BREVIBLOC (Esmolol Hydrochloride) injection is indicated for the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other emergent circumstances where short term control of ventricular rate with a short-acting agent is desirable. BREVIBLOC injection is also indicated in noncompensatory sinus tachycardia where, in the physician’s judgment, the rapid heart rate requires specific intervention. BREVIBLOC injection is intended for short-term use.

BREVIBLOC (Esmolol Hydrochloride) injection is indicated for the short-term treatment of tachycardia and hypertension that occur during induction and tracheal intubation, during surgery, on emergence from anesthesia and in the postoperative period, when in the physician’s judgment such specific intervention is considered indicated.

Use of BREVIBLOC injection to prevent such events is not recommended.

BREVIBLOC injection is administered by continuous intravenous infusion with or without a loading dose. Additional loading doses and/or titration of the maintenance infusion (step-wise dosing) may be necessary based on desired ventricular response.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1 Step-Wise Dosing</span> </caption> <col width="8%"/> <col width="92%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Step</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Action</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">1</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Optional loading dose (500 mcg per kg over 1 minute), then 50 mcg per kg per min for 4 min</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Optional loading dose if necessary, then 100 mcg per kg per min for 4 min</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Optional loading dose if necessary, then 150 mcg per kg per min for 4 min</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">If necessary, increase dose to 200 mcg per kg per min</p> </td> </tr> </tbody> </table></div>

In the absence of loading doses, continuous infusion of a single concentration of esmolol reaches pharmacokinetic and pharmacodynamic steady-state in about 30 minutes.

The effective maintenance dose for continuous and step-wise dosing is 50 to 200 mcg per kg per minute, although doses as low as 25 mcg per kg per minute have been adequate. Dosages greater than 200 mcg per kg per minute provide little added heart rate lowering effect, and the rate of adverse reactions increases.

Maintenance infusions may be continued for up to 48 hours.

In this setting it is not always advisable to slowly titrate to a therapeutic effect. Therefore two dosing options are presented: immediate control and gradual control.

Immediate Control

Gradual Control

Maximum Recommended Doses

After patients achieve adequate control of the heart rate and a stable clinical status, transition to alternative antiarrhythmic drugs may be accomplished.

When transitioning from BREVIBLOC injection to alternative drugs, the physician should carefully consider the labeling instructions of the alternative drug selected and reduce the dosage of BREVIBLOC injection as follows:

BREVIBLOC injection is available in a pre-mixed bag and ready-to-use vial. BREVIBLOC injection is not compatible with Sodium Bicarbonate (5%) solution (limited stability) or furosemide (precipitation).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Premixed Bag

Ready-to-Use Vial

The Ready-to-use Vial may be used to administer a loading dosage by hand-held syringe while the maintenance infusion is being prepared [see How Supplied/Storage and Handling (16.2)].

Compatibility with Commonly Used Intravenous Fluids

BREVIBLOC injection was tested for compatibility with ten commonly used intravenous fluids at a final concentration of 10 mg esmolol hydrochloride per mL. BREVIBLOC injection was found to be compatible with the following solutions and was stable for at least 24 hours at controlled room temperature or under refrigeration:

All BREVIBLOC injection dosage forms are iso-osmotic solutions of esmolol hydrochloride in sodium chloride.

{ "type": "p", "children": [], "text": "All BREVIBLOC injection dosage forms are iso-osmotic solutions of esmolol hydrochloride in sodium chloride." }

<div class="scrollingtable"><table width="94.94%"> <caption> <span>Table 2 BREVIBLOC Injection Presentations</span> </caption> <col width="20%"/> <col width="30%"/> <col width="29%"/> <col width="22%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Product Name</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">BREVIBLOC</p> <p>PREMIXED Injection<br/> </p> <p>(Esmolol Hydrochloride)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">BREVIBLOC</p> <p>PREMIXED Double Strength Injection</p> <p>(Esmolol Hydrochloride)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">BREVIBLOC Injection<br/> </p> <p>(Esmolol Hydrochloride)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Total Dose</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2500 mg / 250 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2000 mg / 100 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">100 mg / 10 mL</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Esmolol Hydrochloride Concentration</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">10 mg/mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">20 mg/mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">10 mg/mL</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Packaging</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">250 mL Bag</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">100 mL Bag</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">10 mL Vial</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"94.94%\">\n<caption>\n<span>Table 2 BREVIBLOC Injection Presentations</span>\n</caption>\n<col width=\"20%\"/>\n<col width=\"30%\"/>\n<col width=\"29%\"/>\n<col width=\"22%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Product Name</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">BREVIBLOC</p>\n<p>PREMIXED Injection<br/>\n</p>\n<p>(Esmolol Hydrochloride)</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">BREVIBLOC</p>\n<p>PREMIXED Double Strength Injection</p>\n<p>(Esmolol Hydrochloride)</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">BREVIBLOC Injection<br/>\n</p>\n<p>(Esmolol Hydrochloride)</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">Total Dose</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">2500 mg / 250 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">2000 mg / 100 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">100 mg / 10 mL</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">Esmolol Hydrochloride Concentration</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">10 mg/mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">20 mg/mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">10 mg/mL</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">Packaging</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">250 mL Bag</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">100 mL Bag</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">10 mL Vial</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

BREVIBLOC (Esmolol Hydrochloride) injection is contraindicated in patients with:

{ "type": "p", "children": [], "text": "BREVIBLOC (Esmolol Hydrochloride) injection is contraindicated in patients with:" }

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Hypotension can occur at any dose but is dose-related. Patients with hemodynamic compromise or on interacting medications are at particular risk. Severe reactions may include loss of consciousness, cardiac arrest, and death. For control of ventricular heart rate, maintenance doses greater than 200 mcg per kg per min are not recommended. Monitor patients closely, especially if pretreatment blood pressure is low. In case of an unacceptable drop in blood pressure, reduce or stop BREVIBLOC injection. Decrease of dose or termination of infusion reverses hypotension, usually within 30 minutes.

Bradycardia, including sinus pause, heart block, severe bradycardia, and cardiac arrest have occurred with the use of BREVIBLOC injection. 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 BREVIBLOC injection [see Contraindications (4)].

If severe bradycardia develops, reduce or stop BREVIBLOC injection.

Beta blockers, like BREVIBLOC injection, can cause depression of myocardial contractility and may precipitate heart failure and cardiogenic shock. At the first sign or symptom of impending cardiac failure, stop BREVIBLOC injection and start supportive therapy [see Overdosage (10)].

Monitor vital signs closely and titrate BREVIBLOC injection slowly in the treatment of patients whose blood pressure is primarily driven by vasoconstriction associated with hypothermia.

Patients with reactive airways disease should, in general, not receive beta blockers. Because of its relative beta1 selectivity and titratability, titrate BREVIBLOC injection to the lowest possible effective dose. In the event of bronchospasm, stop the infusion immediately; a beta2 stimulating agent may be administered with appropriate monitoring of ventricular rates.

Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment.

Infusion site reactions have occurred with the use of BREVIBLOC injection. They include irritation, inflammation, and severe reactions (thrombophlebitis, necrosis, and blistering), in particular when associated with extravasation [see Adverse Reactions (6)]. Avoid infusions into small veins or through a butterfly catheter.

If a local infusion site reaction develops, use an alternative infusion site and avoid extravasation.

Beta blockers may exacerbate anginal attacks in patients with Prinzmetal’s angina because of unopposed alpha receptor–mediated coronary artery vasoconstriction. Do not use nonselective beta blockers.

If BREVIBLOC injection is used in the setting of pheochromocytoma, give it 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 from the attenuation of beta-mediated vasodilation in skeletal muscle.

In hypovolemic patients, BREVIBLOC injection can attenuate reflex tachycardia and increase the risk of hypotension.

In patients with peripheral circulatory disorders (including Raynaud’s disease or syndrome, and peripheral occlusive vascular disease), BREVIBLOC injection may aggravate peripheral circulatory disorders.

Severe exacerbations of angina, myocardial infarction, and ventricular arrhythmias have been reported in patients with coronary artery disease upon abrupt discontinuation of beta blocker therapy. Observe patients for signs of myocardial ischemia when discontinuing BREVIBLOC injection.

Heart rate increases moderately above pretreatment levels 30 minutes after BREVIBLOC injection discontinuation.

Beta blockers, including BREVIBLOC injection, have been associated with increases in serum potassium levels and hyperkalemia. The risk is increased in patients with risk factors such as renal impairment. Intravenous administration of beta blockers has been reported to cause potentially life-threatening hyperkalemia in hemodialysis patients. Monitor serum electrolytes during therapy with BREVIBLOC injection.

Beta blockers, including BREVIBLOC injection, have been reported to cause hyperkalemic renal tubular acidosis. Acidosis in general may be associated with reduced cardiac contractility.

Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Abrupt withdrawal of beta blockade might precipitate a thyroid storm; therefore, monitor patients for signs of thyrotoxicosis when withdrawing beta blocking therapy.

When using beta blockers, patients at risk of anaphylactic reactions may be more reactive to allergen exposure (accidental, diagnostic, or therapeutic).

Patients using beta blockers may be unresponsive to the usual doses of epinephrine used to treat anaphylactic or anaphylactoid reactions [see Drug Interactions (7)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The following adverse reaction rates are based on use of BREVIBLOC (Esmolol Hydrochloride) injection in clinical trials involving 369 patients with supraventricular tachycardia and over 600 intraoperative and postoperative patients enrolled in clinical trials. Most adverse effects observed in controlled clinical trial settings have been mild and transient. The most important and common adverse effect has been hypotension [see Warnings and Precautions (5.1)]. Deaths have been reported in post-marketing experience occurring during complex clinical states where BREVIBLOC injection was presumably being used simply to control ventricular rate [see Warnings and Precautions (5.5)].

<div class="scrollingtable"><table width="464.4pt"> <caption> <span>Table 3 Clinical Trial Adverse Reactions (Frequency ≥3%)</span> </caption> <col width="33%"/> <col width="47%"/> <col width="18%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="top">System Organ Class (SOC)</th><th align="left" class="Botrule Lrule Rrule Toprule" valign="top">Preferred MedDRA Term</th><th align="center" class="Botrule Lrule Rrule Toprule" valign="top">Frequency</th> </tr> </thead> <tbody> <tr class="First"> <td class="Botrule Lrule Rrule" rowspan="3" valign="top"> <p class="First">VASCULAR DISORDERS</p> </td><td valign="middle"> <p class="First">Hypotension*</p> </td><td class="Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td valign="middle"> <dl> <dt> </dt> <dd>Asymptomatic hypotension</dd> </dl> </td><td align="center" class="Lrule Rrule" valign="middle"> <p class="First">25%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <dl> <dt> </dt> <dd>Symptomatic hypotension<br/>(hyperhidrosis, dizziness)</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule" valign="middle"> <p class="First">12%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Infusion site reactions<br/>(inflammation and induration)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">8%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">GASTROINTESTINAL DISORDERS</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Nausea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">7%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First">NERVOUS SYSTEM DISORDERS</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Dizziness</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Somnolence</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="middle"> <p class="First"> <span class="Sup">* </span>Hypotension resolved during BREVIBLOC (Esmolol Hydrochloride) infusion in 63% of patients. In 80% of the remaining patients, hypotension resolved within 30 minutes following discontinuation of infusion.</p> </td> </tr> </tbody> </table></div>

Clinical Trial Adverse Reactions (Frequency <3%)

Psychiatric Disorders

Confusional state and agitation (~2%)Anxiety, depression and abnormal thinking (<1%)

Nervous System Disorders

Headache (~ 2%)Paresthesia, syncope, speech disorder, and lightheadedness (<1%)Convulsions (<1%), with one death

Vascular Disorders

Peripheral ischemia (~1%)Pallor and flushing (<1%)

Gastrointestinal Disorders

Vomiting (~1%)Dyspepsia, constipation, dry mouth, and abdominal discomfort (<1%)

Renal and Urinary Disorders

Urinary retention (<1%)

In addition to the adverse reactions reported in clinical trials, the following adverse reactions have been reported in the post-marketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or to establish a causal relationship to drug exposure.

