ive chronotropic and inotropic effects.

artrate administration should be reinstated 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 tartrate 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 use during major surgery chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and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 occured with the use of metoprolol tartrate. 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 tartrate. if severe bradycardia develops, reduce or stop metoprolol tartrate. exacerbation of bronchospastic disease patients with bronchospastic disease, should, in general, not receive beta blockers, including metoprolol tartrate. because of its relative beta 1 selectivity, however, metoprolol tartrate 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 tartrate and consider administering metoprolol tartrate 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 and 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 tartrate may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. avoid abrupt withdrawal of beta blockade, which might precipitate a thyroid storm.

ily. start patients who appear not to tolerate the full intravenous dose 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.

tients (see warnings ). 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. post-marketing 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 tartrate has not been definitely established). the oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with metoprolol tartrate. myocardial infarction these adverse reactions were reported from treatment regimens where intravenous metoprolol tartrate 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 tartrate 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 tartrate. 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.

ive chronotropic and inotropic effects.

bout 2% of most other populations. poor cyp2d6 metabolizers exhibit severalfold higher plasma concentrations of metoprolol 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.

lly significant differences were observed between treated and control mice of either sex for any type of tumor. all mutagenicity tests performed (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) were negative. reproduction toxicity studies in mice, rats and rabbits did not indicate teratogenic potential for metoprolol tartrate. embryotoxicity and/or fetotoxicity in rats and rabbits were noted starting at doses of 50 mg/kg in rats and 25 mg/kg in rabbits, as demonstrated by increases in preimplantation loss, decreases in the number of viable fetuses per dose, and/or decreases in neonatal survival. high doses were associated with some maternal toxicity, and growth delay of the offspring in utero, which was reflected in minimally lower weights at birth. the oral noaels for embryo-fetal development in mice, rats, and rabbits were considered to be 25, 200, and 12.5 mg/kg. this corresponds to dose levels that are approximately 0.3, 4, and 0.5 times, respectively, when based on surface area, the maximum human oral dose (8 mg/kg/day) of metoprolol tartrate. metoprolol tartrate has been associated with reversible adverse effects on spermatogenesis starting at oral dose levels of 3.5 mg/kg in rats (a dose that is only 0.1-times the human dose, when based on surface area), although other studies have shown no effect of metoprolol tartrate on reproductive performance in male rats.