`
`metoprolol tartrate injection, USP
`
`
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`Rx only
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`Prescribing Information
`
`DESCRIPTION
`
`Lopressor, metoprolol tartrate USP, is a selective beta1-adrenoreceptor blocking agent, available
`in 5-mL ampuls for intravenous administration. Each ampul contains a sterile solution of
`metoprolol tartrate USP, 5 mg, and sodium chloride USP, 45 mg, and water for injection USP.
`Metoprolol tartrate USP is (±)-1-(Isopropylamino)-3-[p-(2-methoxyethyl)phenoxy]-2-propanol L-
`(+)-tartrate (2:1) salt, and its structural formula is:
`
`Metoprolol tartrate USP is a white, practically odorless, crystalline powder with a molecular
`weight of 684.82. It is very soluble in water; freely soluble in methylene chloride, in chloroform,
`and in alcohol; slightly soluble in acetone; and insoluble in ether.
`
`
`
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`
`Lopressor is a beta1-selective (cardioselective) adrenergic receptor blocker. This preferential
`effect is not absolute, however, and at higher plasma concentrations, Lopressor also inhibits
`beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature.
`Clinical pharmacology studies have demonstrated the beta-blocking activity of metoprolol, as
`shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of
`systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4)
`reduction of reflex orthostatic tachycardia.
`
`Hypertension
`
`The mechanism of the antihypertensive effects of beta-blocking agents has not been fully
`elucidated. However, several possible mechanisms have been proposed: (1) competitive
`antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading
`to decreased cardiac output; (2) a central effect leading to 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, Lopressor 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.
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`Myocardial Infarction
`
`The precise mechanism of action of Lopressor in patients with suspected or definite myocardial
`infarction is not known.
`
`Pharmacodynamics
`
`Relative beta1 selectivity is demonstrated by the following: (1) In healthy subjects, Lopressor is
`unable to reverse the beta2-mediated vasodilating effects of epinephrine. This contrasts with the
`effect of nonselective (beta1 plus beta2) beta blockers, which completely reverse the vasodilating
`effects of epinephrine. (2) In asthmatic patients, Lopressor reduces FEV1 and FVC significantly
`less than a nonselective beta blocker, propranolol, at equivalent beta1-receptor blocking doses.
`
`Lopressor 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 Lopressor 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 Lopressor 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: Lopressor 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 Lopressor than extensive metabolizers with normal
`CYP2D6 activity thereby decreasing Lopressor’s cardioselectivity.
`
`Elimination: Elimination of Lopressor 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
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`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 Lopressor 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, Lopressor 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-
`450 mg daily. In controlled, comparative, clinical studies, Lopressor 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, Lopressor, 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 100-400 mg daily. A
`controlled, comparative, clinical trial showed that Lopressor 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, Lopressor
`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 Lopressor or placebo, given in a coronary care or
`comparable unit. Oral maintenance therapy with Lopressor or placebo was then continued for
`3 months. After this double-blind period, all patients were given Lopressor 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
`Lopressor- and placebo-treatment groups. Among patients treated with Lopressor, there were
`comparable reductions in 3-month mortality for those treated early (≤8 hours) and those in whom
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`treatment was started later. Significant reductions in the incidence of ventricular fibrillation and
`in chest pain following initial intravenous therapy were also observed with Lopressor 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.
`
`INDICATIONS AND USAGE
`Myocardial Infarction
`
`Lopressor ampuls are indicated in the treatment of hemodynamically stable patients with definite
`or suspected acute myocardial infarction to reduce cardiovascular mortality when used in
`conjunction with oral Lopressor maintenance therapy. Treatment with intravenous Lopressor can
`be initiated as soon as the patient’s clinical condition allows (see DOSAGE AND
`ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS).
`
`CONTRAINDICATIONS
`
`Hypersensitivity to Lopressor and related derivatives, or to any of the excipients; hypersensitivity
`to other beta blockers (cross sensitivity between beta blockers can occur).
