Metoprolol succinate

Uses and Indications

Metoprolol succinate extended-release tablets are indicated for the treatment of:

Hypertension

Metoprolol succinate is indicated to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. It may be used alone or in combination with other antihypertensive agents.

Angina Pectoris

Metoprolol succinate is indicated for the long-term treatment of angina pectoris.

Heart Failure

Metoprolol succinate is indicated for the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. It has been studied in patients already receiving ACE inhibitors, diuretics, and, in the majority of cases, digitalis. In this population, metoprolol succinate decreased the rate of mortality plus hospitalization, largely through a reduction in cardiovascular mortality and hospitalizations for heart failure.

Limitations of Use

There are no teratogenic or nonteratogenic effects mentioned for metoprolol succinate.

Dosage and Administration

Metoprolol succinate extended-release tablets are intended for once daily administration. The dosing should be individualized, and titration may be necessary based on patient response.

For hypertension, the usual initial dosage is 25 to 100 mg once daily. The dosage may be increased at weekly or longer intervals until optimal blood pressure reduction is achieved. Dosages above 400 mg per day have not been studied.

For angina pectoris, the usual initial dosage is 100 mg once daily. The dosage may be gradually increased at weekly intervals until an optimal clinical response is obtained or until there is an unacceptable bradycardia.

In the case of heart failure, the recommended starting dose is 25 mg once daily for patients 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 dosage level tolerated by the patient or up to 200 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 used.

The whole or half tablet should be swallowed whole and not chewed or crushed.

Contraindications

Metoprolol succinate is contraindicated in patients with known hypersensitivity to any component of the product. It should not be used in individuals with severe bradycardia, which includes conditions such as heart block greater than first degree or sick sinus syndrome without a permanent pacemaker. Additionally, the use of metoprolol succinate is contraindicated in cases of cardiogenic shock or decompensated heart failure.

Warnings and Precautions

Abrupt Cessation of Therapy Abrupt cessation of metoprolol succinate may exacerbate myocardial ischemia. Patients should be warned against interruption or discontinuation of therapy without the physician’s advice, particularly those with ischemic heart disease. When discontinuing therapy, the dosage should be gradually reduced over a period of 1 to 2 weeks, and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, metoprolol administration should be reinstated promptly.

Heart Failure Worsening cardiac failure may occur during treatment with metoprolol succinate. Close monitoring is required, especially during dose adjustments.

Bronchospastic Disease Metoprolol succinate should be avoided in patients with bronchospastic disease, as beta-blockers can exacerbate respiratory conditions.

Pheochromocytoma In patients with pheochromocytoma, therapy should be initiated with an alpha-blocker prior to the use of any beta-blocking agent.

Major Surgery High-dose extended-release metoprolol should not be initiated in patients undergoing non-cardiac surgery due to the risk of bradycardia, hypotension, stroke, and death. Chronic beta-blocker therapy should not be routinely withdrawn prior to surgery.

Hypoglycemia Metoprolol succinate may increase the risk of hypoglycemia and can mask the early warning signs of hypoglycemia, such as tachycardia, particularly in diabetic patients.

Thyrotoxicosis Abrupt withdrawal of metoprolol in patients with thyrotoxicosis may precipitate a thyroid storm.

Peripheral Vascular Disease Patients with peripheral vascular disease may experience aggravated symptoms of arterial insufficiency while on metoprolol succinate.

Anaphylactic Reactions Patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

Concomitant Use with Other Medications Caution should be exercised when using metoprolol succinate in conjunction with glycosides, clonidine, diltiazem, and verapamil, as these combinations can increase the risk of bradycardia.

Hepatic Impairment Metoprolol succinate should be used with caution in patients with impaired hepatic function.

Monitoring Requirements Clinical laboratory findings may include elevated levels of serum transaminase, alkaline phosphatase, and lactate dehydrogenase. Regular monitoring of these parameters is recommended during treatment.

