ypotension. 7.2 epinephrine while taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge and may be unresponsive to the usual doses of epinephrine used to treat an allergic reaction. 7.3 cyp2d6 inhibitors drugs that are strong inhibitors of cyp2d6, such as quinidine, fluoxetine, paroxetine, and propafenone, were shown to double metoprolol concentrations. while there is no information about moderate or weak inhibitors, these too are likely to increase metoprolol concentration. increases in plasma concentration decrease the cardioselectivity of metoprolol [see clinical pharmacology (12.3) ]. monitor patients closely, when the combination cannot be avoided. 7.4 digitalis, clonidine, and calcium channel blockers and other drugs that decrease heart rate digitalis glycosides, clonidine, diltiazem and verapamil slow atrioventricular conduction and decrease heart rate. concomitant administration of beta-blockers with these and other drugs known to decrease heart rate such as sphingosine-1-phosphate receptor modulators (e.g. fingolimod) may result in additive heart rate lowering effects. if clonidine and metoprolol are coadministered, withdraw the metoprolol several days before the gradual withdrawal of clonidine because beta-blockers may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. if replacing clonidine by beta-blocker therapy, delay the introduction of beta-blockers for several days after clonidine administration has stopped . 7.5 drugs that decrease blood pressure concomitant administration of beta-blockers with other drugs known to decrease blood pressure may result in an enhanced hypotensive effect.

ase patients with bronchospastic diseases, in general, should not receive beta-blockers because they can exacerbate bronchospasm. because of its relative beta 1 cardio-selectivity, however, metoprolol may be used in patients with bronchospastic disease for initial treatment of myocardial infarction. bronchodilators, including beta 2 -agonists, should be readily available or administered concomitantly [see dosage and administration (2) ]. 5.4 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. 5.5 peripheral vascular disease beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.

ent with an intravenous administration of three bolus injections of 5 mg each, at approximately 2-minute intervals. monitor blood pressure, heart rate and electrocardiogram ( 2 ). • following administration of metoprolol tartrate injection, transition the patient to an oral formulation of metoprolol ( 2 ).

pproximating rates. 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 a randomized comparison of metoprolol and placebo, the following adverse reactions were reported: metoprolol 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. miscellaneous: unstable diabetes and claudication have been reported. 6.2 post-marketing experience the following adverse reactions have been identified during post-approval use of metoprolol. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. cardiovascular: cold extremities, arterial insufficiency (usually of the raynaud type), palpitations, peripheral edema, syncope, and hypotension. respiratory: wheezing (bronchospasm), dyspnea. central nervous system: confusion, short-term memory loss, headache, nightmares, insomnia, nervousness, hallucinations. gastrointestinal: nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, vomiting. hypersensitive reactions: pruritus. miscellaneous: musculoskeletal pain, arthritis, blurred vision, decreased libido, tinnitus, reversible alopecia, agranulocytosis, dry eyes, worsening of psoriasis, peyronie’s disease, photosensitivity.

ypotension. 7.2 epinephrine while taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge and may be unresponsive to the usual doses of epinephrine used to treat an allergic reaction. 7.3 cyp2d6 inhibitors drugs that are strong inhibitors of cyp2d6, such as quinidine, fluoxetine, paroxetine, and propafenone, were shown to double metoprolol concentrations. while there is no information about moderate or weak inhibitors, these too are likely to increase metoprolol concentration. increases in plasma concentration decrease the cardioselectivity of metoprolol [see clinical pharmacology (12.3) ]. monitor patients closely, when the combination cannot be avoided. 7.4 digitalis, clonidine, and calcium channel blockers and other drugs that decrease heart rate digitalis glycosides, clonidine, diltiazem and verapamil slow atrioventricular conduction and decrease heart rate. concomitant administration of beta-blockers with these and other drugs known to decrease heart rate such as sphingosine-1-phosphate receptor modulators (e.g. fingolimod) may result in additive heart rate lowering effects. if clonidine and metoprolol are coadministered, withdraw the metoprolol several days before the gradual withdrawal of clonidine because beta-blockers may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. if replacing clonidine by beta-blocker therapy, delay the introduction of beta-blockers for several days after clonidine administration has stopped . 7.5 drugs that decrease blood pressure concomitant administration of beta-blockers with other drugs known to decrease blood pressure may result in an enhanced hypotensive effect.

