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#REDIRECT [[Metoprolol tartrate#Warnings]]
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<font color="#F8F8FF">'''WARNING'''</font>
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<font color="#F8F8FF" size="1">''See full prescribing information for complete boxed warning.''</font>
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<b><font color="#F8F8FF">
Ischemic Heart Disease: Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing chronically administered Lopressor, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1-2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, Lopressor 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 Lopressor therapy abruptly even in patients treated only for hypertension.
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===Warnings===
 
====Hypertension and Angina====
 
'''Cardiac Failure''': [[Sympathetic]] stimulation is a vital component supporting circulatory function in [[congestive heart failure]], and [[beta blockade]] carries the potential hazard of further depressing myocardial [[contractility]] and precipitating more severe [[heart failure|failure]].
 
'''In Patients Without a History of Cardiac Failure''': Continued depression of the myocardium with [[beta-blocking agents]] over a period of time can, in some cases, lead to [[cardiac failure]]. At the first sign or symptom of impending [[cardiac failure]], fully [[digitalization|digitalize]] patients and/or give a [[diuretic]]. The response should be observed closely. If [[cardiac failure]] continues, despite adequate [[digitalization]] and [[diuretic]] therapy, withdraw Lopressor.
 
'''Bronchospastic Diseases''': PATIENTS WITH [[BRONCHOSPASTIC DISEASES]] SHOULD, IN GENERAL, NOT RECEIVE [[beta blocker|BETA BLOCKERS]], including Lopressor. Because of its relative [[beta-1]] selectivity, however, Lopressor may be used with caution in patients with [[bronchospastic disease]] who do not respond to, or cannot tolerate, other [[antihypertensive]] treatment. Since [[beta-1]] selectivity is not absolute, a [[beta2]]-stimulating agent should be administered concomitantly, and the lowest possible dose of Lopressor should be used. In these circumstances it would be prudent initially to administer Lopressor 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 [[Lopressor dosage and administration|Dosage and Administration]])''.
 
'''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.
 
'''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 Lopressor 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 blocker]]s 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''': [[Beta-adrenergic]] blockade may mask certain clinical signs (e.g., [[tachycardia]]) of [[hyperthyroidism]]. Avoid abrupt withdrawal of [[beta blockade]], which might precipitate a [[thyroid storm]].
 
====Myocardial Infarction====
 
'''Cardiac Failure''': [[Sympathetic]] stimulation is a vital component supporting circulatory function, and [[beta blockade]] carries the potential hazard of depressing myocardial [[contractility]] and precipitating or exacerbating minimal [[cardiac failure]].
 
During treatment with Lopressor, monitor the [[hemodynamics|hemodynamic]] status of the patient. If [[heart failure]] occurs or persists despite appropriate treatment, discontinue Lopressor.
 
'''Bradycardia''': Lopressor produces a decrease in sinus [[heart rate]] in most patients; this decrease is greatest among patients with high initial [[heart rate]]s and least among patients with low initial [[heart rate]]s. [[Acute myocardial infarction]] (particularly [[inferior MI|inferior infarction]]) may in itself produce significant lowering of the sinus rate. If the sinus rate decreases to <40 beats/min, particularly if associated with evidence of lowered [[cardiac output]], [[atropine]] (0.25-0.5 mg) should be administered intravenously. If treatment with [[atropine]] is not successful, discontinue Lopressor and consider cautious administration of [[isoproterenol]] or installation of a [[cardiac pacemaker]].
 
'''AV Block''': Lopressor slows AV conduction and may produce significant [[First degree AV block|first]]- ([[PR interval]] ≥0.24 sec), [[Second degree AV block|second]]-, or [[Third degree AV block|third-degree heart block]]. [[Acute myocardial infarction]] also produces [[heart block]].
 
If heart block occurs, discontinue Lopressor and administer [[atropine]] (0.25-0.5 mg) intravenously. If treatment with [[atropine]] is not successful, consider administration of [[isoproterenol]] or installation of a [[cardiac pacemaker]].
 
