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. These tablets are specifically designed to provide a controlled and predictable release of metoprolol, allowing for once-daily dosing. Each tablet contains 47.5 mg of metoprolol succinate, which is equivalent to 50 mg of metoprolol tartrate, USP.

The formulation consists 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. 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, and sparingly soluble in ethanol, while being 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 calcium stearate, carboxymethylcellulose sodium, carnauba wax, croscarmellose sodium, glyceryl behenate, hydrogenated vegetable oil, hypromellose, maltodextrin, methacrylic acid copolymer, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone, sodium stearyl fumarate, titanium dioxide, triacetin, triethyl citrate, and vinyl acetate copolymer. The USP dissolution test for this formulation is currently pending.

Uses and Indications

Metoprolol succinate extended-release tablets are indicated for the treatment of hypertension, either as monotherapy or in combination with other antihypertensive agents. Additionally, these tablets are indicated for the long-term management of angina pectoris.

This medication is also indicated for the treatment of stable, symptomatic heart failure classified as NYHA Class II or III, which may be of ischemic, hypertensive, or cardiomyopathic origin. Clinical studies have demonstrated that metoprolol succinate extended-release tablets, when administered to patients already receiving ACE inhibitors, diuretics, and, in most cases, digitalis, significantly reduce the rate of mortality and hospitalization. This effect is primarily attributed to a decrease in cardiovascular mortality and hospitalizations related to heart failure.

No teratogenic or nonteratogenic effects have been reported for metoprolol succinate extended-release tablets.

Dosage and Administration

Metoprolol succinate extended-release tablets are designed for once daily administration.

For the treatment of hypertension and angina, when transitioning from immediate-release metoprolol to metoprolol succinate extended-release tablets, the same total daily dose should be maintained.

The usual initial dosage for hypertension is 25 to 100 mg daily, administered as a single dose, whether used alone or in conjunction with a diuretic. The dosage may be increased at weekly intervals or longer until optimal blood pressure reduction is achieved.

For angina pectoris, the usual initial dosage is 100 mg daily, given in a single dose. This dosage may be gradually increased at weekly intervals until the desired clinical response is obtained or until there is a significant slowing of the heart rate.

In patients with heart failure, the recommended starting dose is 25 mg once daily for two weeks in those with NYHA Class II heart failure, and 12.5 mg once daily for patients with more severe heart failure. The dose should be doubled every two weeks to the highest level tolerated by the patient, not exceeding 200 mg of metoprolol succinate extended-release tablets.

Metoprolol succinate extended-release tablets are scored and can be divided; however, the whole or half tablet must be swallowed whole and should not be chewed or crushed.

Contraindications

Metoprolol succinate extended-release tablets are contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, and sick sinus syndrome unless a permanent pacemaker is in place. Additionally, use is contraindicated in individuals who are hypersensitive to any component of this product. These contraindications are based on the potential for exacerbating cardiac conditions and adverse reactions.

Warnings and Precautions

Following abrupt cessation of therapy with certain beta-blocking agents, including metoprolol succinate extended-release tablets, there is a risk of exacerbations of angina pectoris and, in some cases, myocardial infarction. It is imperative that when discontinuing metoprolol succinate, particularly in patients with ischemic heart disease, the dosage is gradually reduced over a period of 1 to 2 weeks. During this time, patients should be closely monitored. Should there be a marked worsening of angina or the development of acute coronary insufficiency, the administration of metoprolol succinate should be reinstated promptly, at least temporarily, and appropriate measures for managing unstable angina should be implemented. Patients must be advised against interrupting or discontinuing therapy without consulting their physician. Given the prevalence of coronary artery disease, which may often go unrecognized, it is advisable to avoid abrupt discontinuation of metoprolol succinate therapy even in patients being treated solely for hypertension.

Metoprolol succinate extended-release tablets should be administered with caution in individuals with impaired hepatic function. In patients diagnosed with pheochromocytoma, it is essential to initiate an alpha-blocking agent prior to the introduction of any beta-blocking agent. During the up-titration of metoprolol succinate, there is a potential for worsening cardiac failure. If such symptoms arise, it is recommended to increase diuretic therapy and refrain from advancing the dose of metoprolol succinate until clinical stability is achieved. In some cases, it may be necessary to lower the dose or temporarily discontinue the medication. However, these episodes do not preclude the possibility of successful subsequent titration of metoprolol succinate.

Clinical laboratory evaluations may reveal elevated levels of serum transaminase, alkaline phosphatase, and lactate dehydrogenase. Regular monitoring of these parameters is advised to ensure patient safety during treatment with metoprolol succinate extended-release tablets.

