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 formulated to ensure a controlled and predictable release of metoprolol, allowing for once-daily dosing. Each tablet contains metoprolol succinate in a multiple unit system composed of numerous controlled-release pellets, with each pellet functioning as an independent drug delivery unit designed to provide continuous metoprolol release 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-(isopropylamino)-3-p-(2-methoxyethyl) phenoxy-2-propanol succinate (2:1) (salt), and its structural formula is represented as follows:

Metoprolol succinate appears as a white crystalline powder with a molecular weight of 652.8 g/mol. It exhibits solubility characteristics of being 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 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. It is important to note that metoprolol succinate does not comply with the dissolution test outlined in the USP monograph for extended-release tablets.

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.

Dosages of metoprolol succinate extended-release tablets must be individualized, and titration may be necessary for some patients.

For hypertension, the usual initial dosage 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.

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

For 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 then be doubled every two weeks to the highest level tolerated by the patient, not exceeding 200 mg of metoprolol succinate extended-release tablets.

Patients should swallow the whole or half tablet whole, without chewing or crushing.

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 treatment with an alpha-blocking agent prior to the introduction of any beta-blocking agent.

During the up-titration of metoprolol succinate extended-release tablets, 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 titration of metoprolol succinate in the future.

Clinical laboratory evaluations may reveal elevated levels of serum transaminase, alkaline phosphatase, and lactate dehydrogenase, which should be monitored as part of the patient's ongoing assessment.

Side Effects

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

Central nervous system effects are among the most commonly reported adverse reactions. Approximately 10% of patients have experienced tiredness and dizziness, while about 5% reported depression. Other neurological symptoms include mental confusion, short-term memory loss, headaches, somnolence, nightmares, and insomnia. In rare cases, reversible mental depression may progress to catatonia, characterized by disorientation, emotional lability, and decreased performance on neuropsychometric tests.

Cardiovascular adverse reactions have also been noted, with shortness of breath and bradycardia occurring in about 3% of patients. Other cardiovascular issues, including cold extremities, arterial insufficiency (often of the Raynaud type), palpitations, congestive heart failure, peripheral edema, syncope, chest pain, and hypotension, have been reported in approximately 1% of patients. In the MERIT-HF study, dizziness/vertigo (1.8%), bradycardia (1.5%), and accidents/injuries (1.4%) were more prevalent in the metoprolol group compared to placebo. Additional cardiovascular events with an incidence greater than 1% included myocardial infarction, pneumonia, cerebrovascular disorders, and aggravated dyspnea.

Respiratory adverse reactions, such as wheezing (bronchospasm) and dyspnea, have been reported in about 1% of patients. Gastrointestinal disturbances, including diarrhea (5%) and other symptoms like nausea, dry mouth, gastric pain, constipation, flatulence, and heartburn, have been noted in approximately 1% of patients.

Hypersensitive reactions, including pruritus or rash, have occurred in about 5% of patients, with worsening of psoriasis also reported. Rare adverse reactions include Peyronie's disease (fewer than 1 in 100,000 patients), musculoskeletal pain, blurred vision, decreased libido, tinnitus, and reversible alopecia. Postmarketing experiences have revealed additional cardiovascular issues such as 2nd and 3rd degree heart block and cardiogenic shock in patients with acute myocardial infarction.

Hematologic reactions, including agranulocytosis, nonthrombocytopenic purpura, and thrombocytopenic purpura, have been reported. Gastrointestinal adverse events such as hepatitis and vomiting, as well as musculoskeletal complaints like arthralgia, have also been documented. Neurological and psychiatric effects, including anxiety, hallucinations, and paresthesia, have been noted in postmarketing reports. Reproductive issues, such as impotence, and skin reactions like increased sweating, photosensitivity, and urticaria have been observed. Disturbances in taste have also been reported.

A boxed warning highlights the risk of exacerbations of angina pectoris and, in some cases, myocardial infarction following abrupt cessation of therapy with beta-blocking agents. It is recommended that the dosage of metoprolol succinate extended-release tablets be gradually reduced over a period of 1 to 2 weeks in patients with ischemic heart disease, with careful monitoring during this process.