Cardiac Disorders

Cardiac arrest, Coronary arteriospasm

Skin and Subcutaneous Tissue Disorders

Angioedema, Urticaria, Psoriasis

Concomitant use of BREVIBLOC injection with other drugs that can lower blood pressure, reduce myocardial contractility, or interfere with sinus node function or electrical impulse propagation in the myocardium can exaggerate BREVIBLOC injection’s effects on blood pressure, contractility, and impulse propagation. Severe interactions with such drugs can result in, for example, severe hypotension, cardiac failure, severe bradycardia, sinus pause, sinoatrial block, atrioventricular block, and/or cardiac arrest. In addition, with some drugs, beta blockade may precipitate increased withdrawal effects. (See clonidine, guanfacine, and moxonidine below.) BREVIBLOC injection should therefore be used only after careful individual assessment of the risks and expected benefits in patients receiving drugs that can cause these types of pharmacodynamic interactions, including but not limited to:

{ "type": "p", "children": [], "text": "Concomitant use of BREVIBLOC injection with other drugs that can lower blood pressure, reduce myocardial contractility, or interfere with sinus node function or electrical impulse propagation in the myocardium can exaggerate BREVIBLOC injection’s effects on blood pressure, contractility, and impulse propagation. Severe interactions with such drugs can result in, for example, severe hypotension, cardiac failure, severe bradycardia, sinus pause, sinoatrial block, atrioventricular block, and/or cardiac arrest. In addition, with some drugs, beta blockade may precipitate increased withdrawal effects. (See clonidine, guanfacine, and moxonidine below.) BREVIBLOC injection should therefore be used only after careful individual assessment of the risks and expected benefits in patients receiving drugs that can cause these types of pharmacodynamic interactions, including but not limited to:" }

{ "type": "", "children": [], "text": "" }

Esmolol hydrochloride has been shown to produce increased fetal resorptions with minimal maternal toxicity in rabbits when given in doses approximately 8 times the maximum human maintenance dose (300 mcg/kg/min). There are no adequate and well-controlled studies in pregnant women. BREVIBLOC injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Teratogenicity studies in rats at intravenous dosages of esmolol hydrochloride up to 3000 mcg/kg/min (10 times the maximum human maintenance dosage) for 30 minutes daily produced no evidence of maternal toxicity, embryotoxicity or teratogenicity, while a dosage of 10,000 mcg/kg/min produced maternal toxicity and lethality. In rabbits, intravenous dosages up to 1000 mcg/kg/min for 30 minutes daily produced no evidence of maternal toxicity, embryotoxicity or teratogenicity, while 2500 mcg/kg/min produced minimal maternal toxicity and increased fetal resorptions.

Although there are no adequate and well-controlled studies in pregnant women, use of esmolol in the last trimester of pregnancy or during labor or delivery has been reported to cause fetal bradycardia, which continued after termination of drug infusion. BREVIBLOC injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from BREVIBLOC injection, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

The safety and effectiveness of BREVIBLOC injection in pediatric patients have not been established.

Clinical studies of BREVIBLOC injection did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should usually start at the low end of the dosing range, reflecting greater frequency of decreased renal or cardiac function and of concomitant disease or other drug therapy.

No special precautions are necessary in patients with hepatic impairment because BREVIBLOC injection is metabolized by red-blood cell esterases [see Clinical Pharmacology (12)].

No dosage adjustment is required for esmolol in patients with renal impairment receiving a maintenance infusion of esmolol 150 mcg/kg for 4 hours. There is no information on the tolerability of maintenance infusions of esmolol using rates in excess of 150 mcg/kg or maintained longer than 4 hours [see Clinical Pharmacology (12)].

Overdoses of BREVIBLOC (Esmolol Hydrochloride) injection can cause cardiac and central nervous system effects. These effects may precipitate severe signs, symptoms, sequelae, and complications (for example, severe cardiac and respiratory failure, including shock and coma), and may be fatal. Continuous monitoring of the patient is required.

Because of its approximately 9-minute elimination half-life, the first step in the management of toxicity should be to discontinue the BREVIBLOC infusion. Then, based on the observed clinical effects, consider the following general measures.

Bradycardia

Consider intravenous administration of atropine or another anticholinergic drug or cardiac pacing.

Cardiac Failure

Consider intravenous administration of a diuretic or digitalis glycoside. In shock resulting from inadequate cardiac contractility, consider intravenous administration of dopamine, dobutamine, isoproterenol, or inamrinone. Glucagon has been reported to be useful.

Symptomatic hypotension

Consider intravenous administration of fluids or vasopressor agents such as dopamine or norepinephrine.

Bronchospasm

Consider intravenous administration of a beta2 stimulating agent or a theophylline derivative.

Massive accidental overdoses of BREVIBLOC injection have resulted from dilution errors. Use of BREVIBLOC PREMIXED Injection and BREVIBLOC PREMIXED Double Strength Injection may reduce the potential for dilution errors. Some of these overdoses have been fatal while others resulted in permanent disability. Bolus doses in the range of 625 mg to 2.5 g (12.5‑50 mg/kg) have been fatal. Patients have recovered completely from overdoses as high as 1.75 g given over one minute or doses of 7.5 g given over one hour for cardiovascular surgery. The patients who survived appear to be those whose circulation could be supported until the effects of BREVIBLOC injection resolved.

All BREVIBLOC injection presentations are clear, colorless to light yellow, sterile, nonpyrogenic, iso‑osmotic solutions of esmolol hydrochloride in sodium chloride. The formulations for BREVIBLOC PREMIXED Injection, BREVIBLOC PREMIXED Double Strength Injection, and BREVIBLOC Injection are described in the table below:

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 4 BREVIBLOC Injection Formulations</span> </caption> <col width="21%"/> <col width="15%"/> <col width="43%"/> <col width="21%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">BREVIBLOC PREMIXED Injection</p> <p>(Esmolol Hydrochloride)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">BREVIBLOC<br/>PREMIXED Double Strength Injection<br/> </p> <p>(Esmolol Hydrochloride)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">BREVIBLOC Injection<br/> </p> <p>(Esmolol Hydrochloride)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Esmolol Hydrochloride, USP</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">10 mg/mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">20 mg/mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">10 mg/mL</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Sodium Chloride, USP</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">5.9 mg/mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4.1 mg/mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">5.9 mg/mL</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Water for <br/>Injection, USP</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Q.S. to volume<br/>of 250 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Q.S. to volume<br/>of 100 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Q.S. to volume<br/>of 10 mL</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Sodium Acetate Trihydrate, USP</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2.8 mg/mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2.8 mg/mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2.8 mg/mL</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Glacial Acetic <br/>Acid, USP</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0.546 mg/mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0.546 mg/mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0.546 mg/mL</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Sodium Hydroxide</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="3" valign="middle"> <p class="First">Q.S. to adjust pH to 4.5-5.5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Hydrochloric Acid</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="3" valign="middle"> <p class="First">Q.S. to adjust pH to 4.5-5.5</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="4" valign="top"> <p class="First">Q.S. = Quantity sufficient</p> </td> </tr> </tbody> </table></div>

The calculated osmolarity of BREVIBLOC PREMIXED Injection and BREVIBLOC PREMIXED Double Strength Injection is 312 mOsmol/L. The 250 mL and 100 mL bags are non-latex, non-PVC INTRAVIA bags with dual PVC ports. The INTRAVIA bags are manufactured from a specially designed multilayer plastic (PL 2408). Solutions in contact with the plastic container leach out certain chemical compounds from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials.

BREVIBLOC (Esmolol Hydrochloride) injection is a beta1-selective (cardioselective) adrenergic receptor blocking agent with rapid onset, a very short duration of action, and no significant intrinsic sympathomimetic or membrane stabilizing activity at therapeutic dosages. Its elimination half-life after intravenous infusion is approximately 9 minutes. BREVIBLOC injection inhibits the beta1 receptors located chiefly in cardiac muscle, but this preferential effect is not absolute and at higher doses it begins to inhibit beta2 receptors located chiefly in the bronchial and vascular musculature.

Clinical pharmacology studies in normal volunteers have confirmed the beta blocking activity of BREVIBLOC injection, showing reduction in heart rate at rest and during exercise, and attenuation of isoproterenol-induced increases in heart rate. Blood levels of BREVIBLOC injection have been shown to correlate with extent of beta blockade. After termination of infusion, substantial recovery from beta blockade is observed in 10‑20 minutes. The acid metabolite of esmolol exhibits negligible pharmacological activity.

In human electrophysiology studies, BREVIBLOC injection produced effects typical of a beta blocker: a decrease in the heart rate, increase in sinus cycle length, prolongation of the sinus node recovery time, prolongation of the AH interval during normal sinus rhythm and during atrial pacing, and an increase in antegrade Wenckebach cycle length.

In patients undergoing radionuclide angiography, BREVIBLOC injection, at dosages of 200 mcg/kg/min, produced reductions in heart rate, systolic blood pressure, rate pressure product, left and right ventricular ejection fraction and cardiac index at rest, which were similar in magnitude to those produced by intravenous propranolol (4 mg). During exercise, BREVIBLOC injection produced reductions in heart rate, rate pressure product and cardiac index which were also similar to those produced by propranolol, but BREVIBLOC injection produced a significantly larger fall in systolic blood pressure. In patients undergoing cardiac catheterization, the maximum therapeutic dose of 300 mcg/kg/min of BREVIBLOC injection produced similar effects and, in addition, there were small, clinically insignificant increases in the left ventricular end diastolic pressure and pulmonary capillary wedge pressure. At 30 minutes after the discontinuation of BREVIBLOC infusion, all of the hemodynamic parameters had returned to pretreatment levels.

The relative cardioselectivity of BREVIBLOC injection was demonstrated in 10 mildly asthmatic patients. Infusions of BREVIBLOC injection 100, 200 and 300 mcg/kg/min produced no significant increases in specific airway resistance compared to placebo. At 300 mcg/kg/min, BREVIBLOC injection produced slightly enhanced bronchomotor sensitivity to dry air stimulus. These effects were not clinically significant, and BREVIBLOC injection was well tolerated by all patients. Six of the patients also received intravenous propranolol, and at a dosage of 1 mg, two experienced significant, symptomatic bronchospasm requiring bronchodilator treatment. One other propranolol-treated patient also experienced dry air-induced bronchospasm. No adverse pulmonary effects were observed in patients with COPD who received therapeutic dosages of BREVIBLOC injection for treatment of supraventricular tachycardia (51 patients) or in perioperative settings (32 patients).

Esmolol is rapidly metabolized by hydrolysis of the ester linkage, chiefly by the esterases in the cytosol of red blood cells and not by plasma cholinesterases or red cell membrane acetylcholinesterase. Total body clearance in man was found to be about 20 L/kg/hr, which is greater than cardiac output; thus the metabolism of esmolol is not limited by the rate of blood flow to metabolizing tissues such as the liver or affected by hepatic or renal blood flow. Esmolol has a rapid distribution half-life of about 2 minutes and an elimination half-life of about 9 minutes.

Using an appropriate loading dose, steady-state blood levels of BREVIBLOC injection for dosages from 50-300 mcg/kg/min are obtained within five minutes. Steady-state is reached in about 30 minutes without the loading dose. Steady-state blood levels of esmolol increase linearly over this dosage range and elimination kinetics are dose-independent over this range. Steady-state blood levels are maintained during infusion but decrease rapidly after termination of the infusion. Because of its short half-life, blood levels of esmolol can be rapidly altered by increasing or decreasing the infusion rate and rapidly eliminated by discontinuing the infusion.

Consistent with the high rate of blood-based metabolism of esmolol, less than 2% of the drug is excreted unchanged in the urine. Within 24 hours of the end of infusion, the acid metabolite of esmolol in urine accounts for approximately 73-88% of the dosage.

Metabolism of esmolol results in the formation of the corresponding free acid and methanol. The acid metabolite has been shown in animals to have negligible activity and in normal volunteers its blood levels do not correspond to the level of beta blockade. The acid metabolite has an elimination half-life of about 3.7 hours and is excreted in the urine with a clearance approximately equivalent to the glomerular filtration rate. After a 4 hour maintenance infusion of 150 mcg/kg, the plasma concentrations of esmolol are similar in subjects with normal renal function and in patients with ESRD on dialysis. The half-life of the acid metabolite of BREVIBLOC injection, which is primarily excreted unchanged by the kidney, is increased about 12-fold to 48 hours in patients with ESRD. The peak concentrations of the acid metabolite are doubled in ESRD.

Methanol blood levels, monitored in subjects receiving BREVIBLOC injection for up to 6 hours at 300 mcg/kg/min and 24 hours at 150 mcg/kg/min, approximated endogenous levels and were less than 2% of levels usually associated with methanol toxicity.

BREVIBLOC injection has been shown to be 55% bound to human plasma protein, while the acid metabolite is only 10% bound.

Because of its short-term usage, no carcinogenicity, mutagenicity, or reproductive performance studies have been conducted with esmolol.

