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BREVIBLOC PREMIXED Injection esmolol hydrochloride
www.baxter.ca
June 10, 2008 Submission Control No: 122460 Brevibloc, Brevibloc Premixed and IntraVia are trademarks of Baxter International Inc.
Table of Contents
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 6 DRUG INTERACTIONS 8 DOSAGE AND ADMINISTRATION 9 OVERDOSAGE 11 ACTION AND CLINICAL PHARMACOLOGY 12 STORAGE AND STABILITY 14 SPECIAL HANDLING INSTRUCTIONS 15 DOSAGE FORMS, COMPOSITION AND PACKAGING 16
PHARMACEUTICAL INFORMATION 17 DETAILED PHARMACOLOGY 17 TOXICOLOGY 18 REFERENCES 20
Pr BREVIBLOC Injection esmolol hydrochloride
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BREVIBLOC PREMIXED Injection esmolol hydrochloride
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Injection | 10 mL (10 mg/mL) Vials | Sodium acetate trihydrate, Glacial acetic acid, Sodium chloride, Hydrochloric acid, Sodium hydroxide, Water for Injection |
| Injection | 250 mL (10 mg/mL) Premixed Bags |
BREVIBLOC Injection / BREVIBLOC PREMIXED Injection (esmolol hydrochloride) is indicated for:
the perioperative management of tachycardia and hypertension in patients in whom there is a concern for compromised myocardial oxygen balance and who, in the judgement of the physician, are clearly at risk of developing haemodynamically-induced myocardial ischemia.
the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in acute situations when the use of a short-acting agent is desirable.
BREVIBLOC Injection / BREVIBLOC PREMIXED Injection is not indicated for use in chronic settings.
Geriatrics:
The safety and effectiveness of BREVIBLOC (esmolol hydrochloride) in elders have not been established.
Pediatrics:
The safety and effectiveness of BREVIBLOC (esmolol hydrochloride) in children have not been established.
BREVIBLOC Injection / BREVIBLOC PREMIXED Injection (esmolol hydrochloride) is contraindicated in patients who require inotropic agents and/or vasopressors to maintain systemic blood pressure and cardiac output. BREVIBLOC Injection / BREVIBLOC PREMIXED Injection is also contraindicated in patients with hypotension, sinus bradycardia, second and third degree A-V block, right ventricular failure secondary to pulmonary hypertension, overt cardiac failure, or cardiogenic shock (see WARNINGS).
DURING THE ADMINISTRATION OF BREVIBLOC INJECTION / BREVIBLOC PREMIXED INJECTION (esmolol hydrochloride) PATIENTS SHOULD BE CAREFULLY MONITORED, WITH PARTICULAR ATTENTION TO HEART RATE AND BLOOD PRESSURE
General
Abrupt Cessation of Therapy with BREVIBLOC (esmolol hydrochloride): Abrupt cessation of BREVIBLOC Injection / BREVIBLOC PREMIXED Injection in patients has not been reported to produce the withdrawal effects which may occur with abrupt withdrawal of beta-blockers following chronic use in coronary artery disease patients. However, caution should be used in discontinuing BREVIBLOC (esmolol hydrochloride) infusions abruptly in these patients. The use of intravenous verapamil with a beta-blocker may cause severe depression of ventricular function. Accordingly, patients with atrial fibrillation or atrial flutter who have received verapamil should only be administered BREVIBLOC Injection / BREVIBLOC PREMIXED Injection if the benefits outweigh the risk.
Cardiovascular
Hypotension:
The administration of BREVIBLOC Injection / BREVIBLOC PREMIXED Injection has been associated with excessive hypotension. The hypotensive effect of BREVIBLOC Injection / BREVIBLOC PREMIXED Injection is dose related and may increase in the presence of both narcotic analgesics and inhalational anaesthetics. In patients with low pretreatment blood pressure or with a propensity to develop hypotension (e.g., hypovolemic patients) BREVIBLOC (esmolol hydrochloride) should be used with special caution, and only when in the physician's judgement the potential benefits outweigh the risk. In the event of hypotension, the dosage of BREVIBLOC Injection / BREVIBLOC PREMIXED Injection should be reduced or the drug should be discontinued.
