Metoprolol succinate

Description

Metoprolol succinate is a beta 1-selective (cardioselective) adrenoceptor blocking agent intended for oral administration, available as extended-release tablets. These tablets are formulated 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 numerous controlled release granules, with each granule functioning as an independent drug delivery unit designed to deliver metoprolol continuously throughout the dosage interval.

The tablets are available in two strengths, containing 95 mg and 190 mg of metoprolol succinate, which is equivalent to 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 provided in the official documentation. Metoprolol succinate, USP is characterized as a white crystalline powder with a molecular weight of 652.8.

It exhibits solubility properties as follows: 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, diethyl ether, and heptane. The formulation includes inactive ingredients such as colloidal silicon dioxide, crospovidone, ethylcellulose, ethylene glycol and vinyl alcohol graft copolymer, glycerol monocaprylocaprate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, povidone, talc, titanium dioxide, and triethyl citrate. Notably, the formulation contains no ingredients derived from gluten-containing grains (wheat, barley, or rye) and meets the USP Dissolution Test 7.

Uses and Indications

Metoprolol Succinate Extended-Release Tablets USP, containing metoprolol succinate, are indicated for the treatment of the following conditions:

Hypertension This drug is indicated for the management of hypertension. Lowering blood pressure with metoprolol succinate reduces the risk of both fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions.

Angina Pectoris Metoprolol succinate is also indicated for the treatment of angina pectoris, providing symptomatic relief and improving exercise tolerance.

Heart Failure This medication is indicated for the treatment of heart failure. It has been shown to reduce the risk of cardiovascular mortality and hospitalizations due to heart failure in affected patients.

Limitations of Use There are no teratogenic or nonteratogenic effects associated with metoprolol succinate as per the available data.

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 mg or 25 mg.

When switching from immediate-release metoprolol to Metoprolol Succinate Extended-Release Tablets, the same total daily dose of Metoprolol Succinate Extended-Release Tablets 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 cases of cardiogenic shock or decompensated heart failure, as these conditions may exacerbate the patient's clinical status.

Warnings and Precautions

Abrupt cessation of beta-blocker therapy may lead to exacerbation of myocardial ischemia. Therefore, it is crucial for healthcare professionals to consider the potential risks associated with sudden discontinuation of treatment.

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, beta-blockers should be avoided due to the potential for bronchospasm. Alternative therapies should be considered to manage these patients effectively.

Concomitant use 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 surgery, particularly non-cardiac procedures, 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 with diabetes should be aware that beta-blockers may increase the risk of hypoglycemia and can mask the early warning signs of low blood sugar. Regular monitoring of blood glucose levels is recommended for these patients.

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

For patients 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, it is important to note that patients receiving beta-blockers may be unresponsive to the usual doses of epinephrine used for the treatment of allergic reactions. Healthcare professionals should consider alternative treatment strategies in these cases.

Side Effects

Patients receiving treatment with Metoprolol Succinate Extended-Release Tablets 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 observed. 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 the use of beta-blockers due to the potential for bronchospasm. Additionally, the concomitant use of glycosides, clonidine, diltiazem, and verapamil with beta-blockers may increase the risk of bradycardia.

In patients with pheochromocytoma, it is recommended to initiate therapy with an alpha-blocker prior to starting beta-blocker treatment. During major surgery, the initiation of high-dose extended-release metoprolol should be avoided, and chronic beta-blocker therapy should not routinely be withdrawn before surgery. Patients with a history of hypoglycemia may experience an increased risk for hypoglycemia and may have masked early warning signs. Abrupt withdrawal in patients with thyrotoxicosis could precipitate a thyroid storm, and those with peripheral vascular disease may find that 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. Contraindications for the use of Metoprolol Succinate Extended-Release Tablets 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.

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.

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 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 during the withdrawal period of clonidine in patients who are also receiving beta-blockers to manage any potential hypertensive episodes effectively.

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) 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 age group, no clinically relevant differences in the adverse event profile were observed when comparing pediatric patients to 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 years and older to determine whether these elderly patients respond differently compared to younger individuals. However, other clinical experiences in hypertensive patients have not identified 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 Extended-Release Tablets, 50% of the participants were aged 65 years and older, and 12% were 75 years of age 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 greater frequency of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies in elderly patients, it is generally recommended to initiate treatment with a low starting dose in this population. Careful monitoring is advised to ensure safety and efficacy 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/m 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, 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. Pregnant women with hypertension should be carefully monitored and managed accordingly, as stroke volume and heart rate increase during pregnancy, leading to increased cardiac output, particularly during the first trimester. Additionally, there is 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 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 average amount of 71.5 mcg/day (range 17.0 to 158.7 mcg). The estimated relative infant dosage is 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 providers monitor the breastfed infant for bradycardia and other symptoms of beta-blockade, such as listlessness (hypoglycemia). There is no information regarding the effects of metoprolol on milk production. In two women taking unspecified amounts of metoprolol, the estimated amount of metoprolol and alpha-hydroxy metoprolol in breast milk was reported to be less than 2% of the mother’s weight-adjusted dosage.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding 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 lack of information necessitates careful clinical judgment and monitoring.

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 may present with a range of severe clinical symptoms. The most notable signs include severe bradycardia, hypotension, and cardiogenic shock. Additional manifestations 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 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 enhance the elimination of metoprolol from the body. Therefore, supportive care and the aforementioned interventions are critical in managing an overdose situation 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 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

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.

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 adverse reactions encompass nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, and vomiting. Hypersensitive reactions have included pruritus. Miscellaneous events reported are 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.

Additionally, there are potential adverse reactions not specifically listed above that have been associated with other beta-adrenergic blocking agents, which may also be relevant for Metoprolol Succinate Extended-Release Tablets. These include central nervous system effects such as reversible mental depression progressing to catatonia, and an acute reversible syndrome 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. Hypersensitive reactions may also involve laryngospasm and respiratory distress.

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 take only the next scheduled dose and should not double the dose.

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 necessity of maintaining communication regarding any changes in medication regimen.

Patients should be cautioned 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 fully determined. Additionally, patients should be instructed to contact their physician if they experience any difficulty in breathing. They should also 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 advise them to consult their physician if they notice any signs or symptoms of worsening heart failure, such as weight gain or increasing shortness of breath.

Lastly, healthcare providers should inform patients or their caregivers about the risk of hypoglycemia associated with Metoprolol Succinate Extended-Release Tablets, particularly in patients who are fasting or experiencing vomiting. Patients and caregivers should be instructed on how to monitor for signs of hypoglycemia to ensure timely intervention if necessary.

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 permitted between 15° to 30°C (59° to 86°F). Proper storage conditions are essential to maintain the integrity of the product.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)