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. When these medications are used together, 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 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 events between older and younger patients.

In general, dose selection for geriatric patients should be approached with caution. It is recommended 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 and assessment of the patient's response to treatment are advised to ensure safety and efficacy in this population.

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. Given that animal reproduction studies may not always predict human outcomes, metoprolol tartrate should be used during pregnancy only if the potential benefits justify the potential risks to the fetus. 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 no specific information regarding dosage adjustments, special monitoring, or safety considerations provided in the text. Therefore, healthcare professionals should exercise caution and consider individual patient factors when prescribing to this population. Regular monitoring of renal function may be warranted in patients with reduced kidney function to ensure safety and efficacy.

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 available beyond animal toxicology studies. However, due to the pharmacological similarities between metoprolol succinate (metoprolol succinate salt) and conventional metoprolol tablets (metoprolol tartrate salt), the overdosage recommendations for conventional metoprolol tablets are applicable to metoprolol succinate extended-release tablets.

Potential Symptoms of Overdosage

Overdosage may result in a range of serious clinical manifestations, 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 warranted. Healthcare professionals should monitor the patient closely for the aforementioned symptoms and initiate appropriate supportive measures. Management may include the administration of intravenous fluids, vasopressors for hypotension, and atropine for bradycardia. In cases of severe bronchospasm, bronchodilators may be indicated. Continuous cardiac monitoring is recommended to detect any arrhythmias or other cardiac complications that may arise.

Prompt recognition and intervention are critical to mitigate the potential life-threatening effects of metoprolol succinate extended-release tablet overdosage.

Nonclinical Toxicology

Long-term studies in animals have been conducted to evaluate the carcinogenic potential of metoprolol tartrate. In two-year studies involving rats at three oral dosage levels of up to 800 mg/kg/day, which is 41 times the daily dose of 200 mg for a 60-kg patient on a mg/m² basis, there was no increase in the development of spontaneously occurring benign or malignant neoplasms of any type. The only histologic changes observed that were related to the drug included a mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia.

In a separate 21-month study conducted in Swiss albino mice at three oral dosage levels of up to 750 mg/kg/day, equivalent to 18 times the daily dose of 200 mg for a 60-kg patient on a mg/m² basis, benign lung tumors (small adenomas) were found to occur more frequently in female mice receiving the highest dose compared to 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 study was subsequently repeated in CD-1 mice, where 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, yielded negative results. Additionally, metoprolol succinate was also tested in a Salmonella/mammalian-microsome mutagenicity test, which returned negative results as well.

No evidence of impaired fertility due to metoprolol tartrate was observed in a study performed in rats at doses up to 22 times the daily dose of 200 mg for a 60-kg patient on a mg/m² basis.

Postmarketing Experience

Postmarketing experience has identified several adverse events reported voluntarily or through surveillance programs.

Cardiovascular events include cases of 2nd and 3rd degree heart block and cardiogenic shock in patients experiencing acute myocardial infarction. Gastrointestinal events reported consist of hepatitis and vomiting. Hematologic events include instances of thrombocytopenia.

Musculoskeletal events have been noted, specifically arthralgia. In the nervous system and psychiatric categories, reports of anxiety or nervousness, hallucinations, and paresthesia have been documented.

In the reproductive system, male patients have reported impotence. Dermatological events include increased sweating, photosensitivity, and urticaria. Additionally, disturbances in taste have been reported under 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.

Healthcare providers should emphasize that patients must not interrupt or discontinue metoprolol succinate extended-release tablets without first consulting their physician. Additionally, 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 fully determined.

Patients should be instructed to contact their physician if they experience any difficulty in breathing. Furthermore, it is essential for patients to 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 any 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 25°C (77°F), with permissible excursions between 15° and 30°C (59° and 86°F) as outlined 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 potential laboratory abnormalities when evaluating patients.

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)