population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical consideration disease-associated maternal and/or embryo/fetal risk hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. pregnant women with hypertension should be carefully monitored and managed accordingly. stroke volume and heart rate increase during pregnancy, increasing cardiac output, especially during the first trimester. there is a risk for preterm birth with pregnant women with chronic heart failure in 3 rd trimester of pregnancy. fetal/neonatal adverse reactions metoprolol crosses the placenta. neonates born to mothers who are receiving metoprolol during pregnancy, may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. observe neonates for symptoms of hypotension, bradycardia, hypoglycemia and respiratory depression and manage accordingly. data human data data from published observational studies did not demonstrate an association of major congenital malformations and use of metoprolol in pregnancy. the published literature has reported inconsistent findings of intrauterine growth retardation, preterm birth and perinatal mortality with maternal use of metoprolol during pregnancy; however, these studies have methodological limitations hindering interpretation. methodological limitations include retrospective design, concomitant use of other medications, and other unadjusted confounders that may account for the study findings including the underlying disease in the mother. these observational studies cannot definitely establish or exclude any drug-associated risk during pregnancy. animal data metoprolol has been shown to increase post-implantation loss and decrease neonatal survival in rats at oral dosages of 500 mg/kg/day, i.e. 24 times, on a mg/m 2 basis, the daily dose of 200 mg in a 60-kg patient. no fetal abnormalities were observed when pregnant rats received metoprolol orally up to a dose of 200 mg/kg/day, i.e. 10 times, the daily dose of 200 mg in a 60-kg patient. 8.2 lactation risk summary limited available data from published literature report that metoprolol is present in human milk. the estimated daily infant dose of metoprolol received from breastmilk range from 0.05 mg to less than 1 mg. the estimated relative infant dosage was 0.5% to 2% of the mother's weight-adjusted dosage (see data). no adverse reactions of metoprolol on the breastfed infant have been identified. there is no information regarding the effects of metoprolol on milk production. clinical consideration monitoring for adverse reactions for a lactating woman who is a slow metabolizer of metoprolol, monitor the breastfed infant for bradycardia and other symptoms of beta blockade such as dry mouth, skin or eyes, diarrhea or constipation. in a report of 6 mothers taking metoprolol, none reported adverse effects in her breastfed infant. data limited published cases estimate the infant daily dose of metoprolol received from breast milk range from 0.05 mg to less than 1 mg. in 2 women who were taking unspecified amount of metoprolol, milk samples were taken after one dose of metoprolol. the estimated amount of metoprolol and alpha-hydroxymetoprolol in breast milk is reported to be less than 2% of the mother's weight-adjusted dosage. in a small study, breast milk was collected every 2 to 3 hours over one dosage interval, in three mothers (at least 3 months postpartum) who took metoprolol of unspecified amount. the average amount of metoprolol present in breast milk was 71.5 mcg/day (range 17.0 to 158.7). the average relative infant dosage was 0.5% of the mother's weight-adjusted dosage. 8.3 females and males of reproductive potential risk summary based on the published literature, beta blockers (including metoprolol) may cause erectile dysfunction and inhibit sperm motility. in animal fertility studies, metoprolol has been associated with reversible adverse effects on spermatogenesis starting at oral dose level of 3.5 mg/kg in rats, which would correspond to a dose of 34 mg/day in humans in mg/m 2 equivalent, although other studies have shown no effect of metoprolol on reproductive performance in male rats. no evidence of impaired fertility due to metoprolol was observed in rats [see nonclinical toxicology (13.1) ]. 8.4 pediatric use safety and effectiveness in pediatric patients have not been established. 8.5 geriatric use in worldwide clinical trials of metoprolol in myocardial infarction, where approximately 478 patients were over 65 years of age (0 over 75 years of age), no age-related differences in safety and effectiveness were found. other reported clinical experience in myocardial infarction has not identified differences in response between the elderly and younger patients. however, greater sensitivity of some elderly individuals taking metoprolol cannot be categorically ruled out. therefore, in general, it is recommended that dosing proceed with caution in this population. 8.6 hepatic impairment no studies have been performed with metoprolol in patients with hepatic impairment. because metoprolol is metabolized by the liver, metoprolol blood levels are likely to increase substantially with poor hepatic function. therefore, initiate therapy at doses lower than those recommended for a given indication.