'''Hypotension''': If [[hypotension]] ([[systolic blood pressure]] ≤90 mmHg) occurs, discontinue Lopressor, and assess the hemodynamic status of the patient and the extent of myocardial damage. Invasive monitoring of [[central venous pressure|central venous]], [[pulmonary capillary wedge pressure|pulmonary capillary wedge]], and [[arterial pressure]]s may be required. Institute appropriate therapy with fluids, positive [[inotropic agent]]s, [[balloon counterpulsation]], or other treatment modalities. If [[hypotension]] is associated with [[sinus bradycardia]] or [[AV block]], direct treatment at reversing these (see above).
 
===Precautions===
 
====General====
 
Start at a low dose and uptitrate slowly in patients with impaired [[Liver function tests|hepatic function]].
 
====Information for Patients====
 
Advise patients to take Lopressor regularly and continuously, as directed, with or immediately following meals. If a dose should be missed, the patient should take only the next scheduled dose (without doubling it). Patients should not discontinue Lopressor without consulting the physician.
 
Advise patients to:
 
* Avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient’s response to therapy with Lopressor has been determined.
 
* Contact the physician if any difficulty in breathing occurs.
 
* Inform the physician or dentist before any type of surgery that he or she is taking Lopressor.
 
====Drug Interactions====
 
======Catecholamine-depleting drugs======
 
[[Catecholamine]]-depleting drugs (e.g., [[reserpine]]) may have an additive effect when given with [[beta-blocking agents]] or [[monoamine oxidase]] (MAO) inhibitors.
 
Observe patients treated with Lopressor plus a catecholamine depletor for evidence of [[hypotension]] or marked [[bradycardia]], which may produce [[vertigo]], [[syncope]], or [[postural hypotension]]. In addition, possibly significant [[hypertension]] may theoretically occur up to 14 days following discontinuation of the concomitant administration with an irreversible MAO inhibitor.
 
======Digitalis glycosides and beta blockers======
 
Both [[digitalis glycoside]]s and [[beta blocker]]s slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of [[bradycardia]]. Monitor [[heart rate]] and [[PR interval]].
 
======Calcium channel blockers======
 
Concomitant administration of a beta-adrenergic antagonist with a [[calcium channel blocker]] may produce an additive reduction in myocardial [[contractility]] because of negative [[chronotropic]] and [[inotropic]] effects.
 
======Risk of Anaphylactic Reaction======
 
While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of [[allergens]] may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of [[epinephrine]] used to treat allergic reaction.
 
======General Anesthetics======
 
Some inhalation [[anesthetics]] may enhance the cardiodepressant effect of [[beta blocker]]s ''(see WARNINGS, Major Surgery)''.
 
======CYP2D6 Inhibitors======
 
Potent inhibitors of the [[CYP]]2D6 enzyme may increase the plasma concentration of Lopressor which would mimic the pharmacokinetics of CYP2D6 poor metabolizer ''(see [[Lopressor clinical pharmacology#Pharmacokinetics|pharmacokinetics]] section)''. Increase in plasma concentrations of metoprolol would decrease the cardioselectivity of metoprolol. Known clinically significant potent inhibitors of CYP2D6 are [[antidepressants]] such as [[fluvoxamine]], [[fluoxetine]], [[paroxetine]], [[sertraline]], [[bupropion]], [[clomipramine]], and [[desipramine]]; [[antipsychotics]] such as [[chlorpromazine]], [[fluphenazine]], [[haloperidol]], and [[thioridazine]]; [[antiarrhythmics]] such as [[quinidine]] or [[propafenone]]; antiretrovirals such as [[ritonavir]]; [[antihistamines]] such as [[diphenhydramine]]; [[antimalarials]] such as [[hydroxychloroquine]] or [[quinidine]]; [[antifungals]] such as [[terbinafine]].
 
======Hydralazine======
 
Concomitant administration of [[hydralazine]] may inhibit presystemic metabolism of metoprolol leading to increased concentrations of metoprolol.
 