`
`Myocardial Infarction
`
`Lopressor is contraindicated in patients with a heart rate <45 beats/min; second- and third-degree
`heart block; significant first-degree heart block (P-R interval ≥0.24 sec); systolic blood pressure
`<100 mmHg; or moderate-to-severe cardiac failure (see WARNINGS).
`
`WARNINGS
`Heart Failure
`
`Beta blockers, like Lopressor, can cause depression of myocardial contractility and may
`precipitate heart failure and cardiogenic shock. If signs or symptoms of heart failure develop,
`treat the patient according to recommended guidelines. It may be necessary to lower the dose of
`Lopressor or to discontinue it.
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`Ischemic Heart Disease
`
`Do not abruptly discontinue Lopressor therapy in patients with coronary artery disease. Severe
`exacerbation of angina, myocardial infarction, and ventricular arrhythmias have been reported in
`patients with coronary artery disease following the abrupt discontinuation of therapy with beta-
`blockers. When discontinuing chronically administered Lopressor, particularly in patients with
`coronary artery 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.
`
`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
`Lopressor. 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 Lopressor.
`If severe bradycardia develops, reduce or stop Lopressor.
`
`Exacerbation of Bronchospastic Disease
`
`Patients with bronchospastic disease, should, in general, not receive beta blockers, including
`Lopressor. Because of its relative beta1 selectivity, however, Lopressor may be used in patients
`with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive
`treatment. Because beta1 selectivity is not absolute use the lowest possible dose of Lopressor and
`consider administering 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
`DOSAGE AND ADMINISTRATION). Bronchodilators, including beta2 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.
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`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
`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
`
`Lopressor may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Avoid abrupt
`withdrawal of beta blockade, which might precipitate a thyroid storm.
`
`PRECAUTIONS
`Risk of Anaphylactic Reactions
`
`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.
`
`Information for Patients
`
`Advise patients (1) 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; (2)
`to contact the physician if any difficulty in breathing occurs; (3) to 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 glycosides and beta blockers 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.
`
`General Anesthetics: Some inhalation anesthetics may enhance the cardiodepressant effect of
`beta blockers (see WARNINGS, Major Surgery).
`
`CYP2D6 Inhibitors: Potent inhibitors of the CYP2D6 enzyme may increase the plasma
`concentration of Lopressor which would mimic the pharmacokinetics of CYP2D6 poor
`metabolizer (see Pharmacokinetics section). Increase in plasma concentrations of metoprolol
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`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 blockers such as
`guanethidine, betanidine, reserpine, alpha-methyldopa or clonidine may be potentiated by beta-
`blockers including Lopressor. Beta- adrenergic blockers 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-blockers may enhance the 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 neoplasms 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 adenomas) 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
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`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.
`
`Pregnancy Category C
`
`Upon confirming the diagnosis of pregnancy, women should immediately inform the doctor.
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`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.
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`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.
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`Fertility
`
`The effects of Lopressor on the fertility of human have not been studied.
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`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
`
`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.
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`ADVERSE REACTIONS
`Hypertension and Angina
`
`These adverse reactions were reported for treatment with oral Lopressor. Most adverse effects
`have been mild and transient.
`
`Central Nervous System: Tiredness and dizziness have occurred in about 10 of 100 patients.
`Depression has been reported in about 5 of 100 patients. Mental confusion and short-term
`memory loss have been reported. Headache, nightmares, and insomnia have also been reported.
`
`Cardiovascular: Shortness of breath and bradycardia have occurred in approximately 3 of 100
`patients. Cold extremities; arterial insufficiency, usually of the Raynaud type; palpitations;
`congestive heart failure; peripheral edema; and hypotension have been reported in about 1 of 100
`patients. Gangrene in patients with pre-existing severe peripheral circulatory disorders has also
`been reported very rarely. (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS.)
