promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. patients should be warned against interruption or discontinuation of therapy without the physician’s advice. because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue metoprolol therapy abruptly even in patients treated only for hypertension. use during major surgery chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. bradycardia bradycardia, including sinus pause, heart block, and cardiac arrest have occurred with the use of metoprolol. patients with first-degree atrioventricular block, sinus node dysfunction, or conduction disorders may be at increased risk. monitor heart rate and rhythm in patients receiving metoprolol. if severe bradycardia develops, reduce or stop metoprolol. exacerbation of bronchospastic disease patients with bronchospastic disease, should, in general, not receive beta-blockers, including metoprolol. because of its relative beta 1 selectivity, however, metoprolol may be used in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. because beta 1 selectivity is not absolute use the lowest possible dose of metoprolol and consider administering metoprolol in smaller doses three times daily, instead of larger doses two times daily, to avoid the higher plasma levels associated with the longer dosing interval (see dosage & administration ). bronchodilators, including beta 2 agonists, should be readily available or administered concomitantly. diabetes and hypoglycemia beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected. pheochromocytoma if metoprolol tartrate is used in the setting of pheochromocytoma, it should be given 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 a paradoxical increase in blood pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle. thyrotoxicosis metoprolol may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. avoid abrupt withdrawal of beta-blockade, which might precipitate a thyroid storm.

who appear not to tolerate the full intravenous on metoprolol tartrate tablets either 25 mg or 50 mg every 6 hours (depending on the degree of intolerance) 15 minutes after the last intravenous dose or as soon as their clinical condition allows. in patients with severe intolerance, discontinue metoprolol tartrate (see warnings ). special populations pediatric patients no pediatric studies have been performed. the safety and efficacy of metoprolol tartrate in pediatric patients have not been established. renal impairment no dose adjustment of metoprolol tartrate is required in patients with renal impairment. hepatic impairment metoprolol tartrate blood levels are likely to increase substantially in patients with hepatic impairment. therefore, metoprolol tartrate should be initiated at low doses with cautious gradual dose titration according to clinical response. geriatric patients (>65 years) in general, use a low initial starting dose in elderly patients given their greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. method of administration parenteral administration of metoprolol tartrate should be done in a setting with intensive monitoring. note: parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

ings). rhinitis has also been reported. gastrointestinal diarrhea has occurred in about 5 of 100 patients. nausea, dry mouth, gastric pain, constipation, flatulence, and heartburn have been reported in about 1 of 100 patients. vomiting was a common occurrence. postmarketing experience reveals very rare reports of hepatitis, jaundice and non-specific hepatic dysfunction. isolated cases of transaminase, alkaline phosphatase, and lactic dehydrogenase elevations have also been reported. hypersensitive reactions pruritus or rash have occurred in about 5 of 100 patients. very rarely, photosensitivity and worsening of psoriasis has been reported. miscellaneous peyronie’s disease has been reported in fewer than 1 of 100,000 patients. musculoskeletal pain, blurred vision, and tinnitus have also been reported. there have been rare reports of reversible alopecia, agranulocytosis, and dry eyes. discontinuation of the drug should be considered if any such reaction is not otherwise explicable. there have been very rare reports of weight gain, arthritis, and retroperitoneal fibrosis (relationship to metoprolol has not been definitely established). the oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with metoprolol. myocardial infarction these adverse reactions were reported from treatment regimens where intravenous metoprolol was administered, when tolerated. central nervous system tiredness has been reported in about 1 of 100 patients. vertigo, sleep disturbances, hallucinations, headache, dizziness, visual disturbances, confusion, and reduced libido have also been reported, but a drug relationship is not clear. cardiovascular in the randomized comparison of metoprolol and placebo described in the clinical pharmacology section, the following adverse reactions were reported: metoprolol tartrate placebo hypotension (systolic bp < 90 mmhg) 27.4% 23.2% bradycardia (heart rate < 40 beats/min) 15.9% 6.7% second- or third-degree heart block 4.7% 4.7% first-degree heart block (p-r ≥ 0.26 sec) 5.3% 1.9% heart failure 27.5% 29.6% respiratory dyspnea of pulmonary origin has been reported in fewer than 1 of 100 patients. gastrointestinal nausea and abdominal pain have been reported in fewer than 1 of 100 patients. dermatologic rash and worsened psoriasis have been reported, but a drug relationship is not clear. miscellaneous unstable diabetes and claudication have been reported, but a drug relationship is not clear. potential adverse reactions a variety of adverse reactions not listed above have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to metoprolol. central nervous system reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics. cardiovascular intensification of av block (see contraindications). hematologic agranulocytosis, nonthrombocytopenic purpura and thrombocytopenic purpura. hypersensitive reactions fever combined with aching and sore throat, laryngospasm and respiratory distress. postmarketing experience the following adverse reactions have been reported during postapproval use of metoprolol tartrate: confusional state, an increase in blood triglycerides and a decrease in high density lipoprotein (hdl). because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency.

