General Administration Information
For storage information, see the specific product information within the How Supplied section.
Oral Solid Formulations
-Swallow unchewed with a glass of water.
-Administer consistently in relation to meals, preferably with or immediately after a meal.
-Extended-release metoprolol tablets are scored and may be halved; however, swallow whole or half tablet without chewing or crushing.
-Administer consistently in relation to meals, preferably with or immediately after a meal.
Extended-release sprinkle capsules
-Swallow whole. For those with swallowing difficulty, capsules can be opened and contents sprinkled over soft food (e.g., applesauce, pudding, yogurt). Swallow contents of the capsules with a small amount (teaspoonful) of soft food. Swallow drug/food mixture within 60 minutes and do not store for future use.
-Nasogastric tube administration: Open capsule, empty contents into an all-plastic oral tip syringe, and add 15 mL water. Gently shake the syringe for approximately 10 seconds. Promptly deliver through a 12 French or larger nasogastric tube. Ensure no granules are left in the syringe. Rinse with additional water if needed.
Extemporaneous 10 mg/mL Metoprolol Oral Suspension Preparation
-Add 12 metoprolol 100 mg tablets to a glass mortar.
-Break with the pestle, and grind tablets into a fine powder.
-Add approximately 20 mL of the chosen vehicle and mix to a uniform paste. Vehicle choices include: 1) a 1:1 mixture of Ora-Sweet and Ora-Plus 2) a 1:1 mixture of Ora-Sweet SF and Ora-Plus 3) cherry syrup.
-Add geometric portions of the vehicle almost to volume and mix thoroughly after each addition.
-Transfer the contents to a calibrated bottle and add enough vehicle to bring to a total volume of 120 mL.
-Storage: The resulting suspension is reported stable for 60 days at 5 and 25 degrees C when protected from light.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-No dilution necessary.
-Monitor blood pressure, heart rate, and ECG during administration.
The adverse effects of metoprolol are generally mild and temporary; they usually occur at the onset of therapy and diminish over time.
Some cardiovascular adverse reactions of metoprolol are manifestations of its therapeutic effect such as sinus bradycardia, AV block, and hypotension. Congestive heart failure is more likely to occur in patients with preexisting left ventricular dysfunction and usually will respond to discontinuation of metoprolol therapy. Shortness of breath and bradycardia were each reported in about 3% of adult patients receiving metoprolol during controlled clinical trials of angina and hypertension. Less frequent cardiovascular reactions (1%) reported during angina and hypertension trials in adult patients included: palpitations, congestive heart failure, peripheral edema, and hypotension; chest pain (unspecified) and syncope were reported only after use of extended-release metoprolol, but syncope is a possible effect of any dosage form. Adult patients receiving metoprolol during a myocardial infarction trial experienced a higher rate of adverse cardiovascular reactions. Some of the adverse reactions reported during the trial included hypotension (27.4%), bradycardia (15.9%), AV block (4.7% to 5.3%), and heart failure (27.5%). The MERIT-HF study (adult heart failure patients) has reported a 1.5% frequency of bradycardia (vs. 0.4% placebo) with extended-release metoprolol. Increased rates of stroke (1% vs. 0.5%), hypotension (15% vs. 9.7%), bradycardia (6.6% vs. 2.4%), and death (3.1% vs. 2.3%) were seen in a placebo-controlled study of adult patients receiving extended-release metoprolol prior to and for 30 days after non-cardiac surgery. The product labeling recommends that initiation of high dose, extended-release metoprolol tablets be avoided in patients undergoing non-cardiac surgery; however, chronic beta-blocker therapy should not be routinely withdrawn prior to surgery. Sinus bradycardia and hypotension are rarely serious and can be reversed with IV atropine if necessary. AV block, secondary to depressed conduction at the AV node, can necessitate sympathomimetic and/or pressor therapy or use of a temporary pacemaker.