======Alpha-adrenergic agents======
 
[[Antihypertensive]] effect of [[alpha-adrenergic blocker]]s such as [[guanethidine]], [[betanidine]], [[reserpine]], alpha-[[methyldopa]] or [[clonidine]] may be potentiated by [[beta-blocker]]s including Lopressor. [[Beta-adrenergic blocker]]s may also potentiate the postural hypotensive effect of the first dose of [[prazosin]], probably by preventing [[reflex tachycardia]]. On the contrary, beta adrenergic blockers may also potentiate the hypertensive response to withdrawal of [[clonidine]] in patients receiving concomitant [[clonidine]] and [[beta-adrenergic blocker]]. If a patient is treated with [[clonidine]] and Lopressor concurrently, and clonidine treatment is to be discontinued, stop Lopressor several days before clonidine is withdrawn. Rebound [[hypertension]] that can follow withdrawal of clonidine may be increased in patients receiving concurrent beta-blocker treatment.
 
======Ergot alkaloid======
 
Concomitant administration with [[beta-blocker]]s may enhance the [[vasoconstriction|vasoconstrictive]] action of [[ergot alkaloids]].
 
======Dipyridamole======
 
In general, administration of a [[beta-blocker]] should be withheld before [[dipyridamole]] testing, with careful monitoring of heart rate following the [[dipyridamole]] injection.
 
====Carcinogenesis, Mutagenesis, Impairment of Fertility====
 
Long-term studies in animals have been conducted to evaluate carcinogenic potential. In a 2-year study in rats at three oral dosage levels of up to 800 mg/kg per day, there was no increase in the development of spontaneously occurring benign or malignant [[neoplasm]]s of any type. The only histologic changes that appeared to be drug related were an increased incidence of generally mild focal accumulation of foamy [[macrophages in pulmonary [[alveoli]] and a slight increase in biliary [[hyperplasia]]. In a 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg per day, benign lung tumors (small [[adenoma]]s) occurred more frequently in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (benign plus malignant) lung tumors, or 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 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.
 
===={{pcat}} C====
 
Upon confirming the diagnosis of pregnancy, women should immediately inform the doctor.
 
Lopressor has been shown to increase postimplantation loss and decrease neonatal survival in rats at doses up to 11 times the maximum daily human dose of 450 mg, when based on surface area. Distribution studies in mice confirm exposure of the fetus when Lopressor is administered to the pregnant animal. These limited animal studies do not indicate direct or indirect harmful effects with respect to [[teratogenicity]] (see Carcinogenesis, Mutagenesis, Impairment of Fertility).
 
There are no adequate and well-controlled studies in pregnant women. The amount of data on the use of metoprolol in pregnant women is limited. The risk to the fetus/mother is unknown. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
 
====Nursing Mothers====
 
 
Lopressor is excreted in breast milk in a very small quantity. An infant consuming 1 liter of breast milk daily would receive a dose of less than 1 mg of the drug.
 
====Fertility====
 
 
The effects of Lopressor on the fertility of humans have not been studied.
 
 
Lopressor showed effects on spermatogenesis in male rats at a therapeutic dose level, but had no effect on rates of conception at higher doses in animal fertility studies (see Carcinogenesis, Mutagenesis, Impairment of Fertility).
 
 
====Pediatric Use====
 
 
Safety and effectiveness in pediatric patients have not been established.
 
====Geriatric Use====
 
Clinical trials of Lopressor in [[hypertension]] did not include sufficient numbers of elderly patients to determine whether patients over 65 years of age differ from younger subjects in their response to Lopressor. Other reported clinical experience in elderly hypertensive patients has not identified any difference in response from younger patients.
 
 
In worldwide clinical trials of Lopressor 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 Lopressor cannot be categorically ruled out. Therefore, in general, it is recommended that dosing proceed with caution in this population.<ref name="dailymed.nlm.nih.gov">{{Cite web  | last =  | first =  | title = LOPRESSOR (METOPROLOL TARTRATE) TABLET [NOVARTIS PHARMACEUTICALS CORPORATION] | url =http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=bb05420c-fd24-4672-9f62-fdd313819287 | publisher =  | date =  | accessdate = }}</ref>
 
==References==
 
{{Reflist}}
 
{{FDA}}
 
[[Category:Beta blockers]]
[[Category:Cardiovascular Drugs]]
[[Category:Drugs]]

Latest revision as of 03:51, 22 July 2014

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