Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING BREVIBLOC PREMIXED INJECTION ESMOLOL HYDROCHLORIDE IN SODIUM CHLORIDE is supplied in the following dosage forms. NDC 51662-1427-1 BREVIBLOC PREMIXED INJECTION ESMOLOL HYDROCHLORIDE IN SODIUM CHLORIDE 2,500mg/250mL (10mg/mL) 250mL BAG HF Acquisition Co LLC, DBA HealthFirst Mukilteo, WA 98275 Also supplied in the following manufacture supplied dosage forms 16.1 How Supplied BREVIBLOC PREMIXED Injection • NDC 10019-055-61, 2500 mg / 250 mL (10 mg/mL) Ready-to-use INTRAVIA Bags BREVIBLOC PREMIXED Double Strength Injection • NDC 10019-075-87, 2000 mg / 100 mL (20 mg/mL) Ready-to-use INTRAVIA Bags BREVIBLOC Injection • NDC 10019-115-01, 100 mg / 10 mL (10 mg/mL) Ready-to-use Vials, Package of 25 16.2 Storage 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 Once drug has been withdrawn from ready-to-use bag, the bag should be used within 24 hours, with any unused portion discarded.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: • Use aseptic technique. • Suspend premixed bag from eyelet support. • Remove plastic protector from delivery port at bottom of bag. • Attach administration set. • Refer to complete directions accompanying set.; PRINCIPAL DISPLAY PANEL - BAG LABEL BAG LABEL; PRINCIPAL DISPLAY PANEL - OUTER PACKAGING OUTER PACKAGING; PRINCIPAL DISPLAY PANEL - SERIALIZED BAG LABELING SERIALIZED BAG LABELING
- 16 HOW SUPPLIED/STORAGE AND HANDLING BREVIBLOC PREMIXED INJECTION ESMOLOL HYDROCHLORIDE IN SODIUM CHLORIDE is supplied in the following dosage forms. NDC 51662-1427-1 BREVIBLOC PREMIXED INJECTION ESMOLOL HYDROCHLORIDE IN SODIUM CHLORIDE 2,500mg/250mL (10mg/mL) 250mL BAG HF Acquisition Co LLC, DBA HealthFirst Mukilteo, WA 98275 Also supplied in the following manufacture supplied dosage forms 16.1 How Supplied BREVIBLOC PREMIXED Injection • NDC 10019-055-61, 2500 mg / 250 mL (10 mg/mL) Ready-to-use INTRAVIA Bags BREVIBLOC PREMIXED Double Strength Injection • NDC 10019-075-87, 2000 mg / 100 mL (20 mg/mL) Ready-to-use INTRAVIA Bags BREVIBLOC Injection • NDC 10019-115-01, 100 mg / 10 mL (10 mg/mL) Ready-to-use Vials, Package of 25 16.2 Storage 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: • Use aseptic technique. • Suspend premixed bag from eyelet support. • Remove plastic protector from delivery port at bottom of bag. • Attach administration set. • Refer to complete directions accompanying set.
- PRINCIPAL DISPLAY PANEL - BAG LABEL BAG LABEL
- PRINCIPAL DISPLAY PANEL - OUTER PACKAGING OUTER PACKAGING
- PRINCIPAL DISPLAY PANEL - SERIALIZED BAG LABELING SERIALIZED BAG LABELING
Overview
BREVIBLOC (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: Esmolol hydrochloride has the empirical formula C16H26NO4Cl and a molecular weight of 331.8. It has one asymmetric center and exists as an enantiomeric pair. • Esmolol hydrochloride 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 BREVIBLOC Injection Dosage Forms 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: 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. STRUCTURE DESCRIPTION
Indications & Usage
INDICATIONS & USAGE 1.1 Supraventricular Tachycardia or Noncompensatory Sinus Tachycardia 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. 1.2 Intraoperative and Postoperative Tachycardia and/or Hypertension 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.