{ "type": "p", "children": [], "text": "Because of its short-term usage, no carcinogenicity, mutagenicity, or reproductive performance studies have been conducted with esmolol." }

Supraventricular Tachycardia

{ "type": "p", "children": [], "text": "\nSupraventricular Tachycardia\n" }

In two multicenter, randomized, double-blind, controlled comparisons of BREVIBLOC injection with placebo and propranolol, maintenance doses of 50 to 300 mcg/kg/min of BREVIBLOC injection were found to be more effective than placebo and about as effective as propranolol, 3‑6 mg given by bolus injections, in the treatment of supraventricular tachycardia, principally atrial fibrillation and atrial flutter. The majority of these patients developed their arrhythmias postoperatively. About 60-70% of the patients treated with BREVIBLOC injection developed either a 20% reduction in heart rate, a decrease in heart rate to less than 100 bpm, or, rarely, conversion to normal sinus rhythm and about 95% of these patients did so at a dosage of 200 mcg/kg/min or less. The average effective dosage of BREVIBLOC injection was approximately 100 mcg/kg/min in the two studies. Other multicenter baseline-controlled studies gave similar results. In the comparison with propranolol, about 50% of patients in both the BREVIBLOC injection and propranolol groups were on concomitant digoxin. Response rates were slightly higher with both beta blockers in the digoxin-treated patients.

{ "type": "p", "children": [], "text": "In two multicenter, randomized, double-blind, controlled comparisons of BREVIBLOC injection with placebo and propranolol, maintenance doses of 50 to 300 mcg/kg/min of BREVIBLOC injection were found to be more effective than placebo and about as effective as propranolol, 3‑6 mg given by bolus injections, in the treatment of supraventricular tachycardia, principally atrial fibrillation and atrial flutter. The majority of these patients developed their arrhythmias postoperatively. About 60-70% of the patients treated with BREVIBLOC injection developed either a 20% reduction in heart rate, a decrease in heart rate to less than 100 bpm, or, rarely, conversion to normal sinus rhythm and about 95% of these patients did so at a dosage of 200 mcg/kg/min or less. The average effective dosage of BREVIBLOC injection was approximately 100 mcg/kg/min in the two studies. Other multicenter baseline-controlled studies gave similar results. In the comparison with propranolol, about 50% of patients in both the BREVIBLOC injection and propranolol groups were on concomitant digoxin. Response rates were slightly higher with both beta blockers in the digoxin-treated patients." }

In all studies significant decreases of blood pressure occurred in 20-50% of patients, identified either as adverse reaction reports by investigators, or by observation of systolic pressure less than 90 mmHg or diastolic pressure less than 50 mmHg. The hypotension was symptomatic (mainly hyperhidrosis or dizziness) in about 12% of patients, and therapy was discontinued in about 11% of patients, about half of whom were symptomatic. Hypotension was more common with BREVIBLOC injection (53%) than with propranolol (17%). The hypotension was rapidly reversible with decreased infusion rate or after discontinuation of therapy with BREVIBLOC injection. For both BREVIBLOC injection and propranolol, hypotension was reported less frequently in patients receiving concomitant digoxin.

{ "type": "p", "children": [], "text": "In all studies significant decreases of blood pressure occurred in 20-50% of patients, identified either as adverse reaction reports by investigators, or by observation of systolic pressure less than 90 mmHg or diastolic pressure less than 50 mmHg. The hypotension was symptomatic (mainly hyperhidrosis or dizziness) in about 12% of patients, and therapy was discontinued in about 11% of patients, about half of whom were symptomatic. Hypotension was more common with BREVIBLOC injection (53%) than with propranolol (17%). The hypotension was rapidly reversible with decreased infusion rate or after discontinuation of therapy with BREVIBLOC injection. For both BREVIBLOC injection and propranolol, hypotension was reported less frequently in patients receiving concomitant digoxin." }

BREVIBLOC PREMIXED Injection

BREVIBLOC PREMIXED Double Strength Injection

BREVIBLOC Injection

Store at 25˚C (77˚F). Excursions permitted to 15˚-30˚C (59˚-86˚F) [see USP Controlled Room Temperature]. Protect from freezing. Avoid excessive heat.

Each bag contains no preservative. Once drug has been withdrawn from ready-to-use bag, the bag should be used within 24 hours, with any unused portion discarded.

Visually inspect the container. If the administration port protector is damaged, detached, or not present, discard container as solution path sterility may be impaired.

Do not use plastic containers in series connections. Such use could result in an embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.

Do not remove unit from overwrap until ready to use. Do not use if overwrap has been previously opened or damaged. The overwrap is a moisture barrier. The inner bag maintains sterility of the solution. Tear overwrap at notch and remove premixed bag. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.

Check for minute leaks by squeezing the inner bag firmly. If leaks are found, discard solution, as sterility may be impaired. Do not use unless the solution is clear (colorless to light yellow) and the seal is intact.

Preparation for intravenous administration:

Physicians should inform patients of the risks associated with BREVIBLOC injection:

{ "type": "p", "children": [], "text": "Physicians should inform patients of the risks associated with BREVIBLOC injection:" }

{ "type": "", "children": [], "text": "" }

Manufactured for

{ "type": "p", "children": [], "text": "Manufactured for" }

Baxter Healthcare Corporation

{ "type": "p", "children": [], "text": "\nBaxter Healthcare Corporation\n" }

Deerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "Deerfield, IL 60015 USA" }

Baxter, Brevibloc, Brevibloc Premixed and Intravia are trademarks of Baxter International Inc.

{ "type": "p", "children": [], "text": "Baxter, Brevibloc, Brevibloc Premixed and Intravia are trademarks of Baxter International Inc." }

Novaplus is a registered trademark of Vizient, Inc.

{ "type": "p", "children": [], "text": "Novaplus is a registered trademark of Vizient, Inc. " }

0719006353

{ "type": "p", "children": [], "text": "0719006353" }

{ "type": "", "children": [], "text": "" }

LOT EXP

{ "type": "p", "children": [], "text": "LOT EXP" }

NDC 10019-668-10 BREVIBLOCPREMIXEDDOUBLE STRENGTH Injection Esmolol Hydrochloride in Sodium Chloride2,000 mg/100 mL (20 mg/mL)

{ "type": "p", "children": [], "text": "NDC 10019-668-10\nBREVIBLOCPREMIXEDDOUBLE STRENGTH Injection\n\nEsmolol Hydrochloride in Sodium Chloride2,000 mg/100 mL (20 mg/mL)\n" }

100 mLIso-Osmotic • No Preservative AddedSingle Intravenous Use Only Each mL contains 20 mg Esmolol HydrochlorideUSP 4.1 mg Sodium Chloride USP in Waterfor Injection USP Buffered with 2.8 mg SodiumAcetate Trihydrate USP and 0.546 mg GlacialAcetic Acid USP pH adjusted with sodiumhydroxide and/or hydrochloric acid pH 5.0(4.5-5.5) Sterile Nonpyrogenic USUAL DOSAGE See package insert CAUTIONS Check for leaks by squeezingcontainer firmly If leaks are found discard assterility may be impaired Use only if solution isclear colorless to light yellowDiscard unused portion DO NOT INTRODUCE ADDITIVES Must not be used in series connections Store at 25°C (77°F) Excursions permitted to15°-30°C (59°-86°F) [See USP Controlled RoomTemperature] PROTECT FROM FREEZINGAvoid excessive heat Rx only

{ "type": "p", "children": [], "text": "\n100 mLIso-Osmotic • No Preservative AddedSingle Intravenous Use Only\nEach mL contains 20 mg Esmolol HydrochlorideUSP 4.1 mg Sodium Chloride USP in Waterfor Injection USP Buffered with 2.8 mg SodiumAcetate Trihydrate USP and 0.546 mg GlacialAcetic Acid USP pH adjusted with sodiumhydroxide and/or hydrochloric acid pH 5.0(4.5-5.5) Sterile Nonpyrogenic\nUSUAL DOSAGE See package insert\nCAUTIONS Check for leaks by squeezingcontainer firmly If leaks are found discard assterility may be impaired Use only if solution isclear colorless to light yellowDiscard unused portion\nDO NOT INTRODUCE ADDITIVES\nMust not be used in series connections\nStore at 25°C (77°F) Excursions permitted to15°-30°C (59°-86°F) [See USP Controlled RoomTemperature] PROTECT FROM FREEZINGAvoid excessive heat Rx only\n" }

MANUFACTURED BY Baxter Logo USA novaplus logo

{ "type": "p", "children": [], "text": "MANUFACTURED BY\n\nBaxter Logo\nUSA\nnovaplus logo\n" }

0725005676 2J1416

{ "type": "p", "children": [], "text": "0725005676 2J1416\n" }

{ "type": "", "children": [], "text": "" }

LOT EXP

{ "type": "p", "children": [], "text": "LOT EXP" }

NDC 10019-672-10 BREVIBLOCPREMIXEDDouble Strength Injection Esmolol Hydrochloride in Sodium Chloride2,500 mg/250 mL (10 mg/mL)

{ "type": "p", "children": [], "text": "NDC 10019-672-10\nBREVIBLOCPREMIXEDDouble Strength Injection\nEsmolol Hydrochloride in Sodium Chloride2,500 mg/250 mL (10 mg/mL)" }

250 mLIso-Osmotic No Preservative AddedSingle Intravenous Use Only

{ "type": "p", "children": [], "text": "\n250 mLIso-Osmotic No Preservative AddedSingle Intravenous Use Only\n" }

EACH mL CONTAINS 10 mg ESMOLOL HYDROCHLORIDE USP 5.9 mg SODIUM CHLORIDE USP IN WATER FOR INJECTION USP BUFFERED WITH 2.8 mg SODIUMACETATE TRIHYDRATE USP AND 0.546 mg GLACIAL ACETIC ACID USP PH ADJUSTED WITH SODIUM HYDROXIDE AND/OR HYDROCHLORIC ACID PH 5.0 (4.5-5.5) STERILE NONPYROGENIC

{ "type": "p", "children": [], "text": "EACH mL CONTAINS 10 mg ESMOLOL HYDROCHLORIDE USP 5.9 mg SODIUM CHLORIDE USP IN WATER FOR INJECTION USP BUFFERED WITH 2.8 mg SODIUMACETATE TRIHYDRATE USP AND 0.546 mg GLACIAL ACETIC ACID USP PH ADJUSTED WITH SODIUM HYDROXIDE AND/OR HYDROCHLORIC ACID PH 5.0 (4.5-5.5) STERILE NONPYROGENIC" }

USUAL DOSAGE SEE PACKAGE INSERT CAUTIONS CHECK FOR LE AKS BY SQUEEZING CONTAINER FIRMLY IF LEAKS ARE FOUND DISCARD AS STERILITY MAY BE IMPAIRED USE ONLY IF SOLUTION IS CLEAR COLORLESS TO LIGHT YELLOW DISCARD UNUSED PORTION DO NOT INTRODUCE ADDITIVES MUST NOT BE USED IN SERIES CONNECTIONS STORE AT 25°C (77°F) EXCURSIONS PERMITTED TO 15°-30°C (59°-86°F) [SEE USP CONTROLLED ROOM TEMPERATURE] PROTECT FROM FREEZING AVOID EXCESSIVE HEAT RX ONLY

{ "type": "p", "children": [], "text": "\nUSUAL DOSAGE SEE PACKAGE INSERT\nCAUTIONS CHECK FOR LE AKS BY SQUEEZING CONTAINER FIRMLY IF LEAKS ARE FOUND DISCARD AS STERILITY MAY BE IMPAIRED USE ONLY IF SOLUTION IS CLEAR COLORLESS TO LIGHT YELLOW DISCARD UNUSED PORTION\nDO NOT INTRODUCE ADDITIVES\nMUST NOT BE USED IN SERIES CONNECTIONS\nSTORE AT 25°C (77°F) EXCURSIONS PERMITTED TO 15°-30°C (59°-86°F) [SEE USP CONTROLLED ROOM TEMPERATURE] PROTECT FROM FREEZING AVOID EXCESSIVE HEAT RX ONLY\n" }

MANUFACTURED BY BAXTER LOGO novaplus logo USA

{ "type": "p", "children": [], "text": "MANUFACTURED BY\n\nBAXTER LOGO\nnovaplus logo\nUSA" }

INTRAVIA CONTAINER460-327-02 2J1417 FOR PRODUCT INQUIRY1 800 ANA DRUG(1-800-262-3784)

{ "type": "p", "children": [], "text": "INTRAVIA CONTAINER460-327-02 2J1417\nFOR PRODUCT INQUIRY1 800 ANA DRUG(1-800-262-3784)" }

1.1 Supraventricular Tachycardia or Noncompensatory Sinus Tachycardia

{ "type": "p", "children": [], "text": "\n1.1 Supraventricular Tachycardia or Noncompensatory Sinus Tachycardia\n" }

Esmolol hydrochloride injection is indicated for the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other emergent circumstances where short term control of ventricular rate with a short-acting agent is desirable. Esmolol hydrochloride injection is also indicated in noncompensatory sinus tachycardia where, in the physician’s judgment, the rapid heart rate requires specific intervention. Esmolol hydrochloride injection is intended for short-term use.