Central nervous system (CNS) adverse reactions can occur with beta-blockers. Fatigue was reported in 2% of pediatric patients receiving extended-release metoprolol for hypertension in a controlled, dose ranging study (n = 142, age 6 to 16 years). In an open-label extension of this study (n = 100), CNS adverse reactions included headache (30%), fatigue (9%), and dizziness (6%). One patient each discontinued metoprolol due to the following CNS adverse reactions: fatigue, nightmares, anxiety, and dizziness. It has been proposed that lipophilic beta-blockers are more likely to be associated with CNS adverse reactions; however, this theory has been debated based on clinical experience with beta-blockers. Metoprolol is moderately lipid-soluble. Metoprolol has been associated with a 5% incidence of depression in adult patients. Other beta-blockers have been associated with reversible mental depression progressing to catatonia; therefore, consider this a possible adverse reaction to metoprolol. Tiredness (drowsiness or fatigue) and dizziness, were each reported in about 1% to 10% of adult patients receiving metoprolol during controlled clinical trials of angina and hypertension. The MERIT-HF study (adult heart failure patients) has reported a higher frequency of dizziness/vertigo (1.8% vs. 1%) with extended-release metoprolol relative to placebo. In this same trial, a higher frequency of accidental trauma/injury (1.4% vs. 0.8%) was reported in adult patients receiving extended-release metoprolol compared to placebo. Metoprolol has also been infrequently associated with headache, nightmares, vertigo, hallucinations, insomnia, confusion, and short-term memory loss (amnesia) during controlled trials in adults. Blurred vision, visual impairment, and tinnitus have also been reported. Somnolence, anxiety/nervousness, and paresthesias have been reported during postmarketing experience with metoprolol.
Diarrhea, nausea, and vomiting are the most common gastrointestinal (GI) adverse reactions reported during therapy with metoprolol. In an open label study of pediatric patients receiving extended-release metoprolol for hypertension (n = 100, ages 6 to 16 years), diarrhea was reported in 7% of patients. Diarrhea has occurred in about 5% of adult patients receiving metoprolol during angina and hypertension controlled trials. Nausea, xerostomia (dry mouth), constipation, flatulence, and pyrosis (heartburn) have been reported in about 1% of patients; abdominal pain or gastric pain was reported in fewer than 1 of 100 patients. Metoprolol has been associated with elevated hepatic enzymes. Postmarketing experience reveals very rare reports of hepatitis, jaundice, and non-specific hepatic dysfunction. Isolated cases of transaminase, alkaline phosphatase, and lactic acid dehydrogenase elevations have also been reported.
Upper respiratory tract infection (20%), cough (19%), naso-pharyngitis (13%), and pharyngolaryngeal pain (12%) were reported in an open-label study of pediatric patients receiving extended-release metoprolol (n = 100, age: 6 to 16 years). One patient discontinued metoprolol due to asthma. Dyspnea (1%), wheezing/bronchospasm (1%), and rhinitis has been reported in metoprolol-treated patients during adult clinical trials. Hypersensitivity reactions manifested by fever combined with an aching and sore throat, laryngospasm, and respiratory distress have been reported with other beta-blockers.
Beta-blockers may inhibit catecholamine-induced glycogenolysis, gluconeogenesis, and lipolysis, predisposing the patient to hypoglycemia. Additionally, beta-blockers can mask signs of hypoglycemia (e.g., tachycardia), which may be particularly detrimental in patients with labile diabetes mellitus. Beta-blockade also reduces the release of insulin in response to hyperglycemia, which may make it necessary to adjust the dose of antidiabetic drugs. Unstable diabetes has been reported with metoprolol use. In addition to acute blood glucose effects, beta-blockers have been shown to increase the risk of developing diabetes mellitus in adult hypertensive patients; this risk should be evaluated relative to the proven benefits of beta-blockers in reducing cardiovascular events.
Agranulocytosis, nonthrombocytopenic purpura, and thrombotic thrombocytopenic purpura (TTP) have been reported in association with beta-blocker use.
Hypertriglyceridemia and decreased plasma HDL concentrations have been reported with postmarketing metoprolol use. A meta-analysis suggested that these effects are less pronounced with cardioselective agents, such as metoprolol, particularly in diabetics. The clinical implications of these effects, in light of other cardiovascular advantages of beta-blocker therapy, are not known.
Peyronie's disease (abnormal curvature of the penis during erection with penile fibrosis) has been reported during postmarketing use of metoprolol.
Rash (5%), pruritus (5%), and reversible alopecia (rare) have been reported in metoprolol-treated patients during adult clinical trials. Very rarely, worsening of psoriasis and photosensitivity have been reported.