Sinus Bradycardia:
Severe bradycardia and cardiac arrest may occur with the use of BREVIBLOC (esmolol hydrochloride). Therefore, in patients with low pretreatment heart rates BREVIBLOC (esmolol hydrochloride) should be used with special caution, and only when in the physician's judgement the potential benefits outweigh the risk. In the event of bradycardia, the dosage of BREVIBLOC Injection / BREVIBLOC PREMIXED Injection should be reduced or the drug should be discontinued.
Cardiac Failure:
Sympathetic stimulation is a vital component supporting circulatory function in patients with congestive heart failure. Inhibition with beta-blockade always carries the potential hazard of further depressing myocardial contractility. Therefore, special caution should be exercised when administering BREVIBLOC Injection / BREVIBLOC PREMIXED Injection to patients with a history of heart failure. Beta-blockers act selectively without abolishing the inotropic action of digitalis on the heart muscle. The effects of beta-blockers and digitalis are additive in depressing A-V nodal conduction. Even in patients with no history of cardiac failure, continued depression of the myocardium over a period of time can, in some cases, lead to cardiac failure. Therefore, at the first sign or symptom of impending cardiac failure, the dosage of BREVIBLOC (esmolol hydrochloride) should be reduced or the drug should be withdrawn. Because of the short elimination half-life of BREVIBLOC (esmolol hydrochloride), these measures may be sufficient but specific treatment may also be considered.
Endocrine and Metabolism
Diabetes Mellitus/Hypoglycaemia:
BREVIBLOC Injection / BREVIBLOC PREMIXED Injection should be administered with caution to patients subject to spontaneous hypoglycaemia, or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycaemic agents. Beta- adrenergic blockers may mask the premonitory signs and symptoms of acute hypoglycaemia.
Renal
Renal Impairment:
The pharmacokinetics of BREVIBLOC Injection / BREVIBLOC PREMIXED Injection (esmolol hydrochloride) are unchanged in kidney-impaired patients except that the volume of distribution is increased. However, the acid metabolite of BREVIBLOC (esmolol hydrochloride) is primarily excreted unchanged by the kidney, thus BREVIBLOC Injection / BREVIBLOC PREMIXED Injection should be administered with caution to patients with impaired renal function. The elimination half-life of the acid metabolite was prolonged ten-fold and the plasma level was considerably elevated in patients with end-stage renal disease.
Respiratory
Bronchospastic Diseases: Patients with bronchospastic diseases should not, in general, receive beta-blockers. Because of its relative beta-1 selectivity and titratability, BREVIBLOC Injection / BREVIBLOC PREMIXED Injection may be used with caution in patients with bronchospastic diseases. Since beta-1 selectivity is not absolute, BREVIBLOC (esmolol hydrochloride) should be carefully titrated to obtain the lowest possible effective dose. In the event of bronchospasm, the infusion should be terminated immediately and a beta-2 stimulating agent may be administered if conditions warrant.
Special Populations
There are no studies in pregnant women. BREVIBLOC (esmolol hydrochloride) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
It is not known whether BREVIBLOC (esmolol hydrochloride) is excreted in human milk. Caution, however, should be exercised when BREVIBLOC Injection / BREVIBLOC PREMIXED Injection is administered to a nursing mother.
: The safety and effectiveness of BREVIBLOC (esmolol hydrochloride) in children have not been established.
: The safety and effectiveness of BREVIBLOC (esmolol hydrochloride) in elders have not been established.
Monitoring and Laboratory Tests
During the administration of BREVIBLOC (esmolol hydrochloride) patients should be carefully monitored, with particular attention to heart rate and blood pressure.