Side Effects

Patients receiving metoprolol succinate may experience a range of adverse reactions, which can be categorized by frequency and seriousness.

Most Common Adverse Reactions

The following adverse reactions have been reported frequently (≥2% incidence):

• Tiredness

• Dizziness

• Depression

• Shortness of breath

• Bradycardia

• Hypotension

• Diarrhea

• Pruritus

• Rash

Serious Adverse Reactions

• Heart Failure: Worsening cardiac failure may occur.

• Ischemic Heart Disease: Abrupt cessation of therapy may exacerbate angina pectoris and, in some cases, lead to myocardial infarction. It is recommended that the dosage be gradually reduced over a period of 1 to 2 weeks when discontinuing therapy, particularly in patients with ischemic heart disease.

• Bronchospastic Disease: Patients with this condition should avoid beta-blockers.

• Pheochromocytoma: Therapy should be initiated with an alpha blocker.

• Major Surgery: High-dose extended-release metoprolol should not be initiated in patients undergoing non-cardiac surgery, and chronic beta-blocker therapy should not be routinely withdrawn prior to surgery.

• Hypoglycemia: Metoprolol may mask the early warning signs of hypoglycemia.

• Thyrotoxicosis: Abrupt withdrawal in patients with thyrotoxicosis might precipitate a thyroid storm.

• Peripheral Vascular Disease: Symptoms of arterial insufficiency may be aggravated.

Additional Adverse Reactions

• Central Nervous System: Mental confusion, short-term memory loss, headache, somnolence, nightmares, and insomnia have been reported.

• Cardiovascular: Cold extremities, palpitations, congestive heart failure, peripheral edema, syncope, and chest pain have been noted.

• Respiratory: Wheezing (bronchospasm) and dyspnea have been reported.

• Gastrointestinal: Nausea, dry mouth, gastric pain, constipation, flatulence, digestive tract disorders, and heartburn have been observed.

• Hypersensitive Reactions: Pruritus or rash, worsening of psoriasis, and rare reports of reversible alopecia, agranulocytosis, and dry eyes have been documented.

• Miscellaneous: Musculoskeletal pain, blurred vision, decreased libido, and tinnitus have also been reported.

Overdosage

Overdosage of metoprolol succinate may lead to severe bradycardia, hypotension, and cardiogenic shock. Clinical presentations can include:

• Atrioventricular block

• Heart failure

• Bronchospasm

• Hypoxia

• Impairment of consciousness/coma

• Nausea and vomiting

Contraindications

Metoprolol succinate is contraindicated in patients with:

• Known hypersensitivity to product components

• Severe bradycardia (greater than first-degree heart block or sick sinus syndrome without a pacemaker)

• Cardiogenic shock

• Decompensated heart failure

Fetal/Neonatal Adverse Reactions

Neonates born to mothers receiving metoprolol during pregnancy may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. Monitoring and management of these conditions are advised.

Drug Interactions

Catecholamine-depleting drugs, such as reserpine and monoamine oxidase (MAO) inhibitors, may have an additive effect when administered with beta-blocking agents like metoprolol. Patients receiving metoprolol succinate extended-release tablets in conjunction with these agents should be closely monitored for signs of hypotension or significant bradycardia, which could lead to vertigo, syncope, or postural hypotension.

Inhibitors of the CYP2D6 enzyme, including quinidine, fluoxetine, paroxetine, and propafenone, are likely to increase the concentration of metoprolol. Clinical studies have demonstrated that coadministration of quinidine with metoprolol can significantly elevate the plasma levels of metoprolol, potentially reducing its cardioselectivity. For instance, in healthy subjects, the combination of quinidine and metoprolol resulted in a threefold increase in the concentration of S-metoprolol and a doubling of its elimination half-life. In patients with cardiovascular conditions, the use of propafenone alongside metoprolol has been associated with two- to five-fold increases in steady-state concentrations of metoprolol.