Exacerbation of peripheral vasoconstriction (e.g., Raynaud's phenomenon) can occur with metoprolol administration (approximately 1%). Gangrene (with associated tissue necrosis) has been reported very rarely in adult patients with pre-existing severe peripheral circulatory disorders.
Dysgeusia (taste disturbances) or hyperhidrosis (sweating) have been reported during postmarketing experience with metoprolol.
Xerophthalmia or dry eyes have been rarely reported after treatment with metoprolol.
Cases of weight gain, arthritis or arthralgia, retroperitoneal fibrosis, musculoskeletal pain, and claudication have been reported with metoprolol therapy. Some beta-blockers (e.g., atenolol) have been rarely reported to be associated with the development of antinuclear antibodies (ANA) and lupus-like symptoms; however, the incidence of such reactions is thought to be quite rare.
Withdrawal symptoms, including headache, diaphoresis, palpitations, sinus tachycardia, tremor, and hypertension, have been associated with abrupt discontinuation of beta-blockers in hypertensive patients. Gradual tapering and/or prolonged administration of small doses of metoprolol prior to complete cessation may prevent adverse reactions.
Metoprolol is contraindicated in patients with known metoprolol hypersensitivity or hypersensitivity to any of the product excipients. According to the product labeling, metoprolol is also contraindicated in patients with known beta-blocker hypersensitivity. Cross-sensitivity between beta-blockers may occur. Use metoprolol with caution in patients with a history of anaphylactic reactions. These patients may have a more severe reaction if rechallenge to the allergen occurs while receiving a beta-blocker. The patient may also be unresponsive to the usual doses of epinephrine used to treat the reaction.
If metoprolol is to be discontinued, gradually withdraw therapy over 1-2 weeks whenever possible, and instruct patients to avoid significant physical activity during the withdrawal. Abrupt discontinuation of beta-blockers in adult patients has been associated with severe angina, myocardial infarction, ventricular arrhythmias, and hypertension, particularly in patients with preexisting cardiac disease. The clinical significance of this in pediatric patients is unknown. Advise patients and caregivers against interruption or cessation of therapy without the advice of their physician.
Use metoprolol with caution in patients with hyperthyroidism or thyrotoxicosis because the drug can mask tachycardia, which is a useful monitoring parameter in thyroid disease. Abrupt withdrawal of beta-blockers in a patient with hyperthyroidism can precipitate thyroid storm. However, certain beta-blockers are generally useful in the symptomatic treatment of hyperthyroid-related states, like thyrotoxicosis. Beta-blockers can reduce tachycardia, tremor, and anxiety in the hyperthyroid patient.
Because beta-blockers depress conduction through the AV node, metoprolol is contraindicated in patients with severe bradycardia, sick sinus syndrome, or advanced AV block (second or third-degree AV block) unless a functioning pacemaker is present. In general, beta-blockers are contraindicated in patients with cardiogenic shock or acute heart failure, particularly in those with severe left ventricular dysfunction, and should not be used in patients with acute pulmonary edema because the negative inotropic effect of these drugs can further depress cardiac output. In patients with stable, chronic heart failure, however, some beta-blockers, including metoprolol, given in appropriate doses can be beneficial. Beta-blockers have also been used for the treatment of hypertrophic cardiomyopathy. In the treatment of myocardial infarction in adult patients, metoprolol is contraindicated in patients with bradycardia (heart rate < 45 beats/min), hypotension (SBP < 100 mmHg), second or third-degree AV block, significant first-degree heart block (PR interval >= 0.24 sec), or moderate-to-severe heart failure.
Beta-1-selective beta-blockers such as metoprolol are preferred over nonselective agents in patients with asthma or other pulmonary disease (e.g., chronic lung disease (CLD)) in which acute bronchospasm would put them at risk. However, because beta-1-selectivity is not absolute, use the lowest dose of metoprolol in these patients and have bronchodilators (e.g., beta-2 agonists) readily available. For the immediate-release tablets, consider dividing the total daily doses and administering three times daily instead of twice daily to avoid higher plasma concentrations.