Side Effects

Adverse reactions associated with metoprolol succinate extended-release tablets have been observed in clinical trials and postmarketing experiences, categorized by seriousness and frequency.

Serious adverse reactions include potential exacerbations of ischemic heart disease following abrupt cessation of therapy. Patients may experience worsening angina pectoris or, in some cases, myocardial infarction. It is recommended that the dosage be gradually reduced over a period of 1 to 2 weeks in patients with ischemic heart disease, with careful monitoring for any significant changes in angina or acute coronary insufficiency.

Common adverse reactions reported in clinical trials include central nervous system effects such as tiredness and dizziness, occurring in approximately 10% of patients, and depression, reported in about 5% of patients. Other central nervous system effects include mental confusion, short-term memory loss, headache, somnolence, nightmares, and insomnia. Cardiovascular reactions such as shortness of breath and bradycardia were noted in about 3% of patients, while cold extremities, arterial insufficiency (Raynaud type), palpitations, congestive heart failure, peripheral edema, syncope, chest pain, and hypotension were reported in about 1% of patients.

Respiratory adverse reactions, including wheezing (bronchospasm) and dyspnea, were reported in about 1% of patients. Gastrointestinal reactions such as diarrhea occurred in about 5% of patients, with nausea, dry mouth, gastric pain, constipation, flatulence, digestive tract disorders, and heartburn reported in about 1% of patients. Hypersensitive reactions, including pruritus or rash, were observed in about 5% of patients, with worsening of psoriasis also reported.

Additional adverse reactions include musculoskeletal pain, blurred vision, decreased libido, tinnitus, and rare occurrences of reversible alopecia, agranulocytosis, and dry eyes. In the MERIT-HF study, dizziness/vertigo (1.8%), bradycardia (1.5%), and accidents/injuries (1.4%) were reported at higher rates in the metoprolol group compared to placebo.

Postmarketing experiences have revealed serious cardiovascular events such as 2nd and 3rd degree heart block and cardiogenic shock in patients with acute myocardial infarction. Other postmarketing adverse reactions include gastrointestinal issues like hepatitis and vomiting, hematologic concerns such as thrombocytopenia, musculoskeletal complaints like arthralgia, and nervous system/psychiatric effects including anxiety, hallucinations, and paresthesia. Reproductive issues such as impotence and skin reactions like increased sweating, photosensitivity, and urticaria have also been reported. Disturbances in taste have been noted among special sense organ reactions.

Patients with a history of severe anaphylactic reactions may exhibit increased reactivity to allergens while on beta-blockers and may not respond to standard doses of epinephrine used for treatment.

Drug Interactions

Catecholamine-depleting drugs, such as reserpine and monoamine oxidase (MAO) inhibitors, may exhibit an additive effect when administered alongside beta-blocking agents, including metoprolol succinate extended-release tablets. Patients receiving this combination should be closely monitored for signs of hypotension or significant bradycardia, which may lead to symptoms such as vertigo, syncope, or postural hypotension.

Inhibitors of CYP2D6, including quinidine, fluoxetine, paroxetine, and propafenone, have the potential to elevate metoprolol concentrations. In studies involving healthy subjects with the CYP2D6 extensive metabolizer phenotype, the coadministration of quinidine (100 mg) with immediate-release metoprolol (200 mg) resulted in a threefold increase in the concentration of S-metoprolol and a doubling of the metoprolol elimination half-life. Additionally, in patients with cardiovascular disease, the combination of propafenone (150 mg t.i.d.) with immediate-release metoprolol (50 mg t.i.d.) led to two- to five-fold increases in the steady-state concentration of metoprolol. Such elevations in plasma concentration may reduce the cardioselectivity of metoprolol.

The concomitant use of digitalis glycosides and beta-blockers is associated with a heightened risk of bradycardia due to their shared effects of slowing atrioventricular conduction and decreasing heart rate.

Furthermore, beta-blockers may worsen rebound hypertension that can occur following the withdrawal of clonidine. In cases where both medications are prescribed, it is advisable to discontinue the beta-blocker several days prior to the gradual tapering of clonidine. If a beta-blocker is to replace clonidine therapy, the initiation of the beta-blocker should be postponed for several days after the cessation of clonidine administration.

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

Safety and effectiveness of metoprolol succinate have not been established in pediatric patients under 6 years of age. Due to AstraZeneca's marketing exclusivity rights, this generic drug product is not labeled for pediatric use. However, pediatric use information is approved for AstraZeneca's metoprolol succinate extended-release tablets.

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 they respond differently from younger subjects. However, other reported clinical experiences in hypertensive patients have not identified significant differences in responses between elderly patients and their younger counterparts.