{ "type": "p", "children": [], "text": "Esmolol hydrochloride injection is indicated for the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other emergent circumstances where short term control of ventricular rate with a short-acting agent is desirable. Esmolol hydrochloride injection is also indicated in noncompensatory sinus tachycardia where, in the physician’s judgment, the rapid heart rate requires specific intervention. Esmolol hydrochloride injection is intended for short-term use." }

1.2 Intraoperative and Postoperative Tachycardia and/or Hypertension

{ "type": "p", "children": [], "text": "\n1.2 Intraoperative and Postoperative Tachycardia and/or Hypertension\n" }

Esmolol hydrochloride injection is indicated for the short-term treatment of tachycardia and hypertension that occur during induction and tracheal intubation, during surgery, on emergence from anesthesia and in the postoperative period, when in the physician’s judgment such specific intervention is considered indicated.

{ "type": "p", "children": [], "text": "Esmolol hydrochloride injection is indicated for the short-term treatment of tachycardia and hypertension that occur during induction and tracheal intubation, during surgery, on emergence from anesthesia and in the postoperative period, when in the physician’s judgment such specific intervention is considered indicated." }

Use of esmolol hydrochloride injection to prevent such events is not recommended.

{ "type": "p", "children": [], "text": "Use of esmolol hydrochloride injection to prevent such events is not recommended." }

2.1 Dosing for the Treatment of Supraventricular Tachycardia or Noncompensatory Sinus Tachycardia

{ "type": "p", "children": [], "text": "\n2.1 Dosing for the Treatment of Supraventricular Tachycardia or Noncompensatory Sinus Tachycardia\n" }

Esmolol hydrochloride injection is administered by continuous intravenous infusion with or without a loading dose. Additional loading doses and/or titration of the maintenance infusion (step-wise dosing) may be necessary based on desired ventricular response.

{ "type": "p", "children": [], "text": "Esmolol hydrochloride injection is administered by continuous intravenous infusion with or without a loading dose. Additional loading doses and/or titration of the maintenance infusion (step-wise dosing) may be necessary based on desired ventricular response." }

In the absence of loading doses, continuous infusion of a single concentration of esmolol reaches pharmacokinetic and pharmacodynamic steady-state in about 30 minutes.

{ "type": "p", "children": [], "text": "In the absence of loading doses, continuous infusion of a single concentration of esmolol reaches pharmacokinetic and pharmacodynamic steady-state in about 30 minutes." }

The effective maintenance dose for continuous and step-wise dosing is 50 to 200 mcg per kg per minute, although doses as low as 25 mcg per kg per minute have been adequate. Dosages greater than 200 mcg per kg per minute provide little added heart rate lowering effect, and the rate of adverse reactions increases.

{ "type": "p", "children": [], "text": "The effective maintenance dose for continuous and step-wise dosing is 50 to 200 mcg per kg per minute, although doses as low as 25 mcg per kg per minute have been adequate. Dosages greater than 200 mcg per kg per minute provide little added heart rate lowering effect, and the rate of adverse reactions increases." }

Maintenance infusions may be continued for up to 48 hours.

{ "type": "p", "children": [], "text": "Maintenance infusions may be continued for up to 48 hours." }

2.2 Intraoperative and Postoperative Tachycardia and Hypertension

{ "type": "p", "children": [], "text": "\n2.2 Intraoperative and Postoperative Tachycardia and Hypertension\n" }

In this setting it is not always advisable to slowly titrate to a therapeutic effect. Therefore two dosing options are presented: immediate control and gradual control.

{ "type": "p", "children": [], "text": "In this setting it is not always advisable to slowly titrate to a therapeutic effect. Therefore two dosing options are presented: immediate control and gradual control." }

Immediate Control

{ "type": "p", "children": [], "text": "Immediate Control" }

         • Administer 1 mg per kg as a bolus dose over 30 seconds followed by an infusion of 150 mcg per kg per min if necessary.

{ "type": "p", "children": [], "text": "         • Administer 1 mg per kg as a bolus dose over 30 seconds followed by an infusion of 150 mcg per kg per min if necessary." }

         • Adjust the infusion rate as required to maintain desired heart rate and blood pressure. Refer to Maximum Recommended Doses below.

{ "type": "p", "children": [], "text": "         • Adjust the infusion rate as required to maintain desired heart rate and blood pressure. Refer to Maximum Recommended Doses below." }

Gradual Control

{ "type": "p", "children": [], "text": "Gradual Control" }

         • Administer 500 mcg per kg as a bolus dose over 1 minute followed by a maintenance infusion of 50 mcg per kg per min for 4 minutes.

{ "type": "p", "children": [], "text": "         • Administer 500 mcg per kg as a bolus dose over 1 minute followed by a maintenance infusion of 50 mcg per kg per min for 4 minutes." }

         • Depending on the response obtained, continue dosing as outlined for supraventricular tachycardia. Refer to Maximum Recommended             Doses below.

{ "type": "p", "children": [], "text": "         • Depending on the response obtained, continue dosing as outlined for supraventricular tachycardia. Refer to Maximum Recommended             Doses below." }

Maximum Recommended Doses

{ "type": "p", "children": [], "text": "Maximum Recommended Doses" }

         •For the treatment of tachycardia, maintenance infusion dosages greater than 200 mcg per kg per min are not recommended; dosages            greater than 200 mcg per kg per min provide little additional heart rate-lowering effect, and the rate of adverse reactions increases.

{ "type": "p", "children": [], "text": "         •For the treatment of tachycardia, maintenance infusion dosages greater than 200 mcg per kg per min are not recommended; dosages            greater than 200 mcg per kg per min provide little additional heart rate-lowering effect, and the rate of adverse reactions increases." }

         •For the treatment of hypertension, higher maintenance infusion dosages (250-300 mcg per kg per min) may be required. The safety of            doses above 300 mcg per kg per minute has not been studied.

{ "type": "p", "children": [], "text": "         •For the treatment of hypertension, higher maintenance infusion dosages (250-300 mcg per kg per min) may be required. The safety of            doses above 300 mcg per kg per minute has not been studied." }

2.3 Transition from Esmolol Hydrochloride Injection Therapy to Alternative Drugs

{ "type": "p", "children": [], "text": "\n2.3 Transition from Esmolol Hydrochloride Injection Therapy to Alternative Drugs\n" }

After patients achieve adequate control of the heart rate and a stable clinical status, transition to alternative antiarrhythmic drugs may be accomplished.

{ "type": "p", "children": [], "text": "After patients achieve adequate control of the heart rate and a stable clinical status, transition to alternative antiarrhythmic drugs may be accomplished." }

When transitioning from esmolol hydrochloride injection to alternative drugs, the physician should carefully consider the labeling instructions of the alternative drug selected and reduce the dosage of esmolol hydrochloride injection as follows:

{ "type": "p", "children": [], "text": "When transitioning from esmolol hydrochloride injection to alternative drugs, the physician should carefully consider the labeling instructions of the alternative drug selected and reduce the dosage of esmolol hydrochloride injection as follows:" }

         1.Thirty minutes following the first dose of the alternative drug, reduce the esmolol hydrochloride infusion rate by one-half (50%).

{ "type": "p", "children": [], "text": "         1.Thirty minutes following the first dose of the alternative drug, reduce the esmolol hydrochloride infusion rate by one-half (50%)." }

         2.After administration of the second dose of the alternative drug, monitor the patient's response and if satisfactory control is maintained               for the first hour, discontinue the esmolol hydrochloride infusion.

{ "type": "p", "children": [], "text": "         2.After administration of the second dose of the alternative drug, monitor the patient's response and if satisfactory control is maintained               for the first hour, discontinue the esmolol hydrochloride infusion." }

2.4 Directions for Use

{ "type": "p", "children": [], "text": "\n2.4 Directions for Use\n" }

Esmolol hydrochloride injection is available in a single-dose vial. Esmolol hydrochloride injection is not compatible with Sodium Bicarbonate (5%) solution (limited stability) or furosemide (precipitation).

{ "type": "p", "children": [], "text": "Esmolol hydrochloride injection is available in a single-dose vial. Esmolol hydrochloride injection is not compatible with Sodium Bicarbonate (5%) solution (limited stability) or furosemide (precipitation)." }

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

{ "type": "p", "children": [], "text": "Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit." }

Discard unused portion.

{ "type": "p", "children": [], "text": "Discard unused portion." }

Single-Dose Vial: The single-dose vial may be used to administer a loading dosage by hand-held syringe while the maintenance infusion is being prepared.

{ "type": "p", "children": [], "text": "\nSingle-Dose Vial: The single-dose vial may be used to administer a loading dosage by hand-held syringe while the maintenance infusion is being prepared." }

Esmolol hydrochloride injection is contraindicated in patients with:

{ "type": "p", "children": [], "text": "Esmolol hydrochloride injection is contraindicated in patients with:" }

• Severe sinus bradycardia: May precipitate or worsen bradycardia resulting in cardiogenic shock and cardiac arrest [see Warnings and Precautions (5.2)].• Heart block greater than first degree: Second- or third-degree atrioventricular block may precipitate or worsen bradycardia resulting in cardiogenic shock and cardiac arrest [see Warnings and Precautions (5.2)].• Sick sinus syndrome: May precipitate or worsen bradycardia resulting in cardiogenic shock and cardiac arrest [see Warnings and Precautions (5.2)].• Decompensated heart failure: May worsen heart failure.• Cardiogenic shock: May precipitate further cardiovascular collapse and cause cardiac arrest.• IV administration of cardiodepressant calcium-channel antagonists (e.g., verapamil) and esmolol hydrochloride injection in close proximity (i.e., while cardiac effects from the other are still present); fatal cardiac arrests have occurred in patients receiving esmolol hydrochloride injection and intravenous verapamil.• Pulmonary hypertension: May precipitate cardiorespiratory compromise.• Hypersensitivity reactions, including anaphylaxis, to esmolol or any of the inactive ingredients of the product (cross-sensitivity between beta blockers is possible).

{ "type": "p", "children": [], "text": "• Severe sinus bradycardia: May precipitate or worsen bradycardia resulting in cardiogenic shock and cardiac arrest [see Warnings and Precautions (5.2)].• Heart block greater than first degree: Second- or third-degree atrioventricular block may precipitate or worsen bradycardia resulting in cardiogenic shock and cardiac arrest [see Warnings and Precautions (5.2)].• Sick sinus syndrome: May precipitate or worsen bradycardia resulting in cardiogenic shock and cardiac arrest [see Warnings and Precautions (5.2)].• Decompensated heart failure: May worsen heart failure.• Cardiogenic shock: May precipitate further cardiovascular collapse and cause cardiac arrest.• IV administration of cardiodepressant calcium-channel antagonists (e.g., verapamil) and esmolol hydrochloride injection in close proximity (i.e., while cardiac effects from the other are still present); fatal cardiac arrests have occurred in patients receiving esmolol hydrochloride injection and intravenous verapamil.• Pulmonary hypertension: May precipitate cardiorespiratory compromise.• Hypersensitivity reactions, including anaphylaxis, to esmolol or any of the inactive ingredients of the product (cross-sensitivity between beta blockers is possible)." }

5.1 Hypotension

{ "type": "p", "children": [], "text": "\n5.1 Hypotension\n" }

Hypotension can occur at any dose but is dose-related. Patients with hemodynamic compromise or on interacting medications are at particular risk. Severe reactions may include loss of consciousness, cardiac arrest, and death. For control of ventricular heart rate, maintenance doses greater than 200 mcg per kg per min are not recommended. Monitor patients closely, especially if pretreatment blood pressure is low. In case of an unacceptable drop in blood pressure, reduce or stop esmolol hydrochloride injection. Decrease of dose or termination of infusion reverses hypotension, usually within 30 minutes.

{ "type": "p", "children": [], "text": "Hypotension can occur at any dose but is dose-related. Patients with hemodynamic compromise or on interacting medications are at particular risk. Severe reactions may include loss of consciousness, cardiac arrest, and death. For control of ventricular heart rate, maintenance doses greater than 200 mcg per kg per min are not recommended. Monitor patients closely, especially if pretreatment blood pressure is low. In case of an unacceptable drop in blood pressure, reduce or stop esmolol hydrochloride injection. Decrease of dose or termination of infusion reverses hypotension, usually within 30 minutes." }

5.2 Bradycardia

{ "type": "p", "children": [], "text": "\n5.2 Bradycardia\n" }

Bradycardia, including sinus pause, heart block, severe bradycardia, and cardiac arrest have occurred with the use of esmolol hydrochloride injection. 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 esmolol hydrochloride injection [see Contraindications (4)].

{ "type": "p", "children": [], "text": "Bradycardia, including sinus pause, heart block, severe bradycardia, and cardiac arrest have occurred with the use of esmolol hydrochloride injection. 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 esmolol hydrochloride injection [see Contraindications (4)]." }

If severe bradycardia develops, reduce or stop esmolol hydrochloride injection.