Beta-blockers, like metoprolol, may cause dizziness or drowsiness in some patients. Advise patients and their caregivers to use caution when performing activities requiring coordination and concentration (e.g., riding a bicycle) until the response is known.
Beta-blockers have been shown to increase the risk of developing diabetes mellitus in hypertensive adult patients; however, this risk should be evaluated relative to the proven benefits of beta-blockers in reducing cardiovascular events. The potential risk for pediatric patients is not known. Use metoprolol with caution in patients with poorly controlled diabetes mellitus and monitor blood glucose levels closely. Beta-blockers can prolong or enhance hypoglycemia by interfering with glycogenolysis; this effect may be less pronounced with beta-1-selective beta-blockers than with nonselective agents. Beta-blockers can also mask signs of hypoglycemia, especially tachycardia, palpitations, and tremors; in contrast, diaphoresis and the hypertensive response to hypoglycemia are not suppressed with beta-blockade. Beta-blockers can occasionally cause hyperglycemia. This is thought to be due to blockade of beta-2-receptors on pancreatic islet cells, which would inhibit insulin secretion.
The necessity or desirability of withdrawing beta-blockers prior to major surgery is controversial; evaluate the risks versus benefits in individual patients. According to the product labeling, avoid initiating high-dose extended-release metoprolol in patients undergoing non-cardiac surgery because such use in patients with cardiovascular risk factors has been associated with bradycardia, hypotension, stroke, and death. Monitor patients receiving metoprolol before or during surgery involving the use of general anesthetics with negative inotropic effects closely for signs of heart failure. Severe, protracted hypotension and difficulty in restarting the heart have been reported after surgery in patients receiving beta-blockers. Because beta-blocker therapy reduces the ability of the heart to respond to beta-adrenergically mediated sympathetic reflex stimuli, the risks of general anesthesia and surgical procedures may be augmented. Although, gradual withdrawal of beta-blockers is sometimes recommended prior to general anesthesia to limit the potential for hypotension and heart failure, the product labeling does not recommend withdrawal of chronically-administered metoprolol prior to major surgery. The risk of precipitating adverse cardiac events (e.g., myocardial infarction, tachycardia) after preoperative withdrawal of beta-blockers may outweigh the risks of ongoing beta-blocker therapy, particularly in patients with co-existing cardiovascular disease. Consider the type of surgery (e.g., cardiac vs. noncardiac), anesthetic strategy, and co-existing health conditions. The anesthetic technique may be modified to reduce the risk of concurrent beta-blockade. If needed, the negative inotropic effects of beta-blockers may be cautiously reversed by sufficient doses of adrenergic agonists such as isoproterenol, dopamine, dobutamine, or norepinephrine. Vagal dominance, if it occurs, may be corrected with atropine.
Use metoprolol with caution in patients with hepatic disease because drug clearance may be reduced. Metoprolol is extensively metabolized by the liver and dosage adjustments may be required in patients with hepatic impairment. Initiate metoprolol at a low dose in patients with hepatic impairment and gradually increase to optimal clinical response.
Metoprolol immediate-release tablets are contraindicated in patients with severe peripheral arterial circulatory disorders; gangrene has been reported very rarely during metoprolol therapy in such patients. Use metoprolol with caution in patients with Raynaud's phenomenon or peripheral vascular disease because reduced cardiac output and the relative increase in alpha-receptor stimulation can exacerbate symptoms. Use beta-blocker monotherapy with caution in patients with vasospastic angina (Prinzmetal's angina) because of the risk of hypertension secondary to unopposed alpha-receptor stimulation.
Use beta-blocker therapy with caution in patients with a known or suspected pheochromocytoma. If metoprolol is required, give in combination with an alpha-blocker and only after the alpha-blocker has been initiated. Administration of beta-blockers alone in the setting of pheochromocytoma has been associated with paradoxical hypertension due to attenuation of beta-mediated vasodilation.
Although the relationship between depression and beta-blockers has not been definitively established, depression is reported by approximately 5% of adult patients receiving metoprolol. Therefore, metoprolol should be used with caution in patients with pre-existing depression.
Beta-blockers, such as metoprolol, may exacerbate psoriasis.
Beta-blockers, such as metoprolol, may potentiate muscle weakness and double vision in patients with myasthenia gravis. Monitor patients carefully.
