METOPROLOL TARTRATE (Generic for LOPRESSOR)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Oral Solid Formulations
Immediate-release tablets

-Swallow unchewed with a glass of water.
-Administer consistently in relation to meals, preferably with or immediately after a meal.

Extended-release tablets
-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 Compounding-Oral
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.



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-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.

Hypotension (27.4%), bradycardia (1.5% to 15.9%), AV block (4.7% to 5.3%), heart failure (27.5%), and shortness of breath (3%) were reported in metoprolol-treated patients during adult clinical trials. Palpitations, congestive heart failure, peripheral edema, and hypotension were reported in approximately 1% of patients. Gangrene in patients with pre-existing severe peripheral circulatory disorders has rarely been reported. Cold extremities, arterial insufficiency (usually Raynaud's phenomenon), syncope, and chest pain (unspecified) have been reported with postmarketing use. 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 before, and for 30 days after, noncardiac surgery.

Headache (30%), fatigue (2% to 9%), and dizziness (6%) were reported in a pediatric dose-ranging study for extended-release metoprolol. One patient each discontinued metoprolol due to fatigue, nightmares, anxiety, or dizziness. It has been proposed that lipophilic beta-blockers are more likely to be associated with central nervous system reactions; however, this theory has been debated based on clinical experience. Metoprolol is moderately lipid-soluble. In adult patients, metoprolol has been associated with a 5% incidence of depression; reversible mental depression progressing to catatonia has been reported with other beta-blocker use. Tiredness/drowsiness (1% to 10%), and dizziness (10%) were reported in metoprolol-treated patients during adult clinical trials. Vertigo, sleep disturbances, insomnia, nightmares, hallucinations, headache, visual impairment, confusion, and short-term memory loss (amnesia) have also been reported during clinical trials. Anxiety or nervousness, paresthesias, visual impairment, blurred vision, tinnitus have been reported with postmarketing use. An acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, clouded sensorium, and decreased neuropsychometrics has been associated with other beta-blockers.

Diarrhea was reported in 7% of patients in an open-label study of pediatric patients receiving extended-release metoprolol (n = 100, age: 6 to 16 years). Diarrhea was reported in 5% of patients, while nausea, abdominal pain, xerostomia, abdominal pain, constipation, flatulence, and pyrosis (heartburn) have been reported in approximately 1% of adult patients during clinical trials. Vomiting was also common. Hepatitis, jaundice, and nonspecific hepatic dysfunction have been reported with postmarketing use. Isolated cases of elevated hepatic enzymes (transaminase, alkaline phosphatase, and lactic dehydrogenase) 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) and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in persons with diabetes or children and persons who are fasting (i.e., surgery, not eating regularly, or are vomiting). Persons should be instructed to seek emergency treatment if severe hypoglycemia occurs. 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 (an abnormal curvature of the penis during erection with penile fibrosis) has been reported in fewer than 1 in 100,000 patients receiving metoprolol therapy. In adult males, impotence (erectile dysfunction), has also been reported.

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. Abrupt withdrawal of metoprolol in patients with coronary artery disease may result in exacerbation of angina, myocardial infarction, or ventricular dysrhythmias. When discontinuing chronically administered oral metoprolol, gradually reduce the dose over 1 to 2 weeks. Carefully observe the patient and advise them to limit physical activity. If angina significantly worsens or acute coronary insufficiency develops, reintroduce metoprolol, at least temporarily, and institute other measures appropriate for the management of unstable angina.

Metoprolol is contraindicated in patients with hypersensitivity to metoprolol or any of the product excipients or those 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.

Abrupt discontinuation of metoprolol in patients with coronary artery disease may result in exacerbation of angina, myocardial infarction, or ventricular dysrhythmias. When discontinuing chronically administered oral metoprolol, gradually reduce the dose over 1 to 2 weeks. Carefully observe the patient and advise them to limit physical activity. If angina significantly worsens or acute coronary insufficiency develops, reintroduce metoprolol, at least temporarily, and institute other measures appropriate for the management of unstable angina. The clinical significance of this in pediatric patients is unknown.

Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Abrupt withdrawal of beta-blockade might precipitate a thyroid storm; therefore, monitor patients for signs of thyrotoxicosis when withdrawing beta-blocking therapy.