{ "type": "p", "children": [], "text": "If severe bradycardia develops, reduce or stop esmolol hydrochloride injection." }

5.3 Cardiac Failure

{ "type": "p", "children": [], "text": "\n5.3 Cardiac Failure\n" }

Beta blockers, like esmolol hydrochloride injection, can cause depression of myocardial contractility and may precipitate heart failure and cardiogenic shock. At the first sign or symptom of impending cardiac failure, stop esmolol hydrochloride injection and start supportive therapy [see Overdosage (10)].

{ "type": "p", "children": [], "text": "Beta blockers, like esmolol hydrochloride injection, can cause depression of myocardial contractility and may precipitate heart failure and cardiogenic shock. At the first sign or symptom of impending cardiac failure, stop esmolol hydrochloride injection and start supportive therapy [see Overdosage (10)]." }

5.4 Intraoperative and Postoperative Tachycardia and/or Hypertension

{ "type": "p", "children": [], "text": "\n5.4 Intraoperative and Postoperative Tachycardia and/or Hypertension\n" }

Monitor vital signs closely and titrate esmolol hydrochloride injection slowly in the treatment of patients whose blood pressure is primarily driven by vasoconstriction associated with hypothermia.

{ "type": "p", "children": [], "text": "Monitor vital signs closely and titrate esmolol hydrochloride injection slowly in the treatment of patients whose blood pressure is primarily driven by vasoconstriction associated with hypothermia." }

5.5 Reactive Airways Disease

{ "type": "p", "children": [], "text": "\n5.5 Reactive Airways Disease\n" }

Patients with reactive airways disease should, in general, not receive beta blockers. Because of its relative beta1 selectivity and titratability, titrate esmolol hydrochloride injection to the lowest possible effective dose. In the event of bronchospasm, stop the infusion immediately; a beta2 stimulating agent may be administered with appropriate monitoring of ventricular rates.

{ "type": "p", "children": [], "text": "Patients with reactive airways disease should, in general, not receive beta blockers. Because of its relative beta1 selectivity and titratability, titrate esmolol hydrochloride injection to the lowest possible effective dose. In the event of bronchospasm, stop the infusion immediately; a beta2 stimulating agent may be administered with appropriate monitoring of ventricular rates." }

5.6 Hypoglycemia

{ "type": "p", "children": [], "text": "\n5.6 Hypoglycemia\n" }

Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment.

{ "type": "p", "children": [], "text": "Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment." }

5.7 Infusion Site Reactions

{ "type": "p", "children": [], "text": "\n5.7 Infusion Site Reactions\n" }

Infusion site reactions have occurred with the use of esmolol hydrochloride injection. They include irritation, inflammation, and severe reactions (thrombophlebitis, necrosis, and blistering), in particular when associated with extravasation [see Adverse Reactions (6)]. Avoid infusions into small veins or through a butterfly catheter.

{ "type": "p", "children": [], "text": "Infusion site reactions have occurred with the use of esmolol hydrochloride injection. They include irritation, inflammation, and severe reactions (thrombophlebitis, necrosis, and blistering), in particular when associated with extravasation [see Adverse Reactions (6)]. Avoid infusions into small veins or through a butterfly catheter." }

If a local infusion site reaction develops, use an alternative infusion site and avoid extravasation.

{ "type": "p", "children": [], "text": "If a local infusion site reaction develops, use an alternative infusion site and avoid extravasation." }

5.8 Use in Patients with Prinzmetal’s Angina

{ "type": "p", "children": [], "text": "\n5.8 Use in Patients with Prinzmetal’s Angina\n" }

Beta blockers may exacerbate anginal attacks in patients with Prinzmetal’s angina because of unopposed alpha receptor–mediated coronary artery vasoconstriction. Do not use nonselective beta blockers.

{ "type": "p", "children": [], "text": "Beta blockers may exacerbate anginal attacks in patients with Prinzmetal’s angina because of unopposed alpha receptor–mediated coronary artery vasoconstriction. Do not use nonselective beta blockers." }

5.9 Use in Patients with Pheochromocytoma

{ "type": "p", "children": [], "text": "\n5.9 Use in Patients with Pheochromocytoma\n" }

If esmolol hydrochloride injection is used in the setting of pheochromocytoma, give it 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 from the attenuation of beta-mediated vasodilation in skeletal muscle.

{ "type": "p", "children": [], "text": "If esmolol hydrochloride injection is used in the setting of pheochromocytoma, give it 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 from the attenuation of beta-mediated vasodilation in skeletal muscle." }

5.10 Use in Hypovolemic Patients

{ "type": "p", "children": [], "text": "\n5.10 Use in Hypovolemic Patients\n" }

In hypovolemic patients, esmolol hydrochloride injection can attenuate reflex tachycardia and increase the risk of hypotension.

{ "type": "p", "children": [], "text": "In hypovolemic patients, esmolol hydrochloride injection can attenuate reflex tachycardia and increase the risk of hypotension." }

5.11 Use in Patients with Peripheral Circulatory Disorders

{ "type": "p", "children": [], "text": "\n5.11 Use in Patients with Peripheral Circulatory Disorders\n" }

In patients with peripheral circulatory disorders (including Raynaud’s disease or syndrome, and peripheral occlusive vascular disease), esmolol hydrochloride injection may aggravate peripheral circulatory disorders.

{ "type": "p", "children": [], "text": "In patients with peripheral circulatory disorders (including Raynaud’s disease or syndrome, and peripheral occlusive vascular disease), esmolol hydrochloride injection may aggravate peripheral circulatory disorders." }

5.12 Abrupt Discontinuation of Esmolol Hydrochloride Injection

{ "type": "p", "children": [], "text": "\n5.12 Abrupt Discontinuation of Esmolol Hydrochloride Injection\n" }

Severe exacerbations of angina, myocardial infarction, and ventricular arrhythmias have been reported in patients with coronary artery disease upon abrupt discontinuation of beta blocker therapy. Observe patients for signs of myocardial ischemia when discontinuing esmolol hydrochloride injection.

{ "type": "p", "children": [], "text": "Severe exacerbations of angina, myocardial infarction, and ventricular arrhythmias have been reported in patients with coronary artery disease upon abrupt discontinuation of beta blocker therapy. Observe patients for signs of myocardial ischemia when discontinuing esmolol hydrochloride injection." }

Heart rate increases moderately above pretreatment levels 30 minutes after esmolol hydrochloride injection discontinuation.

{ "type": "p", "children": [], "text": "Heart rate increases moderately above pretreatment levels 30 minutes after esmolol hydrochloride injection discontinuation." }

5.13 Hyperkalemia

{ "type": "p", "children": [], "text": "\n5.13 Hyperkalemia\n" }

Beta blockers, including esmolol hydrochloride injection, have been associated with increases in serum potassium levels and hyperkalemia. The risk is increased in patients with risk factors such as renal impairment. Intravenous administration of beta blockers has been reported to cause potentially life-threatening hyperkalemia in hemodialysis patients. Monitor serum electrolytes during therapy with esmolol hydrochloride injection.

{ "type": "p", "children": [], "text": "Beta blockers, including esmolol hydrochloride injection, have been associated with increases in serum potassium levels and hyperkalemia. The risk is increased in patients with risk factors such as renal impairment. Intravenous administration of beta blockers has been reported to cause potentially life-threatening hyperkalemia in hemodialysis patients. Monitor serum electrolytes during therapy with esmolol hydrochloride injection." }

5.14 Use in Patients with Metabolic Acidosis

{ "type": "p", "children": [], "text": "\n5.14 Use in Patients with Metabolic Acidosis\n" }

Beta blockers, including esmolol hydrochloride injection, have been reported to cause hyperkalemic renal tubular acidosis. Acidosis in general may be associated with reduced cardiac contractility.

{ "type": "p", "children": [], "text": "Beta blockers, including esmolol hydrochloride injection, have been reported to cause hyperkalemic renal tubular acidosis. Acidosis in general may be associated with reduced cardiac contractility." }

5.15 Use in Patients with Hyperthyroidism

{ "type": "p", "children": [], "text": "\n5.15 Use in Patients with Hyperthyroidism\n" }

Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Abrupt withdrawal of beta blockade might precipitate a thyroid storm; therefore, monitor patients for signs of thyrotoxicosis when withdrawing beta blocking therapy.

{ "type": "p", "children": [], "text": "Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Abrupt withdrawal of beta blockade might precipitate a thyroid storm; therefore, monitor patients for signs of thyrotoxicosis when withdrawing beta blocking therapy." }

5.16 Use in Patients at Risk of Severe Acute Hypersensitivity Reactions

{ "type": "p", "children": [], "text": "\n5.16 Use in Patients at Risk of Severe Acute Hypersensitivity Reactions\n" }

When using beta blockers, patients at risk of anaphylactic reactions may be more reactive to allergen exposure (accidental, diagnostic, or therapeutic).

{ "type": "p", "children": [], "text": "When using beta blockers, patients at risk of anaphylactic reactions may be more reactive to allergen exposure (accidental, diagnostic, or therapeutic)." }

Patients using beta blockers may be unresponsive to the usual doses of epinephrine used to treat anaphylactic or anaphylactoid reactions [see Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Patients using beta blockers may be unresponsive to the usual doses of epinephrine used to treat anaphylactic or anaphylactoid reactions [see Drug Interactions (7)]." }

6.1 Clinical Trials Experience

{ "type": "p", "children": [], "text": "\n6.1 Clinical Trials Experience\n" }

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

{ "type": "p", "children": [], "text": "Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice." }

The following adverse reaction rates are based on use of esmolol hydrochloride injection in clinical trials involving 369 patients with supraventricular tachycardia and over 600 intraoperative and postoperative patients enrolled in clinical trials. Most adverse effects observed in controlled clinical trial settings have been mild and transient. The most important and common adverse effect has been hypotension [see Warnings and Precautions (5.1)]. Deaths have been reported in post-marketing experience occurring during complex clinical states where esmolol hydrochloride injection was presumably being used simply to control ventricular rate [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "The following adverse reaction rates are based on use of esmolol hydrochloride injection in clinical trials involving 369 patients with supraventricular tachycardia and over 600 intraoperative and postoperative patients enrolled in clinical trials. Most adverse effects observed in controlled clinical trial settings have been mild and transient. The most important and common adverse effect has been hypotension [see Warnings and Precautions (5.1)]. Deaths have been reported in post-marketing experience occurring during complex clinical states where esmolol hydrochloride injection was presumably being used simply to control ventricular rate [see Warnings and Precautions (5.5)]." }

*Hypotension resolved during esmolol hydrochloride infusion in 63% of patients. In 80% of the remaining patients, hypotension resolved within 30 minutes following discontinuation of infusion.

{ "type": "p", "children": [], "text": "*Hypotension resolved during esmolol hydrochloride infusion in 63% of patients. In 80% of the remaining patients, hypotension resolved within 30 minutes following discontinuation of infusion." }

Clinical Trial Adverse Reactions (Frequency < 3%):

{ "type": "p", "children": [], "text": "\nClinical Trial Adverse Reactions (Frequency < 3%):\n" }

Psychiatric Disorders:

{ "type": "p", "children": [], "text": "Psychiatric Disorders:" }

Confusional state and agitation (~2%)Anxiety, depression and abnormal thinking (< 1%)

{ "type": "p", "children": [], "text": "Confusional state and agitation (~2%)Anxiety, depression and abnormal thinking (< 1%)" }

Nervous System Disorders:

{ "type": "p", "children": [], "text": "Nervous System Disorders:" }

Headache (~2%)Paresthesia, syncope, speech disorder, and lightheadedness (< 1%)Convulsions (< 1%), with one death

{ "type": "p", "children": [], "text": "Headache (~2%)Paresthesia, syncope, speech disorder, and lightheadedness (< 1%)Convulsions (< 1%), with one death" }

Vascular Disorders:

{ "type": "p", "children": [], "text": "Vascular Disorders:" }

Peripheral ischemia (~1%)Pallor and flushing (< 1%)

{ "type": "p", "children": [], "text": "Peripheral ischemia (~1%)Pallor and flushing (< 1%)" }

Gastrointestinal Disorders:

{ "type": "p", "children": [], "text": "Gastrointestinal Disorders:" }

Vomiting (~1%)Dyspepsia, constipation, dry mouth, and abdominal discomfort (< 1%)

{ "type": "p", "children": [], "text": "Vomiting (~1%)Dyspepsia, constipation, dry mouth, and abdominal discomfort (< 1%)" }

Renal and Urinary Disorders:

{ "type": "p", "children": [], "text": "Renal and Urinary Disorders:" }

Urinary retention (< 1%)

{ "type": "p", "children": [], "text": "Urinary retention (< 1%)" }

6.2 Post-Marketing Experience

{ "type": "p", "children": [], "text": "\n6.2 Post-Marketing Experience\n" }

In addition to the adverse reactions reported in clinical trials, the following adverse reactions have been reported in the post-marketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or to establish a causal relationship to drug exposure.