Because of potential effects of beta-blockade on blood pressure and pulse, use metoprolol with caution in patients with cerebrovascular insufficiency (cerebrovascular disease) or stroke. If signs or symptoms suggesting reduced cerebral blood flow develop after initiation of beta-blocker, consider alternative therapy.
Description: Metoprolol is a competitive beta1-selective (cardioselective) adrenergic antagonist. It has moderate lipid solubility, lacks intrinsic sympathomimetic activity (ISA), and has weak membrane stabilizing activity (MSA). The degree of lipid solubility effects metoprolol's route of elimination (extensively metabolized) and, theoretically, its potential for central nervous system adverse reactions. Metoprolol has a relatively short elimination half-life compared to other cardioselective beta-blockers. In pediatric patients, it is used for the treatment of hypertension and heart failure. In adult patients with moderate to severe heart failure, treatment with extended-release metoprolol reduced the incidence of sudden death and mortality. Mortality data is not available in pediatric patients receiving metoprolol for the treatment of heart failure; however, several small, uncontrolled studies have shown significant improvements in ejection fraction when metoprolol was added to conventional therapy (digoxin, diuretics, and ACE inhibitors). Extended-release metoprolol is FDA-approved for the treatment of hypertension in pediatric patients as young as 6 years; other formulations of metoprolol are not FDA-approved in pediatric patients.
For the treatment of hypertension:
Oral dosage (immediate-release tablets)*:
Children and Adolescents: 1 to 2 mg/kg/day PO divided twice daily titrated up based on clinical response to a maximum of 6 mg/kg/day PO (Max: 200 mg/day PO).
Oral dosage (extended-release tablets and sprinkle capsules):
Children and Adolescents 6 to 17 years: 1 mg/kg/dose PO once daily (Max: 50 mg) titrated up based on clinical response to a maximum of 2 mg/kg/day PO (Max: 200 mg/day). Of note, the 25 mg tablet can be split in half to provide a 12.5 mg dose.
For the treatment of heart failure* (ischemic origin or cardiomyopathy*) usually in conjunction with digoxin, diuretics, or ACE inhibitor therapy:
Oral dosage (immediate-release tablets):
Children and Adolescents: Initial doses of 0.2 to 0.4 mg/kg/day PO divided twice daily have been used in several small studies (n = 4 to 15, ages 2.5 to 15.6 years). Doses were gradually titrated up to the maximally tolerated dose, ranging from 0.4 to 2.4 mg/kg/day. Patients in these studies were initiated on metoprolol after having received conventional therapy of digoxin, diuretics, and ACE inhibitors without echocardiographic or symptomatic improvement. Over a follow-up period of 1.2 to 102 months, the mean ejection fraction improved significantly.
Maximum Dosage Limits:
Safety and efficacy have not been established.
Safety and efficacy have not been established.
1 to 5 years: Safety and efficacy have not been established. However, up to 6 mg/kg/day PO (Max: 200 mg/day) of the immediate-release tablets has been used off-label for hypertension; up to 2.4 mg/kg/day PO has been used off-label for heart failure.
6 to 12 years: 2 mg/kg/day PO (Max: 200 mg/day) of extended-release metoprolol for hypertension. Safety and efficacy of intravenous or oral immediate-release tablets have not been established. However, up to 6 mg/kg/day PO (Max: 200 mg/day) of the immediate-release tablets has been used off-label for hypertension; up to 2.4 mg/kg/day PO has been used off-label for heart failure.
2 mg/kg/day PO (Max: 200 mg/day) of extended-release metoprolol for hypertension. Safety and efficacy of intravenous or oral immediate-release tablets have not been established. However, up to 6 mg/kg/day PO (Max: 200 mg/day) of the immediate-release tablets has been used off-label for hypertension; up to 2.4 mg/kg/day PO has been used off-label for heart failure.
Patients with Hepatic Impairment Dosing
Initiate therapy at a reduced dosage and carefully titrate to clinical response; quantitative recommendations are not available.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears no dosage adjustments are needed.