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 indicated no notable differences in efficacy or the rate of adverse events between older and younger patients.

In general, dose selection for geriatric patients should be approached with caution. It is advisable to start at the low end of the dosing range, taking into account the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies. Regular monitoring of these patients is recommended to ensure safety and efficacy.

Pregnancy

Metoprolol tartrate is classified as a Pregnancy Category C medication. Animal studies have demonstrated that metoprolol tartrate can increase post-implantation loss and decrease neonatal survival in rats at doses up to 22 times the daily dose of 200 mg in a 60 kg patient, based on a mg/m² comparison. Additionally, distribution studies in mice indicate that the fetus is exposed to metoprolol tartrate when administered to pregnant animals.

While these studies have not shown evidence of impaired fertility or teratogenicity, there are no adequate and well-controlled studies in pregnant women. Therefore, due to the potential risks observed in animal studies and the lack of human data, metoprolol tartrate should be used during pregnancy only if the benefits clearly outweigh the risks. Healthcare professionals are advised to carefully consider the necessity of this medication in pregnant patients.

Lactation

Metoprolol is excreted in breast milk in very small quantities. An infant consuming 1 liter of breast milk daily would receive a dose of less than 1 mg of the drug. Caution should be exercised when metoprolol succinate extended-release tablets are administered to a nursing woman.

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 of these patients.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to this medication. Consequently, there are no dosage adjustments, special monitoring requirements, or precautions outlined 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 prescribing information.

Overdosage

In cases of overdosage with metoprolol succinate extended-release tablets, there have been limited reports, and specific overdosage data for this formulation is not well-documented. However, it is important to note that metoprolol succinate contains the same active ingredient, metoprolol, as conventional metoprolol tablets. Therefore, the recommendations for managing overdosage of conventional metoprolol tablets are applicable to metoprolol succinate extended-release tablets.

Potential Symptoms of Overdosage

Overdosage may result in a range of serious symptoms, including but not limited to:

• Severe hypotension

• Sinus bradycardia

• Atrioventricular block

• Heart failure

• Cardiogenic shock

• Cardiac arrest

• Bronchospasm

• Impairment of consciousness or coma

• Nausea and vomiting

• Cyanosis

Management Procedures

In the event of suspected overdosage, immediate medical attention is required. Healthcare professionals should monitor the patient closely for the aforementioned symptoms. Supportive care should be initiated, and specific interventions may include:

• Administration of intravenous fluids to manage hypotension.

• Use of atropine or other agents to counteract bradycardia or heart block.

• Consideration of cardiac pacing in cases of severe bradycardia or heart block.

• Bronchodilators may be necessary for bronchospasm.

• Continuous monitoring of vital signs and cardiac function is essential.

Given the potential severity of symptoms associated with overdosage, prompt recognition and management are critical to ensure patient safety and mitigate adverse effects.

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. Similarly, metoprolol succinate was also tested in a Salmonella/mammalian-microsome mutagenicity test with 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

The following adverse reactions have been reported in worldwide postmarketing experience with metoprolol succinate extended-release tablets, regardless of causality.

Cardiovascular events include 2nd and 3rd degree heart block and cardiogenic shock in patients with acute myocardial infarction. Gastrointestinal reactions consist of hepatitis and vomiting. Hematologic events reported include thrombocytopenia. Musculoskeletal issues such as arthralgia have also been noted.

Nervous system and psychiatric reactions include anxiety/nervousness, hallucinations, and paresthesia. In the reproductive system, cases of impotence have been reported in males. Dermatological reactions include increased sweating, photosensitivity, and urticaria. Additionally, disturbances in taste have been observed in the special sense organs.

Patient Counseling

Patients should be advised to take metoprolol succinate regularly and continuously, as directed, preferably with or immediately following meals. It is important for patients to understand that if a dose is missed, they should take only the next scheduled dose without doubling it.

Patients must not interrupt or discontinue metoprolol succinate extended-release tablets without first consulting their physician. Healthcare providers should emphasize the importance of adherence to the prescribed regimen.

Patients should be cautioned against 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.

In the event of any difficulty in breathing, patients should be instructed to contact their physician promptly. Additionally, patients 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 experience signs or symptoms of worsening heart failure, such as weight gain or increasing shortness of breath.

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 20°-25°C (68°-77°F), as defined by the United States Pharmacopeia (USP) guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Clinical laboratory findings in patients may reveal elevated levels of serum transaminase, alkaline phosphatase, and lactate dehydrogenase. Clinicians should consider these parameters when evaluating patient health and treatment responses.

FDA Insert (PDF)

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

View full prescribing information (PDF)