ideration disease-associated maternal and/or embryo/fetal risk hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. pregnant women with hypertension should be carefully monitored and managed accordingly. stroke volume and heart rate increase during pregnancy, increasing cardiac output, especially during the first trimester. there is a risk for preterm birth with pregnant women with chronic heart failure in 3 rd trimester of pregnancy. fetal/neonatal adverse reactions metoprolol crosses the placenta. neonates born to mothers who are receiving metoprolol during pregnancy, may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. observe neonates for symptoms of hypotension, bradycardia, hypoglycemia and respiratory depression and manage accordingly. data human data data from published observational studies did not demonstrate an association of major congenital malformations and use of metoprolol in pregnancy. the published literature has reported inconsistent findings of intrauterine growth retardation, preterm birth and perinatal mortality with maternal use of metoprolol during pregnancy; however, these studies have methodological limitations hindering interpretation. methodological limitations include retrospective design, concomitant use of other medications, and other unadjusted confounders that may account for the study findings including the underlying disease in the mother. these observational studies cannot definitely establish or exclude any drug-associated risk during pregnancy. animal data metoprolol has been shown to increase post-implantation loss and decrease neonatal survival in rats at oral dosages of 500 mg/kg/day, i.e. 24 times, on a mg/m 2 basis, the daily dose of 200 mg in a 60-kg patient. no fetal abnormalities were observed when pregnant rats received metoprolol orally up to a dose of 200 mg/kg/day, i.e. 10 times, the daily dose of 200 mg in a 60-kg patient.

1 and fvc significantly less than a nonselective beta-blocker, propranolol, at equivalent beta 1 -receptor blocking doses. the precise mechanism of action of metoprolol in patients with suspected or definite myocardial infarction is not known. 12.2 pharmacodynamics 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. 12.3 pharmacokinetics distribution about 12% of the drug is bound to human serum albumin. metoprolol crosses the blood-brain barrier and has been reported in the csf in a concentration 78% of the simultaneous plasma concentration. elimination elimination is mainly by biotransformation in the liver, and the plasma half-life ranges from approximately 3 to 7 hours. metabolism metoprolol is a racemic mixture of r- and s- enantiomers, and is primarily metabolized by cyp2d6. when administered orally, it exhibits stereoselective metabolism that is dependent on oxidation phenotype. excretion less than 5% of an oral dose of metoprolol is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no beta-blocking activity. following intravenous administration of metoprolol, the urinary recovery of unchanged drug is approximately 10%. mean dialytic clearance of metoprolol following oral administration in patients receiving high-flux hemodialysis is 87 ml/min. mean total systemic clearance of metoprolol following intravenous administration in patients with chronic renal failure is 1 l/min. drug interactions cyp2d6 metoprolol is metabolized predominantly by cyp2d6. in healthy subjects with cyp2d6 extensive metabolizer phenotype, coadministration of quinidine 100 mg, a potent cyp2d6 inhibitor, and immediate-release metoprolol 200 mg tripled the concentration of s-metoprolol and doubled the metoprolol elimination half-life. in four patients with cardiovascular disease, coadministration of propafenone 150 mg t.i.d. with immediate-release metoprolol 50 mg t.i.d. resulted in steady-state concentration of metoprolol 2-to 5-fold what is seen with metoprolol alone. extensive metabolizers who concomitantly use cyp2d6 inhibiting drugs will have increased (several-fold) metoprolol blood levels, decreasing metoprolol's cardioselectivity [see drug interactions (7.2) ] . 12.5 pharmacogenomics cyp2d6 is absent in about 8% of caucasians (poor metabolizers) and about 2% of most other populations. cyp2d6 can be inhibited by several drugs. poor metabolizers of cyp2d6 will have increased (several-fold) metoprolol blood levels, decreasing metoprolol's cardioselectivity.

ml/min. mean total systemic clearance of metoprolol following intravenous administration in patients with chronic renal failure is 1 l/min. drug interactions cyp2d6 metoprolol is metabolized predominantly by cyp2d6. in healthy subjects with cyp2d6 extensive metabolizer phenotype, coadministration of quinidine 100 mg, a potent cyp2d6 inhibitor, and immediate-release metoprolol 200 mg tripled the concentration of s-metoprolol and doubled the metoprolol elimination half-life. in four patients with cardiovascular disease, coadministration of propafenone 150 mg t.i.d. with immediate-release metoprolol 50 mg t.i.d. resulted in steady-state concentration of metoprolol 2-to 5-fold what is seen with metoprolol alone. extensive metabolizers who concomitantly use cyp2d6 inhibiting drugs will have increased (several-fold) metoprolol blood levels, decreasing metoprolol's cardioselectivity [see drug interactions (7.2) ] .

ase 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 (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) and 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 24 times, on a mg/m 2 basis, the daily dose of 200 mg in a 60-kg patient.

(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 (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) and 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 24 times, on a mg/m 2 basis, the daily dose of 200 mg in a 60-kg patient.

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.