Clinical Trial Adverse Drug Reactions
During Management of Perioperative Tachycardia and Associated Hypertension:
In clinical trials 763 patients were treated with BREVIBLOC Injection (esmolol hydrochloride) in operative settings. BREVIBLOC Injection as a bolus of 100 mg and 200 mg was given in a total of 367 patients during clinical studies. Hypotension was reported in 16% among esmolol treated patients compared to 8% in the placebo group (187 patients). Bradycardia occurred in 4% of patients, in both the esmolol and placebo groups. Other adverse effects with a frequency of less than 1% occurred as frequently in the esmolol as it did with the placebo group. They were: bronchospasm, pain at injection and wheezing. When BREVIBLOC (esmolol hydrochloride) was infused in 396 patients, hypotension was the most commonly observed side effect in 5% of patients. The other reported adverse effect was bradycardia (heart rate less than 50 beats per minute), observed in 1% of patients. Other adverse effects occurring with a less than 1% incidence were the following: S-T segment depression, ECG changes, myocardial ischemia, junctional rhythm, hypertension, atrial fibrillation, bronchospasm, agitation, nausea, vomiting, urticaria and itching. None of these side effects were judged to be severe, and all resolved after the discontinuation of BREVIBLOC (esmolol hydrochloride).
During Management of Atrial Fibrillation and Atrial Flutter: Most adverse effects reported in clinical trials with BREVIBLOC Injection in 390 patients with atrial fibrillation and atrial flutter have been mild and transient. The most serious adverse reaction observed was symptomatic hypotension (12%). BREVIBLOC (esmolol hydrochloride) was discontinued in about 11% of the patients. Other adverse reactions, grouped by system, are:
Cardiovascular:
Symptomatic hypotension (diaphoresis, dizziness) (12%), asymptomatic hypotension (25%), diaphoresis (9%), premature ventricular contraction and dyspnea (1%).
Central Nervous System:
Dizziness (3%), somnolence (3%), headache (3%), confusion, agitation
(2%), fatigue (1%).
Gastrointestinal:
Nausea (6%), vomiting (1%)
Local Dermatological Reactions:
Inflammation (2%), induration (2%), I.V. infiltration (2%)
Less Common Clinical Trial Adverse Drug Reactions (<1%)
Cardiovascular:
Pallor, flushing, bradycardia (<50 beats per minute), chest pain, syncope, pulmonary edema, junctional rhythm, heart block, increased PAP, abnormal ECG, narrowed pulse pressure, recurrence of SVT, angina, ventricular ectopy, peripheral ischemia (<1%).
Central Nervous System:
Paraesthesia, asthenia, depression, abnormal thinking, anxiety, anorexia, one brief episode of grand mal seizure (30 seconds), lightheadedness, weakness, irritability, drowsiness (<1%).
Gastrointestinal: Dyspepsia, constipation, dry mouth, abdominal discomfort (<1%). Local Dermatological Reactions: Clamminess, edema, erythema, skin discolouration, ecchymosis, burning, enlarged macular area (<1%).
Respiratory:
Bronchospasm, wheezing, dyspnea, nasal congestion, rhonchi, pharyngitis, rales, pleural effusion, atelectasis and common cold, pleural pain (<1%).
Miscellaneous:
Urinary retention, dysuria, oliguria, speech disorder, abnormal vision, midscapular pain, rigors, fever (<1%).
Post-Market Adverse Drug Reactions
In addition, the following adverse events have occurred under conditions where a causal association is uncertain:
Cardiovascular
: Arteriospasm coronary, cardiac failure congestive, electromechanical dissociation, myocardial infarction, supraventricular extrasystoles, ventricular extrasystoles, ventricular fibrillation, hypertensive crisis, Atrioventricular block.
Dermatological Reactions: Blister, Skin exfoliation. Respiratory: Respiratory failure.
Urogenital: Renal tubular necrosis. Neurological: Neuropathy.
Drug-Drug Interactions
Catecholamine-depleting drugs, (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients treated concurrently with BREVIBLOC (esmolol hydrochloride) and a catecholamine depletor should, therefore, be closely observed for evidence of hypotension or marked bradycardia. When digoxin and BREVIBLOC (esmolol hydrochloride) were concomitantly administered intravenously to normal volunteers, a 10-20% increase in digoxin blood level was observed at some time points. Digoxin did not affect BREVIBLOC (esmolol hydrochloride) pharmacokinetics. When the interaction of intravenous morphine and BREVIBLOC (esmolol hydrochloride) was studied in normal subjects, no effect on morphine blood level was seen. However the steady-state blood levels of BREVIBLOC Injection / BREVIBLOC PREMIXED Injection were increased by 46% in the presence of morphine, but no other pharmacokinetic parameters were changed. The effect of BREVIBLOC (esmolol hydrochloride) on the duration of succinylcholine-induced neuromuscular blockade was studied in patients undergoing surgery. The onset of neuromuscular blockade by succinylcholine was unaffected by BREVIBLOC Injection / BREVIBLOC PREMIXED Injection, but the duration of neuromuscular blockade was prolonged from five to eight minutes. A study of interaction between BREVIBLOC (esmolol hydrochloride) and warfarin showed that concomitant administration of BREVIBLOC Injection and warfarin does not alter warfarin plasma levels. BREVIBLOC (esmolol hydrochloride) concentrations were equivocally higher when given with warfarin, but this is not likely to be clinically important. Please see Warnings and Precautions section for the use of intravenous verapamil with BREVIBLOC.