reduced sympathetic outflow to the periphery; and (3) suppression of renin activity. angina pectoris by blocking catecholamine-induced increases in heart rate, in velocity and extent of myocardial contraction, and in blood pressure, metoprolol reduces the oxygen requirements of the heart at any given level of effort, thus making it useful in the long-term management of angina pectoris. myocardial infarction the precise mechanism of action of metoprolol in patients with suspected or definite myocardial infarction is not known. pharmacodynamics relative beta 1 selectivity is demonstrated by the following: (1) in healthy subjects, metoprolol is unable to reverse the beta 2-mediated vasodilating effects of epinephrine. this contrasts with the effect of nonselective (beta 1 plus beta 2) beta-blockers, which completely reverse the vasodilating effects of epinephrine. (2) in asthmatic patients, metoprolol reduces fev 1 and fvc significantly less than a nonselective beta-blocker, propranolol, at equivalent beta 1-receptor blocking doses. metoprolol has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable only at doses much greater than required for beta-blockade. animal and human experiments indicate that metoprolol slows the sinus rate and decreases av nodal conduction. when the drug was infused over a 10-minute period, in normal volunteers, maximum beta-blockade was achieved at approximately 20 minutes. equivalent maximal beta-blocking effect is achieved with oral and intravenous doses in the ratio of approximately 2.5:1. there is a linear relationship between the log of plasma levels and reduction of exercise heart rate. in several studies of patients with acute myocardial infarction, intravenous followed by oral administration of metoprolol caused a reduction in heart rate, systolic blood pressure and cardiac output. stroke volume, diastolic blood pressure and pulmonary artery end diastolic pressure remained unchanged. pharmacokinetics absorption the estimated oral bioavailability of immediate release metoprolol is about 50% because of pre-systemic metabolism which is saturable leading to non-proportionate increase in the exposure with increased dose. distribution metoprolol is extensively distributed with a reported volume of distribution of 3.2 to 5.6 l/kg. about 10% of metoprolol in plasma is bound to serum albumin. metoprolol is known to cross the placenta and is found in breast milk. metoprolol is also known to cross the blood brain barrier following oral administration and csf concentrations close to that observed in plasma have been reported. metoprolol is not a significant p-glycoprotein substrate. metabolism metoprolol is primarily metabolized by cyp2d6. metoprolol is a racemic mixture of r- and s- enantiomers, and when administered orally, it exhibits stereo selective metabolism that is dependent on oxidation phenotype. cyp2d6 is absent (poor metabolizers) in about 8% of caucasians and about 2% of most other populations. poor cyp2d6 metabolizers exhibit several-fold higher plasma concentrations of metoprolol tartrate than extensive metabolizers with normal cyp2d6 activity thereby decreasing metoprolol’s cardioselectivity. elimination elimination of metoprolol is mainly by biotransformation in the liver. the mean elimination half-life of metoprolol is 3 to 4 hours; in poor cyp2d6 metabolizers the half-life may be 7 to 9 hours. approximately 95% of the dose can be recovered in urine. in most subjects (extensive metabolizers), less than 10% of an intravenous dose are excreted as unchanged drug in the urine. in poor metabolizers, up to 30% or 40% of oral or intravenous doses, respectively, may be excreted unchanged; the rest is excreted by the kidneys as metabolites that appear to have no beta blocking activity. the renal clearance of the stereo-isomers does not exhibit stereo-selectivity in renal excretion. special populations geriatric patients the geriatric population may show slightly higher plasma concentrations of metoprolol as a combined result of a decreased metabolism of the drug in elderly population and a decreased hepatic blood flow. however, this increase is not clinically significant or therapeutically relevant. renal impairment the systemic availability and half-life of metoprolol in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. consequently, no reduction in dosage is usually needed in patients with chronic renal failure. hepatic impairment since the drug is primarily eliminated by hepatic metabolism, hepatic impairment may impact the pharmacokinetics of metoprolol. the elimination half-life of metoprolol is considerably prolonged, depending on severity (up to 7.2 h). clinical studies hypertension in controlled clinical studies, metoprolol has been shown to be an effective antihypertensive agent when used alone or as concomitant therapy with thiazide-type diuretics, at oral dosages of 100 to 450 mg daily. in controlled, comparative, clinical studies, metoprolol has been shown to be as effective an antihypertensive agent as propranolol, methyldopa, and thiazide-type diuretics, to be equally effective in supine and standing positions. angina pectoris in controlled clinical trials, metoprolol, administered orally two or four times daily, has been shown to be an effective antianginal agent, reducing the number of angina attacks and increasing exercise tolerance. the oral dosage used in these studies ranged from 100 to 400 mg daily. a controlled, comparative, clinical trial showed that metoprolol was indistinguishable from propranolol in the treatment of angina pectoris. myocardial infarction in a large (1,395 patients randomized), double-blind, placebo-controlled clinical study, metoprolol was shown to reduce 3-month mortality by 36% in patients with suspected or definite myocardial infarction. patients were randomized and treated as soon as possible after their arrival in the hospital, once their clinical condition had stabilized and their hemodynamic status had been carefully evaluated. subjects were ineligible if they had hypotension, bradycardia, peripheral signs of shock, and/or more than minimal basal rales as signs of congestive heart failure. initial treatment consisted of intravenous followed by oral administration of metoprolol or placebo, given in a coronary care or comparable unit. oral maintenance therapy with metoprolol or placebo was then continued for 3 months. after this double-blind period, all patients were given metoprolol and followed up to 1 year. the median delay from the onset of symptoms to the initiation of therapy was 8 hours in both the metoprolol- and placebo-treatment groups. among patients treated with metoprolol, there were comparable reductions in 3-month mortality for those treated early (≤ 8 hours) and those in whom treatment was started later. significant reductions in the incidence of ventricular fibrillation and in chest pain following initial intravenous therapy were also observed with metoprolol and were independent of the interval between onset of symptoms and initiation of therapy. in this study, patients treated with metoprolol received the drug both very early (intravenously) and during a subsequent 3-month period, while placebo patients received no beta-blocker treatment for this period. the study thus was able to show a benefit from the overall metoprolol regimen but cannot separate the benefit of very early intravenous treatment from the benefit of later beta-blocker therapy. nonetheless, because the overall regimen showed a clear beneficial effect on survival without evidence of an early adverse effect on survival, one acceptable dosage regimen is the precise regimen used in the trial. because the specific benefit of very early treatment remains to be defined however, it is also reasonable to administer the drug orally to patients at a later time as is recommended for certain other beta-blockers.