacemaker. For hypotension, treatment should focus on correcting the underlying bradycardia and may involve the use of intravenous vasopressors, such as dopamine or norepinephrine.

Management of heart failure and shock may include volume expansion, glucagon injection, and the intravenous administration of adrenergic drugs like dobutamine. In cases where vasodilation is present, the use of α1 receptor agonists may also be warranted.

Bronchospasm resulting from an overdose can typically be managed with bronchodilators, which are effective in reversing this condition. It is important to recognize that hemodialysis is unlikely to facilitate the elimination of metoprolol in overdose situations.

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

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 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 postmarketing experience details are available in the provided text.

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, it is crucial to 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.

Healthcare providers should also inform patients or caregivers about the risk of hypoglycemia associated with metoprolol succinate extended-release tablets, particularly in patients who are fasting or 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 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). Temporary excursions are permissible between 15° to 30°C (59° to 86°F), in accordance with USP Controlled Room Temperature guidelines. Proper container requirements must be adhered to, and special handling needs should be followed to ensure product integrity.

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 Ingenus Pharmaceuticals, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)