Metoprolol is contraindicated in patients with severe bradycardia, second- or third-degree AV block, cardiogenic shock, decompensated heart failure, and sick sinus syndrome unless a functioning pacemaker is present. The negative inotropic effects produced by beta-blockers can exacerbate heart failure; although use should be avoided in decompensated heart failure, labetalol can be used with caution in stable patients. If symptoms occur, increase diuretics. It may be necessary to dose reduce or temporarily discontinue metoprolol. Patients with first-degree AV block, sinus node dysfunction, or conduction disorders may be at increased risk of bradycardia, including sinus pause, heart block, and cardiac arrest. Monitor heart rate and rhythm and dose reduce or discontinue metoprolol if severe bradycardia develops. When used for the treatment of myocardial infarction in adult patients, metoprolol is contraindicated in patients with bradycardia (heart rate less than 45 bpm), hypotension (systolic blood pressure less than 100 mmHg), second or third-degree AV block unless a functioning pacemaker is present, significant first-degree heart block (PR interval of 0.24 seconds or more), or decompensated heart failure.

In general, patients with bronchospastic disease (e.g., asthma, chronic lung disease (CLD), bronchitis) should not receive beta-blockers. However, cardioselective beta-blockers such as metoprolol are preferred over nonselective agents if other antihypertensive treatment is not effective or cannot be tolerated. Because beta1-selectivity is not absolute, use the lowest possible dose and have bronchodilators (e.g., beta2-agonists) readily available. For the immediate-release tablets, consider administering the total daily dose in 3 increments instead of 2 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 may inhibit catecholamine-induced glycogenolysis, gluconeogenesis, and lipolysis, predisposing to hypoglycemia. Additionally, beta-blockers can mask signs of hypoglycemia (e.g., tachycardia) and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in persons with diabetes or children and persons who are fasting (i.e., surgery, not eating regularly, or are vomiting). Persons should be instructed to seek emergency treatment if severe hypoglycemia occurs. Beta-blockade also reduces the release of insulin in response to hyperglycemia, which may make it necessary to adjust the dose of antidiabetic drugs. 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.

Do not routinely withdraw chronic beta-blocker therapy before surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may increase the risk of surgical procedures and general anesthesia. Avoid initiation of a high-dose regimen of extended-release metoprolol undergoing noncardiac surgery; use in such patients with cardiovascular risk factors has been associated with bradycardia, hypotension, stroke, and death. Evaluate the risks versus benefits in individual patients by considering the type of surgery (e.g., cardiac vs. noncardiac), coexisting health conditions, and anesthetic strategy. Guidelines recommend continuance in patients already on beta-blocker therapy; however, initiation well before a planned procedure and careful perioperative titration to achieve adequate heart rate control while avoiding significant bradycardia or hypotension are suggested.

Consider initiating metoprolol at doses lower than those recommended in patients with hepatic disease; gradually titrate to optimal clinical response and monitor for adverse events. Metoprolol is extensively metabolized by the liver and blood concentrations are likely to increase substantially in those with hepatic impairment.

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. Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.

If metoprolol is used in the setting of pheochromocytoma, give it in combination with an alpha-blocker, and only after the alpha-blocker has been initiated. Beta-blocker monotherapy is associated with a paradoxical hypertensive response due to the attenuation of beta-mediated vasodilation in the skeletal muscle.

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 (Max: 200 mg/day).
Oral dosage (extended-release tablets and sprinkle capsules):
Children and Adolescents 6 to 17 years: 1 mg/kg/dose (Max: 50 mg/dose) PO once daily titrated up based on clinical response to a maximum of 2 mg/kg/day (Max: 200 mg/day).

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: 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.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
1 to 5 years: Safety and efficacy have not been established; however, up to 6 mg/kg/day (Max: 200 mg/day) PO of the immediate-release formulation has been used off-label.
6 to 12 years: 2 mg/kg/day (Max: 200 mg/day) PO of the extended-release formulation. Safety and efficacy of other dosage forms have not been established; however, up to 6 mg/kg/day (Max: 200 mg/day) PO of the immediate-release formulation has been used off-label.
-Adolescents
2 mg/kg/day (Max: 200 mg/day) PO of the extended-release formulation. Safety and efficacy of other dosage forms have not been established; however, up to 6 mg/kg/day (Max: 200 mg/day) PO of the immediate-release formulation has been used off-label.

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.

*non-FDA-approved indication

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%).


-Route-Specific Pharmacokinetics
Oral Route
Immediate-release tablets
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.

Extended-release tablets
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.

Intravenous Route
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.


-Special Populations
Pediatrics
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.

Hepatic Impairment
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.

Renal Impairment
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.

Other
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%).