Monograph content under development
Mechanism of Action: Metoprolol is a cardioselective (beta1-selective) beta-blocker. At higher concentrations, metoprolol also inhibits beta2-receptors in the bronchial and vascular smooth muscles. The beta-blocking activity of metoprolol results in negative chronotropic and inotropic effects that decrease heart rate and cardiac output, reduction of sympathetic outflow to the periphery, and suppression of renin activity. Equivalent maximal beta-blocking effect is achieved with oral and intravenous doses in the ratio of approximately 2.5:1.
Pharmacokinetics: Metoprolol is widely distributed throughout the body, with a reported volume of distribution of 3.2 to 5.6 L/kg. The drug is approximately 10% to 12% bound to serum albumin. Metoprolol is moderately lipid-soluble; it is more lipid-soluble than atenolol, but less lipid-soluble than propranolol or betaxolol. Metoprolol crosses the blood-brain barrier, with 78% of plasma concentration distributing to cerebrospinal fluid. Metabolism occurs primarily in the liver via CYP2D6. Plasma half-life ranges from approximately 3 to 7 hours. Metabolites do not contribute significantly to metoprolol's beta-blocking effect. Metoprolol is excreted mainly via the kidney; approximately 95% of a dose can be recovered in the urine. In most patients, less than 10% of a dose is excreted as unchanged drug.
Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6
Metoprolol is metabolized predominantly by CYP2D6. Compared to extensive metabolizers, poor metabolizers of CYP2D6 demonstrate a longer half-life (7 to 9 hours vs. 3 to 4 hours) and a larger percentage of the drug is excreted unchanged in the urine (30% to 40% vs. less than 10%).
Absorption is rapid and complete; however, estimated oral bioavailability is only about 50% due to a significant first-pass effect. The pre-systemic metabolism is saturable, leading to a non-proportionate increase in exposure with an increased dose. Significant beta-blockade effect (as measured by reduction of exercise heart rate) occurs within 60 minutes of administration. Duration is variable and dose-related; a 50% reduction of maximum heart rate after single doses of 20, 50, and 100 mg occurs at 3.3, 5, and 6.4 hours, respectively. The antihypertensive effects, however, do not appear to be directly related to plasma concentrations; the full therapeutic effect is generally evident after 1 week of therapy.
Absorption is rapid and complete. At steady state, bioavailability is approximately 77% of the corresponding dose of immediate-release tablets, but beta-blockade is comparable over the 24-hour dosing interval. Peak metoprolol serum concentrations are approximately one-fourth to one-half of those attained with immediate-release tablets, and there is significantly lower peak to trough variation.
Extended-release sprinkle capsules
At steady state, bioavailability is reduced by 25% relative to the corresponding dose of immediate-release tablets. Peak plasma concentrations, attained 10 hours after administration of the capsule, are reduced by 50% to 75% on average in comparison to the corresponding dose of immediate-release tablets. Exposure (Cmax and AUC) of the extended-release capsule is similar to that of the extended-release tablet. Administration with a high-fat, high-calorie meal did not significantly affect absorption. When administered under fasting conditions by sprinkling the contents on applesauce, Tmax, Cmax, and AUC were not significantly altered.
Maximal beta-blockade occurs within 20 minutes after intravenous administration over 10 minutes. The plasma concentrations attained after IV administration are approximately 2.5 times those reached with the immediate-release oral tablet.
Children and Adolescents
The pharmacokinetics of metoprolol are similar in children and adolescents 6 to 17 years of age when compared to adults. Oral clearance increases linearly with body weight.
Due to extensive hepatic metabolism, the elimination half-life of metoprolol is likely to be prolonged (possibly doubled) in hepatic impairment, depending on the severity.
The systemic availability and half-life of metoprolol in patients with renal failure are similar to that of healthy patients. Mean dialytic clearance of metoprolol after oral administration in patients receiving high-flux hemodialysis is 87 mL/minute. Mean total systemic clearance of metoprolol after intravenous administration in patients with chronic renal failure is 1,000 mL/minute.
CYP2D6 Poor Metabolizers
Poor metabolizers of CYP2D6 will have increased metoprolol blood concentrations, which will decrease cardioselectivity. Compared to extensive metabolizers, poor metabolizers demonstrate a longer half-life (7 to 9 hours vs. 3 to 4 hours), and a larger percentage of the drug is excreted unchanged in the urine (30% to 40% vs. less than 10%).