`
`Respiratory: Wheezing (bronchospasm) and dyspnea have been reported in about 1 of 100
`patients (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. 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 Lopressor has not been definitely established).
`
`The oculomucocutaneous syndrome associated with the beta blocker practolol has not been
`reported with Lopressor.
`
`Myocardial Infarction
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`These adverse reactions were reported from treatment regimens where intravenous Lopressor 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 Lopressor and placebo described in the
`CLINICAL PHARMACOLOGY section, the following adverse reactions were reported:
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`Lopressor®
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`Placebo
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`Hypotension (systolic BP <90 mmHg)
`
`Bradycardia (heart rate <40 beats/min)
`
`Second- or third-degree heart block
`
`First-degree heart block (P-R ≥0.26 sec)
`
`Heart failure
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`27.4%
`
`15.9%
`
`4.7%
`
`5.3%
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`27.5%
`
`23.2%
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`6.7%
`
`4.7%
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`1.9%
`
`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 Lopressor.
`
`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 Lopressor:
`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.
`
`OVERDOSAGE
`Acute Toxicity
`
`Several cases of overdosage have been reported, some leading to death.
`
`Oral LD 50’s (mg/kg): mice, 1158-2460; rats, 3090-4670.
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`Signs and Symptoms
`
`Potential signs and symptoms associated with overdosage with Lopressor are bradycardia,
`hypotension, bronchospasm, myocardial infarction, cardiac failure, and death.
`
`Management
`
`There is no specific antidote.
`
`In general, patients with acute or recent myocardial infarction may be more hemodynamically
`unstable than other patients and should be treated accordingly (see WARNINGS, Myocardial
`Infarction).
`
`On the basis of the pharmacologic actions of Lopressor, the following general measures should be
`employed:
`
`Elimination of the Drug: Gastric lavage should be performed.
`
`Other clinical manifestations of overdose should be managed symptomatically based on modern
`methods of intensive care.
`
`Hypotension: Administer a vasopressor, e.g., levarterenol or dopamine.
`
`Bronchospasm: Administer a beta2-stimulating agent and/or a theophylline derivative.
`
`Cardiac Failure: Administer digitalis glycoside and diuretic. In shock resulting from inadequate
`cardiac contractility, consider administration of dobutamine, isoproterenol, or glucagon.
`
`DOSAGE AND ADMINISTRATION
`Myocardial Infarction
`
`Early Treatment: During the early phase of definite or suspected acute myocardial infarction,
`initiate treatment with Lopressor as soon as possible after the patient’s arrival in the hospital.
`Such treatment should be initiated in a coronary care or similar unit immediately after the
`patient’s hemodynamic condition has stabilized.
`
`Begin treatment in this early phase with the intravenous administration of three bolus injections
`of 5 mg of Lopressor each; give the injections at approximately 2-minute intervals. During the
`intravenous administration of Lopressor, monitor blood pressure, heart rate, and
`electrocardiogram.
`
`In patients who tolerate the full intravenous dose (15 mg), initiate Lopressor tablets, 50 mg every
`6 hours, 15 minutes after the last intravenous dose and continue for 48 hours. Thereafter, the
`maintenance dosage is 100 mg orally twice daily.
`
`Start patients who appear not to tolerate the full intravenous dose on Lopressor 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 Lopressor (see WARNINGS).
`
`Special Populations
`
`Pediatric patients: No pediatric studies have been performed. The safety and efficacy of
`Lopressor in pediatric patients have not been established.
`
`
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`Lower Drug Prices for Consumers v. Forest Labs. Holdings Ltd.
`IPR2016-00379
`Patent Owner Forest Labs - Ex. 2004, p. 11
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`Renal impairment: No dose adjustment of Lopressor is required in patients with renal
`impairment.
`
`Hepatic impairment: Lopressor blood levels are likely to increase substantially in patients with
`hepatic impairment. Therefore, Lopressor 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 Lopressor (ampoule) should be done in a setting