{ "type": "p", "children": [], "text": "In addition to the adverse reactions reported in clinical trials, the following adverse reactions have been reported in the post-marketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or to establish a causal relationship to drug exposure." }

Cardiac Disorders:

{ "type": "p", "children": [], "text": "Cardiac Disorders:" }

Cardiac arrest, Coronary arteriospasm

{ "type": "p", "children": [], "text": "Cardiac arrest, Coronary arteriospasm" }

Skin and Subcutaneous Tissue Disorders:

{ "type": "p", "children": [], "text": "Skin and Subcutaneous Tissue Disorders:" }

Angioedema, Urticaria, Psoriasis

{ "type": "p", "children": [], "text": "Angioedema, Urticaria, Psoriasis" }

Concomitant use of esmolol hydrochloride injection with other drugs that can lower blood pressure, reduce myocardial contractility, or interfere with sinus node function or electrical impulse propagation in the myocardium can exaggerate esmolol hydrochloride injection’s effects on blood pressure, contractility, and impulse propagation. Severe interactions with such drugs can result in, for example, severe hypotension, cardiac failure, severe bradycardia, sinus pause, sinoatrial block, atrioventricular block, and/or cardiac arrest. In addition, with some drugs, beta blockade may precipitate increased withdrawal effects. (See clonidine, guanfacine, and moxonidine below.) Esmolol hydrochloride injection should therefore be used only after careful individual assessment of the risks and expected benefits in patients receiving drugs that can cause these types of pharmacodynamic interactions, including but not limited to:

{ "type": "p", "children": [], "text": "Concomitant use of esmolol hydrochloride injection with other drugs that can lower blood pressure, reduce myocardial contractility, or interfere with sinus node function or electrical impulse propagation in the myocardium can exaggerate esmolol hydrochloride injection’s effects on blood pressure, contractility, and impulse propagation. Severe interactions with such drugs can result in, for example, severe hypotension, cardiac failure, severe bradycardia, sinus pause, sinoatrial block, atrioventricular block, and/or cardiac arrest. In addition, with some drugs, beta blockade may precipitate increased withdrawal effects. (See clonidine, guanfacine, and moxonidine below.) Esmolol hydrochloride injection should therefore be used only after careful individual assessment of the risks and expected benefits in patients receiving drugs that can cause these types of pharmacodynamic interactions, including but not limited to:" }

• Digitalis glycosides: Concomitant administration of digoxin and esmolol hydrochloride injection leads to an approximate 10% to 20% increase of    digoxin blood levels at some time points. Digoxin does not affect esmolol hydrochloride injection pharmacokinetics. Both digoxin and beta    blockers slow atrioventricular conduction and decrease heart rate. Concomitant use increases the risk of bradycardia.• Anticholinesterases: Esmolol hydrochloride injection prolonged the duration of succinylcholine-induced neuromuscular blockade and moderately    prolonged clinical duration and recovery index of mivacurium.• Antihypertensive agents clonidine, guanfacine, or moxonidine: Beta blockers also increase the risk of clonidine-, guanfacine-, or moxonidine-   withdrawal rebound hypertension. If, during concomitant use of a beta blocker, antihypertensive therapy needs to be interrupted or    discontinued, discontinue the beta blocker first, and the discontinuation should be gradual.• Calcium channel antagonists: In patients with depressed myocardial function, use of esmolol hydrochloride injection with cardiodepressant    calcium channel antagonists (e.g., verapamil) can lead to fatal cardiac arrests.• Sympathomimetic drugs: Sympathomimetic drugs having beta-adrenergic agonist activity will counteract effects of esmolol hydrochloride    injection.•  Vasoconstrictive and positive inotropic agents: Because of the risk of reducing cardiac contractility in presence of high systemic vascular       resistance, do not use esmolol hydrochloride injection to control tachycardia in patients receiving drugs that are vasoconstrictive and have    positive inotropic effects, such as epinephrine, norepinephrine, and dopamine.

{ "type": "p", "children": [], "text": "• Digitalis glycosides: Concomitant administration of digoxin and esmolol hydrochloride injection leads to an approximate 10% to 20% increase of    digoxin blood levels at some time points. Digoxin does not affect esmolol hydrochloride injection pharmacokinetics. Both digoxin and beta    blockers slow atrioventricular conduction and decrease heart rate. Concomitant use increases the risk of bradycardia.• Anticholinesterases: Esmolol hydrochloride injection prolonged the duration of succinylcholine-induced neuromuscular blockade and moderately    prolonged clinical duration and recovery index of mivacurium.• Antihypertensive agents clonidine, guanfacine, or moxonidine: Beta blockers also increase the risk of clonidine-, guanfacine-, or moxonidine-   withdrawal rebound hypertension. If, during concomitant use of a beta blocker, antihypertensive therapy needs to be interrupted or    discontinued, discontinue the beta blocker first, and the discontinuation should be gradual.• Calcium channel antagonists: In patients with depressed myocardial function, use of esmolol hydrochloride injection with cardiodepressant    calcium channel antagonists (e.g., verapamil) can lead to fatal cardiac arrests.• Sympathomimetic drugs: Sympathomimetic drugs having beta-adrenergic agonist activity will counteract effects of esmolol hydrochloride    injection.•  Vasoconstrictive and positive inotropic agents: Because of the risk of reducing cardiac contractility in presence of high systemic vascular       resistance, do not use esmolol hydrochloride injection to control tachycardia in patients receiving drugs that are vasoconstrictive and have    positive inotropic effects, such as epinephrine, norepinephrine, and dopamine." }

8.1 Pregnancy

{ "type": "p", "children": [], "text": "\n8.1 Pregnancy\n" }

Esmolol hydrochloride has been shown to produce increased fetal resorptions with minimal maternal toxicity in rabbits when given in doses approximately 8 times the maximum human maintenance dose (300 mcg/kg/min). There are no adequate and well-controlled studies in pregnant women. Esmolol hydrochloride injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

{ "type": "p", "children": [], "text": "Esmolol hydrochloride has been shown to produce increased fetal resorptions with minimal maternal toxicity in rabbits when given in doses approximately 8 times the maximum human maintenance dose (300 mcg/kg/min). There are no adequate and well-controlled studies in pregnant women. Esmolol hydrochloride injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus." }

Teratogenicity studies in rats at intravenous dosages of esmolol hydrochloride up to 3000 mcg/kg/min (10 times the maximum human maintenance dosage) for 30 minutes daily produced no evidence of maternal toxicity, embryotoxicity or teratogenicity, while a dosage of 10,000 mcg/kg/min produced maternal toxicity and lethality. In rabbits, intravenous dosages up to 1000 mcg/kg/min for 30 minutes daily produced no evidence of maternal toxicity, embryotoxicity or teratogenicity, while 2500 mcg/kg/min produced minimal maternal toxicity and increased fetal resorptions.

{ "type": "p", "children": [], "text": "Teratogenicity studies in rats at intravenous dosages of esmolol hydrochloride up to 3000 mcg/kg/min (10 times the maximum human maintenance dosage) for 30 minutes daily produced no evidence of maternal toxicity, embryotoxicity or teratogenicity, while a dosage of 10,000 mcg/kg/min produced maternal toxicity and lethality. In rabbits, intravenous dosages up to 1000 mcg/kg/min for 30 minutes daily produced no evidence of maternal toxicity, embryotoxicity or teratogenicity, while 2500 mcg/kg/min produced minimal maternal toxicity and increased fetal resorptions." }

8.2 Labor and Delivery

{ "type": "p", "children": [], "text": "\n8.2 Labor and Delivery\n" }

Although there are no adequate and well-controlled studies in pregnant women, use of esmolol in the last trimester of pregnancy or during labor or delivery has been reported to cause fetal bradycardia, which continued after termination of drug infusion. Esmolol hydrochloride injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

{ "type": "p", "children": [], "text": "Although there are no adequate and well-controlled studies in pregnant women, use of esmolol in the last trimester of pregnancy or during labor or delivery has been reported to cause fetal bradycardia, which continued after termination of drug infusion. Esmolol hydrochloride injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus." }

8.3 Nursing Mothers

{ "type": "p", "children": [], "text": "\n8.3 Nursing Mothers\n" }

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from esmolol hydrochloride injection, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

{ "type": "p", "children": [], "text": "It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from esmolol hydrochloride injection, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother." }

8.4 Pediatric Use

{ "type": "p", "children": [], "text": "\n8.4 Pediatric Use\n" }

The safety and effectiveness of esmolol hydrochloride injection in pediatric patients have not been established.

{ "type": "p", "children": [], "text": "The safety and effectiveness of esmolol hydrochloride injection in pediatric patients have not been established." }

8.5 Geriatric Use

{ "type": "p", "children": [], "text": "\n8.5 Geriatric Use\n" }

Clinical studies of esmolol hydrochloride injection did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should usually start at the low end of the dosing range, reflecting greater frequency of decreased renal or cardiac function and of concomitant disease or other drug therapy.

{ "type": "p", "children": [], "text": "Clinical studies of esmolol hydrochloride injection did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should usually start at the low end of the dosing range, reflecting greater frequency of decreased renal or cardiac function and of concomitant disease or other drug therapy." }

8.6 Hepatic Impairment

{ "type": "p", "children": [], "text": "\n8.6 Hepatic Impairment\n" }

No special precautions are necessary in patients with hepatic impairment because esmolol hydrochloride injection is metabolized by red-blood cell esterases [see Clinical Pharmacology (12)].

{ "type": "p", "children": [], "text": "No special precautions are necessary in patients with hepatic impairment because esmolol hydrochloride injection is metabolized by red-blood cell esterases [see Clinical Pharmacology (12)]." }

8.7 Renal Impairment

{ "type": "p", "children": [], "text": "\n8.7 Renal Impairment\n" }

No dosage adjustment is required for esmolol in patients with renal impairment receiving a maintenance infusion of esmolol 150 mcg/kg for 4 hours. There is no information on the tolerability of maintenance infusions of esmolol using rates in excess of 150 mcg/kg or maintained longer than 4 hours [see Clinical Pharmacology (12)].

{ "type": "p", "children": [], "text": "No dosage adjustment is required for esmolol in patients with renal impairment receiving a maintenance infusion of esmolol 150 mcg/kg for 4 hours. There is no information on the tolerability of maintenance infusions of esmolol using rates in excess of 150 mcg/kg or maintained longer than 4 hours [see Clinical Pharmacology (12)]." }

10.1 Signs and Symptoms of Overdose

{ "type": "p", "children": [], "text": "\n10.1 Signs and Symptoms of Overdose\n" }

Overdoses of esmolol hydrochloride injection can cause cardiac and central nervous system effects. These effects may precipitate severe signs, symptoms, sequelae, and complications (for example, severe cardiac and respiratory failure, including shock and coma), and may be fatal. Continuous monitoring of the patient is required.

{ "type": "p", "children": [], "text": "Overdoses of esmolol hydrochloride injection can cause cardiac and central nervous system effects. These effects may precipitate severe signs, symptoms, sequelae, and complications (for example, severe cardiac and respiratory failure, including shock and coma), and may be fatal. Continuous monitoring of the patient is required." }

• Cardiac effects include bradycardia, atrioventricular block (1st -, 2nd -, 3rd degree), junctional rhythms, intraventricular conduction delays, decreased cardiac contractility, hypotension, cardiac failure (including cardiogenic shock), cardiac arrest/asystole, and pulseless electrical activity.

{ "type": "p", "children": [], "text": "• Cardiac effects include bradycardia, atrioventricular block (1st -, 2nd -, 3rd degree), junctional rhythms, intraventricular conduction delays, decreased cardiac contractility, hypotension, cardiac failure (including cardiogenic shock), cardiac arrest/asystole, and pulseless electrical activity." }

• Central nervous system effects include respiratory depression, seizures, sleep and mood disturbances, fatigue, lethargy, and coma.

{ "type": "p", "children": [], "text": "• Central nervous system effects include respiratory depression, seizures, sleep and mood disturbances, fatigue, lethargy, and coma." }

• In addition, bronchospasm, mesenteric ischemia, peripheral cyanosis, hyperkalemia, and hypoglycemia (especially in children) may occur.

{ "type": "p", "children": [], "text": "• In addition, bronchospasm, mesenteric ischemia, peripheral cyanosis, hyperkalemia, and hypoglycemia (especially in children) may occur." }

10.2 Treatment Recommendations

{ "type": "p", "children": [], "text": "\n10.2 Treatment Recommendations\n" }

Because of its approximately 9-minute elimination half-life, the first step in the management of toxicity should be to discontinue the esmolol hydrochloride infusion. Then, based on the observed clinical effects, consider the following general measures.