Concomitant use of digitalis glycosides and beta-blockers can also slow atrioventricular conduction and decrease heart rate, thereby increasing the risk of bradycardia. Additionally, beta-blockers, including metoprolol, may exacerbate rebound hypertension following the withdrawal of clonidine. If these two medications are used together, it is recommended that the beta-blocker be discontinued several days prior to the gradual withdrawal of clonidine. If a beta-blocker is to replace clonidine therapy, its initiation should be delayed for several days after stopping clonidine.

Overall, careful monitoring and consideration of these interactions are essential when prescribing metoprolol succinate, particularly in patients receiving other medications that may influence its pharmacokinetics or pharmacodynamics.

Pediatric Use

One hundred forty-four hypertensive pediatric patients aged 6 to 16 years were randomized to placebo or to one of three dose levels of metoprolol succinate extended-release (0.2, 1, or 2 mg/kg once daily) and followed for 4 weeks. The study did not meet its primary endpoint of dose response for reduction in systolic blood pressure (SBP). However, some pre-specified secondary endpoints demonstrated effectiveness, including:

• Dose-response for reduction in diastolic blood pressure (DBP).

• A significant change in SBP with 1 mg/kg versus placebo.

• A significant change in both SBP and DBP with 2 mg/kg versus placebo.

The mean placebo-corrected reductions in SBP ranged from 3 to 6 mmHg, and DBP from 1 to 5 mmHg. The mean reduction in heart rate ranged from 5 to 7 bpm, with considerably greater reductions observed in some individuals.

No clinically relevant differences in the adverse event profile were observed for pediatric patients aged 6 to 16 years compared with adult patients. Safety and effectiveness of metoprolol succinate extended-release tablets have not been established in patients younger than 6 years of age.

For pediatric hypertensive patients aged 6 years and older, the recommended starting dose of metoprolol succinate extended-release is 1 mg/kg once daily, with a maximum initial dose not exceeding 50 mg once daily. Dosage should be adjusted according to blood pressure response, and doses above 2 mg/kg (or in excess of 200 mg) once daily have not been studied in this population.

Geriatric Use

Clinical studies of metoprolol succinate extended-release in hypertension have not included sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. However, other clinical experience in hypertensive patients has not identified significant differences in responses between elderly and younger patients. In the MERIT-HF trial, which included 1,990 patients with heart failure, 50% (990) were aged 65 years and older, and 12% (238) were aged 75 years and older. The trial found 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 recommended to use a low initial starting dose for this population. Careful monitoring and dose adjustments may be necessary to ensure safety and efficacy in geriatric patients.

Pregnancy

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 metoprolol use 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.

Untreated hypertension and heart failure during pregnancy can lead to adverse outcomes for both the mother and the fetus. Hypertension increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications, such as the need for cesarean section and postpartum hemorrhage. Additionally, hypertension poses a fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

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, approximately 24 times the daily dose of 200 mg in a 60-kg patient on a mg/m² basis. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, 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.

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 recommended that neonates be observed and managed accordingly. Data from published observational studies did not demonstrate an association of major congenital malformations with the use of metoprolol in pregnancy. However, the published literature has reported inconsistent findings regarding intrauterine growth retardation, preterm birth, and perinatal mortality, with methodological limitations hindering interpretation. These limitations include retrospective design, concomitant use of other medications, and unadjusted confounders that may account for the study findings, including the underlying disease in the mother. Consequently, these observational studies cannot definitively establish or exclude any drug-associated risk during pregnancy.

In summary, metoprolol should be used during pregnancy only if clearly needed, and careful monitoring of both maternal and fetal health is essential.

Lactation

Metoprolol is excreted in breast milk in very small quantities. The estimated daily infant dose of metoprolol received from breast milk ranges from 0.05 mg to less than 1 mg, which corresponds to an estimated relative infant dosage of 0.5% to 2% of the mother's weight-adjusted dosage. In a small study, the average amount of metoprolol present in breast milk was 71.5 mcg/day (range 17 to 158.7 mcg), with the average relative infant dosage remaining at 0.5% of the mother's weight-adjusted dosage.