Dosage & Administration
DOSAGE & ADMINISTRATION 2.1 Dosing for the Treatment of Supraventricular Tachycardia or Noncompensatory Sinus Tachycardia 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. 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. 2.2 Intraoperative and Postoperative Tachycardia and Hypertension 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 • 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. 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. • Depending on the response obtained, continue dosing as outlined for supraventricular tachycardia. Refer to Maximum Recommended Doses below. 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. • 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 BREVIBLOC Injection Therapy to Alternative Drugs 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: 1. Thirty minutes following the first dose of the alternative drug, reduce the BREVIBLOC 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 BREVIBLOC infusion. 2.4 Directions for Use 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 • The medication port is to be used solely for withdrawing an initial bolus from the bag. • Use aseptic technique when withdrawing the bolus dose. • Do not add any additional Figure 1: Two-Port INTRAVIA Bag Figure 1: Two-Port INTRAVIA 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: • Dextrose (5%) Injection, USP • Dextrose (5%) in Lactated Ringer’s Injection • Dextrose (5%) in Ringer’s Injection • Dextrose (5%) and Sodium Chloride (0.45%) Injection, USP • Dextrose (5%) and Sodium Chloride (0.9%) Injection, USP • Lactated Ringer’s Injection, USP • Potassium Chloride (40 mEq/liter) in Dextrose (5%) Injection, USP • Sodium Chloride (0.45%) Injection, USP • Sodium Chloride (0.9%) Injection, USP DOSAGE 1 DOSAGE IMAGE
Warnings & Precautions
5.1 Hypotension 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. 5.2 Bradycardia 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. 5.3 Cardiac Failure 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 ]. 5.4 Intraoperative and Postoperative Tachycardia and/or Hypertension 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. 5.5 Reactive Airways Disease 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. 5.6 Use in Patients with Diabetes Mellitus and Hypoglycemia In patients with hypoglycemia, or diabetic patients (especially those with labile diabetes) who are receiving insulin or other hypoglycemic agents, beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be masked. Concomitant use of beta blockers and antidiabetic agents can enhance the effect of antidiabetic agents (blood glucose–lowering). 5.7 Infusion Site Reactions 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. 5.8 Use in Patients with Prinzmetal's Angina 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 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. 5.10 Use in Hypovolemic Patients In hypovolemic patients, BREVIBLOC injection can attenuate reflex tachycardia and increase the risk of hypotension. 5.11 Use in Patients with Peripheral Circulatory Disorders In patients with peripheral circulatory disorders (including Raynaud’s disease or syndrome, and peripheral occlusive vascular disease), BREVIBLOC injection may aggravate peripheral circulatory disorders. 5.12 Abrupt Discontinuation of BREVIBLOC Injection 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. 5.13 Hyperkalemia 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. 5.14 Use in Patients with Metabolic Acidosis Beta blockers, including BREVIBLOC 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 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 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 ].
Contraindications
BREVIBLOC (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- 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- 5.2)]. • Sick sinus syndrome: May precipitate or worsen bradycardia resulting in cardiogenic shock and cardiac arrest [see Warnings and Precautions ( 5- 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 BREVIBLOC injection in close proximity (i.e., while cardiac effects from the other are still present); fatal cardiac arrests have occurred in patients receiving BREVIBLOC 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).
Adverse Reactions
6.1 Clinical Trials Experience 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- 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- 5.5)]. 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%) 6.2 Post-Marketing Experience 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 ADVERSE
Drug Interactions
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: • Digitalis glycosides: Concomitant administration of digoxin and BREVIBLOC injection leads to an approximate 10% to 20% increase of digoxin blood levels at some time points. Digoxin does not affect BREVIBLOC injection pharmacokinetics. Both digoxin and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use increases the risk of bradycardia. • Anticholinesterases: BREVIBLOC 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 BREVIBLOC 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 BREVIBLOC injection. • Vasoconstrictive and positive inotropic agents: Because of the risk of reducing cardiac contractility in presence of high systemic vascular resistance, do not use BREVIBLOC injection to control tachycardia in patients receiving drugs that are vasoconstrictive and have positive inotropic effects, such as epinephrine, norepinephrine, and dopamine.
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