{ "type": "p", "children": [], "text": "Because of its approximately 9-minute elimination half-life, the first step in the management of toxicity should be to discontinue the esmolol hydrochloride infusion. Then, based on the observed clinical effects, consider the following general measures." }

Bradycardia:Consider intravenous administration of atropine or another anticholinergic drug or cardiac pacing.

{ "type": "p", "children": [], "text": "\nBradycardia:Consider intravenous administration of atropine or another anticholinergic drug or cardiac pacing." }

Cardiac Failure: Consider intravenous administration of a diuretic or digitalis glycoside. In shock resulting from inadequate cardiac contractility, consider intravenous administration of dopamine, dobutamine, isoproterenol, or inamrinone. Glucagon has been reported to be useful.

{ "type": "p", "children": [], "text": "\nCardiac Failure: Consider intravenous administration of a diuretic or digitalis glycoside. In shock resulting from inadequate cardiac contractility, consider intravenous administration of dopamine, dobutamine, isoproterenol, or inamrinone. Glucagon has been reported to be useful." }

Symptomatic Hypotension: Consider intravenous administration of fluids or vasopressor agents such as dopamine or norepinephrine.

{ "type": "p", "children": [], "text": "\nSymptomatic Hypotension: Consider intravenous administration of fluids or vasopressor agents such as dopamine or norepinephrine." }

Bronchospasm: Consider intravenous administration of a beta2 stimulating agent or a theophylline derivative.

{ "type": "p", "children": [], "text": "\nBronchospasm: Consider intravenous administration of a beta2 stimulating agent or a theophylline derivative." }

10.3 Dilution Errors

{ "type": "p", "children": [], "text": "\n10.3 Dilution Errors\n" }

Massive accidental overdoses of esmolol hydrochloride injection have resulted from dilution errors. Some of these overdoses have been fatal while others resulted in permanent disability. Bolus doses in the range of 625 mg to 2.5 g (12.5-50 mg/kg) have been fatal. Patients have recovered completely from overdoses as high as 1.75 g given over one minute or doses of 7.5 g given over one hour for cardiovascular surgery. The patients who survived appear to be those whose circulation could be supported until the effects of esmolol hydrochloride injection resolved.

{ "type": "p", "children": [], "text": "\nMassive accidental overdoses of esmolol hydrochloride injection have resulted from dilution errors. Some of these overdoses have been fatal while others resulted in permanent disability. Bolus doses in the range of 625 mg to 2.5 g (12.5-50 mg/kg) have been fatal. Patients have recovered completely from overdoses as high as 1.75 g given over one minute or doses of 7.5 g given over one hour for cardiovascular surgery. The patients who survived appear to be those whose circulation could be supported until the effects of esmolol hydrochloride injection resolved." }

Esmolol hydrochloride injection is a beta adrenergic receptor blocker with a very short duration of action (elimination half-life is approximately 9 minutes). Esmolol hydrochloride is:

{ "type": "p", "children": [], "text": "Esmolol hydrochloride injection is a beta adrenergic receptor blocker with a very short duration of action (elimination half-life is approximately 9 minutes). Esmolol hydrochloride is:" }

• (±)-Methyl p-[2-hydroxy-3-(isopropylamino) propoxy] hydrocinnamate hydrochloride and has the following structure:

{ "type": "p", "children": [], "text": "• (±)-Methyl p-[2-hydroxy-3-(isopropylamino) propoxy] hydrocinnamate hydrochloride and has the following structure:" }

• Esmolol hydrochloride has the molecular formula C16H26NO4Cl and a molecular weight of 331.8. It has one asymmetric center and exists as an    enantiomeric pair.• Esmolol hydrochloride, USP is a white to off-white crystalline powder. It is a relatively hydrophilic compound which is very soluble in water and    freely soluble in alcohol. Its partition coefficient (octanol/water) at pH 7.0 is 0.42 compared to 17.0 for propranolol.

{ "type": "p", "children": [], "text": "• Esmolol hydrochloride has the molecular formula C16H26NO4Cl and a molecular weight of 331.8. It has one asymmetric center and exists as an    enantiomeric pair.• Esmolol hydrochloride, USP is a white to off-white crystalline powder. It is a relatively hydrophilic compound which is very soluble in water and    freely soluble in alcohol. Its partition coefficient (octanol/water) at pH 7.0 is 0.42 compared to 17.0 for propranolol." }

11.1 Esmolol Hydrochloride Injection Dosage Forms

{ "type": "p", "children": [], "text": "\n11.1 Esmolol Hydrochloride Injection Dosage Forms\n" }

Esmolol hydrochloride injection is a clear, colorless to light yellow, sterile, nonpyrogenic solution of esmolol hydrochloride. The formulation for esmolol hydrochloride injection is described in the table below:

{ "type": "p", "children": [], "text": "Esmolol hydrochloride injection is a clear, colorless to light yellow, sterile, nonpyrogenic solution of esmolol hydrochloride. The formulation for esmolol hydrochloride injection is described in the table below:" }

12.1 Mechanism of Action

{ "type": "p", "children": [], "text": "\n12.1 Mechanism of Action\n" }

Esmolol hydrochloride injection is a beta1-selective (cardioselective) adrenergic receptor blocking agent with rapid onset, a very short duration of action, and no significant intrinsic sympathomimetic or membrane stabilizing activity at therapeutic dosages. Its elimination half-life after intravenous infusion is approximately 9 minutes. Esmolol hydrochloride injection inhibits the beta1 receptors located chiefly in cardiac muscle, but this preferential effect is not absolute and at higher doses it begins to inhibit beta2 receptors located chiefly in the bronchial and vascular musculature.Esmolol hydrochloride injection is a beta1-selective (cardioselective) adrenergic receptor blocking agent with rapid onset, a very short duration of action, and no significant intrinsic sympathomimetic or membrane stabilizing activity at therapeutic dosages. Its elimination half-life after intravenous infusion is approximately 9 minutes. Esmolol hydrochloride injection inhibits the beta1 receptors located chiefly in cardiac muscle, but this preferential effect is not absolute and at higher doses it begins to inhibit beta2 receptors located chiefly in the bronchial and vascular musculature.

{ "type": "p", "children": [], "text": "Esmolol hydrochloride injection is a beta1-selective (cardioselective) adrenergic receptor blocking agent with rapid onset, a very short duration of action, and no significant intrinsic sympathomimetic or membrane stabilizing activity at therapeutic dosages. Its elimination half-life after intravenous infusion is approximately 9 minutes. Esmolol hydrochloride injection inhibits the beta1 receptors located chiefly in cardiac muscle, but this preferential effect is not absolute and at higher doses it begins to inhibit beta2 receptors located chiefly in the bronchial and vascular musculature.Esmolol hydrochloride injection is a beta1-selective (cardioselective) adrenergic receptor blocking agent with rapid onset, a very short duration of action, and no significant intrinsic sympathomimetic or membrane stabilizing activity at therapeutic dosages. Its elimination half-life after intravenous infusion is approximately 9 minutes. Esmolol hydrochloride injection inhibits the beta1 receptors located chiefly in cardiac muscle, but this preferential effect is not absolute and at higher doses it begins to inhibit beta2 receptors located chiefly in the bronchial and vascular musculature." }

12.2 Pharmacodynamics

{ "type": "p", "children": [], "text": "\n12.2 Pharmacodynamics\n" }

Clinical pharmacology studies in normal volunteers have confirmed the beta blocking activity of esmolol hydrochloride injection, showing reduction in heart rate at rest and during exercise, and attenuation of isoproterenol-induced increases in heart rate. Blood levels of esmolol hydrochloride injection have been shown to correlate with extent of beta blockade. After termination of infusion, substantial recovery from beta blockade is observed in 10-20 minutes. The acid metabolite of esmolol exhibits negligible pharmacological activity.

{ "type": "p", "children": [], "text": "Clinical pharmacology studies in normal volunteers have confirmed the beta blocking activity of esmolol hydrochloride injection, showing reduction in heart rate at rest and during exercise, and attenuation of isoproterenol-induced increases in heart rate. Blood levels of esmolol hydrochloride injection have been shown to correlate with extent of beta blockade. After termination of infusion, substantial recovery from beta blockade is observed in 10-20 minutes. The acid metabolite of esmolol exhibits negligible pharmacological activity." }

In human electrophysiology studies, esmolol hydrochloride injection produced effects typical of a beta blocker: a decrease in the heart rate, increase in sinus cycle length, prolongation of the sinus node recovery time, prolongation of the AH interval during normal sinus rhythm and during atrial pacing, and an increase in antegrade Wenckebach cycle length.

{ "type": "p", "children": [], "text": "In human electrophysiology studies, esmolol hydrochloride injection produced effects typical of a beta blocker: a decrease in the heart rate, increase in sinus cycle length, prolongation of the sinus node recovery time, prolongation of the AH interval during normal sinus rhythm and during atrial pacing, and an increase in antegrade Wenckebach cycle length." }

In patients undergoing radionuclide angiography, esmolol hydrochloride injection, at dosages of 200 mcg/kg/min, produced reductions in heart rate, systolic blood pressure, rate pressure product, left and right ventricular ejection fraction and cardiac index at rest, which were similar in magnitude to those produced by intravenous propranolol (4 mg). During exercise, esmolol hydrochloride injection produced reductions in heart rate, rate pressure product and cardiac index which were also similar to those produced by propranolol, but esmolol hydrochloride injection produced a significantly larger fall in systolic blood pressure. In patients undergoing cardiac catheterization, the maximum therapeutic dose of 300 mcg/kg/min of esmolol hydrochloride injection produced similar effects and, in addition, there were small, clinically insignificant increases in the left ventricular end diastolic pressure and pulmonary capillary wedge pressure. At 30 minutes after the discontinuation of esmolol hydrochloride infusion, all of the hemodynamic parameters had returned to pretreatment levels.

{ "type": "p", "children": [], "text": "In patients undergoing radionuclide angiography, esmolol hydrochloride injection, at dosages of 200 mcg/kg/min, produced reductions in heart rate, systolic blood pressure, rate pressure product, left and right ventricular ejection fraction and cardiac index at rest, which were similar in magnitude to those produced by intravenous propranolol (4 mg). During exercise, esmolol hydrochloride injection produced reductions in heart rate, rate pressure product and cardiac index which were also similar to those produced by propranolol, but esmolol hydrochloride injection produced a significantly larger fall in systolic blood pressure. In patients undergoing cardiac catheterization, the maximum therapeutic dose of 300 mcg/kg/min of esmolol hydrochloride injection produced similar effects and, in addition, there were small, clinically insignificant increases in the left ventricular end diastolic pressure and pulmonary capillary wedge pressure. At 30 minutes after the discontinuation of esmolol hydrochloride infusion, all of the hemodynamic parameters had returned to pretreatment levels." }

The relative cardioselectivity of esmolol hydrochloride injection was demonstrated in 10 mildly asthmatic patients. Infusions of esmolol hydrochloride injection 100, 200 and 300 mcg/kg/min produced no significant increases in specific airway resistance compared to placebo. At 300 mcg/kg/min, esmolol hydrochloride injection produced slightly enhanced bronchomotor sensitivity to dry air stimulus. These effects were not clinically significant, and esmolol hydrochloride injection was well tolerated by all patients. Six of the patients also received intravenous propranolol, and at a dosage of 1 mg, two experienced significant, symptomatic bronchospasm requiring bronchodilator treatment. One other propranolol-treated patient also experienced dry air-induced bronchospasm. No adverse pulmonary effects were observed in patients with COPD who received therapeutic dosages of esmolol hydrochloride injection for treatment of supraventricular tachycardia (51 patients) or in perioperative settings (32 patients).

{ "type": "p", "children": [], "text": "The relative cardioselectivity of esmolol hydrochloride injection was demonstrated in 10 mildly asthmatic patients. Infusions of esmolol hydrochloride injection 100, 200 and 300 mcg/kg/min produced no significant increases in specific airway resistance compared to placebo. At 300 mcg/kg/min, esmolol hydrochloride injection produced slightly enhanced bronchomotor sensitivity to dry air stimulus. These effects were not clinically significant, and esmolol hydrochloride injection was well tolerated by all patients. Six of the patients also received intravenous propranolol, and at a dosage of 1 mg, two experienced significant, symptomatic bronchospasm requiring bronchodilator treatment. One other propranolol-treated patient also experienced dry air-induced bronchospasm. No adverse pulmonary effects were observed in patients with COPD who received therapeutic dosages of esmolol hydrochloride injection for treatment of supraventricular tachycardia (51 patients) or in perioperative settings (32 patients)." }

12.3 Pharmacokinetics

{ "type": "p", "children": [], "text": "\n12.3 Pharmacokinetics\n" }

Esmolol is rapidly metabolized by hydrolysis of the ester linkage, chiefly by the esterases in the cytosol of red blood cells and not by plasma cholinesterases or red cell membrane acetylcholinesterase. Total body clearance in man was found to be about 20 L/kg/hr, which is greater than cardiac output; thus the metabolism of esmolol is not limited by the rate of blood flow to metabolizing tissues such as the liver or affected by hepatic or renal blood flow. Esmolol has a rapid distribution half-life of about 2 minutes and an elimination half-life of about 9 minutes.