No adverse reactions of metoprolol on breastfed infants have been identified, and there is no information regarding its effects on milk production. However, it is recommended that healthcare providers monitor breastfed infants for potential symptoms of beta blockade, such as bradycardia and listlessness, which may indicate hypoglycemia.

Caution should be exercised when administering metoprolol succinate extended-release tablets to nursing women, particularly for those who are slow metabolizers of the drug. Additionally, 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, close observation and management of these neonates are advised.

Renal Impairment

Patients with renal impairment do not require dosage adjustments when using metoprolol succinate. The systemic availability and half-life of metoprolol in individuals with renal failure are not significantly different from those in patients with normal renal function. Consequently, no reduction in dosage is necessary for patients with chronic renal failure.

Overall, there is no specific information provided regarding the need for special monitoring or additional safety considerations for patients with kidney problems. Therefore, standard dosing practices may be followed without modification in this patient population.

Hepatic Impairment

Patients with hepatic impairment may experience increased blood levels of metoprolol due to its hepatic metabolism. Consequently, it is recommended to initiate therapy at lower doses than those typically prescribed for the intended indication. Doses should be increased gradually, taking into account the patient's response and tolerance.

No specific studies have been conducted to evaluate the pharmacokinetics of metoprolol succinate in patients with hepatic impairment. Therefore, careful monitoring of these patients is advised to avoid potential adverse effects associated with elevated drug levels.

For further details, healthcare professionals should refer to the full prescribing information.

Overdosage

Overdosage of metoprolol succinate extended-release tablets may lead to severe bradycardia, hypotension, and cardiogenic shock. Clinical presentations can also include atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness or coma, nausea, and vomiting.

Management of overdose should involve intensive care, particularly for patients with myocardial infarction or heart failure, as they may experience significant hemodynamic instability. It is important to note that beta-blocker overdose can result in considerable resistance to resuscitation with adrenergic agents, including beta-agonists.

The following measures are recommended based on the pharmacologic actions of metoprolol:

• Hemodialysis: This is unlikely to significantly contribute to the elimination of metoprolol.

• Bradycardia: Evaluate the need for atropine, adrenergic-stimulating drugs, or a pacemaker to address bradycardia and conduction disorders.

• Hypotension: Treat the underlying bradycardia and consider intravenous vasopressor infusion, such as dopamine or norepinephrine.

• Heart Failure and Shock: These conditions may be treated with suitable volume expansion, injection of glucagon (if necessary, followed by an intravenous infusion of glucagon), and intravenous administration of adrenergic drugs such as dobutamine. In cases of vasodilation, α1 receptor agonistic drugs may be added.

• Bronchospasm: This can usually be reversed by bronchodilators.

Consultation with a regional poison control center and a medical toxicologist is advisable for further guidance in managing severe cases of overdose.

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, as well as tests on metoprolol succinate (a Salmonella/mammalian-microsome mutagenicity test), were negative.

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.

Storage and Handling

Metoprolol Succinate is supplied in various packaging configurations, including bottles and blister packs. The extended-release tablets are available in film-coated forms and are typically supplied in the following quantities:

• 25 mg and 50 mg tablets are supplied in bottles of 100, 500, and 1,000.

• Additional configurations include 30 tablets in blister packs and 90 tablets in plastic bottles.

The storage conditions for Metoprolol Succinate are as follows:

• Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) See USP Controlled Room Temperature.

• It is important to protect the product from moisture and to preserve it in tight containers as defined in the USP.

Handling requirements include:

• Do not use if the blister is torn or broken.

• Keep this and all medications out of the reach of children.

• Dispense in a tight, light-resistant container using a child-resistant closure when applicable.