{ "type": "p", "children": [], "text": "\nEsmolol is rapidly metabolized by hydrolysis of the ester linkage, chiefly by the esterases in the cytosol of red blood cells and not by plasma cholinesterases or red cell membrane acetylcholinesterase. Total body clearance in man was found to be about 20 L/kg/hr, which is greater than cardiac output; thus the metabolism of esmolol is not limited by the rate of blood flow to metabolizing tissues such as the liver or affected by hepatic or renal blood flow. Esmolol has a rapid distribution half-life of about 2 minutes and an elimination half-life of about 9 minutes." }

Using an appropriate loading dose, steady-state blood levels of esmolol hydrochloride injection for dosages from 50-300 mcg/kg/min are obtained within five minutes. Steady-state is reached in about 30 minutes without the loading dose. Steady-state blood levels of esmolol increase linearly over this dosage range and elimination kinetics are dose-independent over this range. Steady-state blood levels are maintained during infusion but decrease rapidly after termination of the infusion. Because of its short half-life, blood levels of esmolol can be rapidly altered by increasing or decreasing the infusion rate and rapidly eliminated by discontinuing the infusion.

{ "type": "p", "children": [], "text": "Using an appropriate loading dose, steady-state blood levels of esmolol hydrochloride injection for dosages from 50-300 mcg/kg/min are obtained within five minutes. Steady-state is reached in about 30 minutes without the loading dose. Steady-state blood levels of esmolol increase linearly over this dosage range and elimination kinetics are dose-independent over this range. Steady-state blood levels are maintained during infusion but decrease rapidly after termination of the infusion. Because of its short half-life, blood levels of esmolol can be rapidly altered by increasing or decreasing the infusion rate and rapidly eliminated by discontinuing the infusion." }

Consistent with the high rate of blood-based metabolism of esmolol, less than 2% of the drug is excreted unchanged in the urine. Within 24 hours of the end of infusion, the acid metabolite of esmolol in urine accounts for approximately 73-88% of the dosage.

{ "type": "p", "children": [], "text": "Consistent with the high rate of blood-based metabolism of esmolol, less than 2% of the drug is excreted unchanged in the urine. Within 24 hours of the end of infusion, the acid metabolite of esmolol in urine accounts for approximately 73-88% of the dosage." }

Metabolism of esmolol results in the formation of the corresponding free acid and methanol. The acid metabolite has been shown in animals to have negligible activity and in normal volunteers its blood levels do not correspond to the level of beta blockade. The acid metabolite has an elimination half-life of about 3.7 hours and is excreted in the urine with a clearance approximately equivalent to the glomerular filtration rate. After a 4 hour maintenance infusion of 150 mcg/kg, the plasma concentrations of esmolol are similar in subjects with normal renal function and in patients with ESRD on dialysis. The half-life of the acid metabolite of esmolol hydrochloride injection, which is primarily excreted unchanged by the kidney, is increased about 12-fold to 48 hours in patients with ESRD. The peak concentrations of the acid metabolite are doubled in ESRD.

{ "type": "p", "children": [], "text": "Metabolism of esmolol results in the formation of the corresponding free acid and methanol. The acid metabolite has been shown in animals to have negligible activity and in normal volunteers its blood levels do not correspond to the level of beta blockade. The acid metabolite has an elimination half-life of about 3.7 hours and is excreted in the urine with a clearance approximately equivalent to the glomerular filtration rate. After a 4 hour maintenance infusion of 150 mcg/kg, the plasma concentrations of esmolol are similar in subjects with normal renal function and in patients with ESRD on dialysis. The half-life of the acid metabolite of esmolol hydrochloride injection, which is primarily excreted unchanged by the kidney, is increased about 12-fold to 48 hours in patients with ESRD. The peak concentrations of the acid metabolite are doubled in ESRD." }

Methanol blood levels, monitored in subjects receiving esmolol hydrochloride injection for up to 6 hours at 300 mcg/kg/min and 24 hours at 150 mcg/kg/min, approximated endogenous levels and were less than 2% of levels usually associated with methanol toxicity.

{ "type": "p", "children": [], "text": "Methanol blood levels, monitored in subjects receiving esmolol hydrochloride injection for up to 6 hours at 300 mcg/kg/min and 24 hours at 150 mcg/kg/min, approximated endogenous levels and were less than 2% of levels usually associated with methanol toxicity." }

Esmolol hydrochloride injection has been shown to be 55% bound to human plasma protein, while the acid metabolite is only 10% bound.

{ "type": "p", "children": [], "text": "Esmolol hydrochloride injection has been shown to be 55% bound to human plasma protein, while the acid metabolite is only 10% bound." }

Because of its short term usage no carcinogenicity, mutagenicity, or reproductive performance studies have been conducted with esmolol.

{ "type": "p", "children": [], "text": "Because of its short term usage no carcinogenicity, mutagenicity, or reproductive performance studies have been conducted with esmolol." }

Supraventricular Tachycardia: In two multicenter, randomized, double-blind, controlled comparisons of esmolol hydrochloride injection with placebo and propranolol, maintenance doses of 50 to 300 mcg/kg/min of esmolol hydrochloride injection were found to be more effective than placebo and about as effective as propranolol, 3-6 mg given by bolus injections, in the treatment of supraventricular tachycardia, principally atrial fibrillation and atrial flutter. The majority of these patients developed their arrhythmias postoperatively. About 60-70% of the patients treated with esmolol hydrochloride injection developed either a 20% reduction in heart rate, a decrease in heart rate to less than 100 bpm, or, rarely, conversion to normal sinus rhythm and about 95% of these patients did so at a dosage of 200 mcg/kg/min or less. The average effective dosage of esmolol hydrochloride injection was approximately 100 mcg/kg/min in the two studies. Other multicenter baseline-controlled studies gave similar results. In the comparison with propranolol, about 50% of patients in both the esmolol hydrochloride injection and propranolol groups were on concomitant digoxin. Response rates were slightly higher with both beta blockers in the digoxin-treated patients.

{ "type": "p", "children": [], "text": "\nSupraventricular Tachycardia: In two multicenter, randomized, double-blind, controlled comparisons of esmolol hydrochloride injection with placebo and propranolol, maintenance doses of 50 to 300 mcg/kg/min of esmolol hydrochloride injection were found to be more effective than placebo and about as effective as propranolol, 3-6 mg given by bolus injections, in the treatment of supraventricular tachycardia, principally atrial fibrillation and atrial flutter. The majority of these patients developed their arrhythmias postoperatively. About 60-70% of the patients treated with esmolol hydrochloride injection developed either a 20% reduction in heart rate, a decrease in heart rate to less than 100 bpm, or, rarely, conversion to normal sinus rhythm and about 95% of these patients did so at a dosage of 200 mcg/kg/min or less. The average effective dosage of esmolol hydrochloride injection was approximately 100 mcg/kg/min in the two studies. Other multicenter baseline-controlled studies gave similar results. In the comparison with propranolol, about 50% of patients in both the esmolol hydrochloride injection and propranolol groups were on concomitant digoxin. Response rates were slightly higher with both beta blockers in the digoxin-treated patients." }

In all studies significant decreases of blood pressure occurred in 20-50% of patients, identified either as adverse reaction reports by investigators, or by observation of systolic pressure less than 90 mmHg or diastolic pressure less than 50 mmHg. The hypotension was symptomatic (mainly hyperhidrosis or dizziness) in about 12% of patients, and therapy was discontinued in about 11% of patients, about half of whom were symptomatic. Hypotension was more common with esmolol hydrochloride injection (53%) than with propranolol (17%). The hypotension was rapidly reversible with decreased infusion rate or after discontinuation of therapy with esmolol hydrochloride injection. For both esmolol hydrochloride injection and propranolol, hypotension was reported less frequently in patients receiving concomitant digoxin.

{ "type": "p", "children": [], "text": "In all studies significant decreases of blood pressure occurred in 20-50% of patients, identified either as adverse reaction reports by investigators, or by observation of systolic pressure less than 90 mmHg or diastolic pressure less than 50 mmHg. The hypotension was symptomatic (mainly hyperhidrosis or dizziness) in about 12% of patients, and therapy was discontinued in about 11% of patients, about half of whom were symptomatic. Hypotension was more common with esmolol hydrochloride injection (53%) than with propranolol (17%). The hypotension was rapidly reversible with decreased infusion rate or after discontinuation of therapy with esmolol hydrochloride injection. For both esmolol hydrochloride injection and propranolol, hypotension was reported less frequently in patients receiving concomitant digoxin." }

16.1 How Supplied

{ "type": "p", "children": [], "text": "\n16.1 How Supplied\n" }

Esmolol Hydrochloride Injection, 100 mg/10 mL (10 mg/mL) is supplied as:

{ "type": "p", "children": [], "text": "Esmolol Hydrochloride Injection, 100 mg/10 mL (10 mg/mL) is supplied as:" }

NDC 67457-182-10carton containing 10 x 10 mL single-dose vials

{ "type": "p", "children": [], "text": "NDC 67457-182-10carton containing 10 x 10 mL single-dose vials" }

16.2 Storage

{ "type": "p", "children": [], "text": "\n16.2 Storage\n" }

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from freezing. Avoid excessive heat.

{ "type": "p", "children": [], "text": "\nStore at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from freezing. Avoid excessive heat.\n" }

Discard unused portion.

{ "type": "p", "children": [], "text": "Discard unused portion." }

Physicians should inform patients of the risks associated with esmolol hydrochloride injection:

{ "type": "p", "children": [], "text": "Physicians should inform patients of the risks associated with esmolol hydrochloride injection:" }

The most common adverse reactions are symptomatic hypotension (hyperhidrosis, dizziness) and asymptomatic hypotension.Inform patients or caregivers that there is a risk of hypoglycemia when esmolol is given to patients who are fasting or who are vomiting. Monitor for symptoms of hypoglycemia [see Warnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": "The most common adverse reactions are symptomatic hypotension (hyperhidrosis, dizziness) and asymptomatic hypotension.Inform patients or caregivers that there is a risk of hypoglycemia when esmolol is given to patients who are fasting or who are vomiting. Monitor for symptoms of hypoglycemia [see Warnings and Precautions (5.6)]." }

<div class="scrollingtable"><table width="100%"> <caption> <span> Product repackaged by: Henry Schein, Inc., Bastian, VA 24314</span> </caption> <tbody class="Headless"> <tr class="First"> <td>From Original Manufacturer/Distributor's NDC and Unit of Sale</td><td>To Henry Schein Repackaged Product NDC and Unit of Sale</td><td>Total Strength/Total Volume (Concentration) per unit</td> </tr> <tr class="Last"> <td>NDC 67457-182-10<br/>carton containing 10 x 10 mL single- dose vials</td><td>NDC 0404-9785-10<br/>1 10 mL Vial in a bag<br/>(Vial bears NDC 67457-182-00)</td><td>100 mg/10 mL<br/>(10 mg/mL)</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\n<span> Product repackaged by: Henry Schein, Inc., Bastian, VA 24314</span>\n</caption>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td>From Original Manufacturer/Distributor's NDC and Unit of Sale</td><td>To Henry Schein Repackaged Product NDC and Unit of Sale</td><td>Total Strength/Total Volume (Concentration) per unit</td>\n</tr>\n<tr class=\"Last\">\n<td>NDC 67457-182-10<br/>carton containing 10 x 10 mL single- dose vials</td><td>NDC 0404-9785-10<br/>1 10 mL Vial in a bag<br/>(Vial bears NDC 67457-182-00)</td><td>100 mg/10 mL<br/>(10 mg/mL)</td>\n</tr>\n</tbody>\n</table></div>" }

Manufactured for: Mylan Institutional LLC

{ "type": "p", "children": [], "text": "Manufactured for:\nMylan Institutional LLC\n" }

Morgantown, WV 26505 U.S.A.

{ "type": "p", "children": [], "text": "Morgantown, WV 26505 U.S.A." }

Manufactured by: Mylan Institutional

{ "type": "p", "children": [], "text": "Manufactured by:\nMylan Institutional\n" }

Galway, Ireland

{ "type": "p", "children": [], "text": "Galway, Ireland" }

50095569

{ "type": "p", "children": [], "text": "50095569" }

Revised: 9/2023MI:ESMOIJ:R5

{ "type": "p", "children": [], "text": "Revised: 9/2023MI:ESMOIJ:R5" }