Drug-Food Interactions
Interactions with food have not been established.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Interactions
Interactions with laboratory tests have not been established.
Recommended Dose and Dosage Adjustment
Management of Perioperative Tachycardia and Hypertension:
Intubation:
For the management of postintubation tachycardia and hypertension, give 1.5 mg/kg (up to a maximum of 100 mg) as a bolus injection (over 30 seconds) 1 to 2 minutes before intubation.
For Intra- and Postoperative Tachycardia and Hypertension:
For intraoperative and postoperative treatment of tachycardia and/or hypertension give 1.5 mg/kg as a bolus injection (over 30 seconds) followed by 0.15 mg/kg/min infusion. Adjust infusion rate as required up to 0.3 mg/kg/min to maintain desired heart rate and/or blood pressure.
Management of Atrial Fibrillation and Atrial Flutter:
Responses to BREVIBLOC Injection / BREVIBLOC PREMIXED Injection (esmolol hydrochloride) usually (over 95%) occur within the range of 0.05 to 0.2 mg/kg/min. The average effective dosage is approximately 0.1 mg/kg/min (7 mg/70 kg/min) although dosages as low as 0.025 mg/kg/min have been sufficient in some patients. Dosages as high as 0.3 mg/kg/min have been used but provided little added effect with an increased rate of adverse effects, and are not recommended. Dosage of BREVIBLOC (esmolol hydrochloride) must be individualized by titration in which each step consists of a loading dose followed by a maintenance infusion. To initiate treatment, administer a loading dose infusion of 0.5 mg/kg/min of BREVIBLOC Injection / BREVIBLOC PREMIXED Injection for one minute followed by a four-minute maintenance infusion of 0.05 mg/kg/min. If the therapeutic response is inadequate at this point, repeat the same loading dose and increase the maintenance infusion to 0.1 mg/kg/min. Continue the titration procedure as above, repeating the loading dose (0.5 mg/kg/min for one minute), and increasing the maintenance infusion by increments of 0.05 mg/kg/min (for four minutes). As the desired heart rate or a safety end point (e.g., lowered blood pressure) is approached, omit the loading dose and reduce the incremental dose of the maintenance infusion from 0.05 mg/kg/min to 0.025 mg/kg/min or lower. Also if desired, increase the interval between titration steps from five to ten minutes. Maintenance dosages above 0.2 mg/kg/min have not been shown to have significantly increased benefits. The effectiveness of dosages above 0.3 mg/kg/min has not been studied. If a safety end point is exceeded, discontinue the infusion of BREVIBLOC (esmolol hydrochloride) and re-start at a lower dose. In the event of an adverse reaction, the dosage infusion of BREVIBLOC (esmolol hydrochloride) should be discontinued. If a reaction occurs at the site of the local infusion, an alternate infusion site should be used. Avoid the use of butterfly needles. The use of BREVIBLOC (esmolol hydrochloride) infusions up to 24 hours has been well documented. BREVIBLOC Injection / BREVIBLOC PREMIXED Injection (esmolol hydrochloride) 10 mg/mL (100 mg/10 mL vial and 2500 mg/250 mL premixed bag) do not require dilution.
Directions for use
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Samples containing visible particles should be discarded.
This dosage form is prediluted to provide ready-to-use, iso-osmotic solution of 10 mg/mL esmolol hydrochloride in sodium chloride recommended for BREVIBLOC intravenous administration. It may be used to administer the appropriate BREVIBLOC (esmolol hydrochloride) loading dosage infusions by hand-held syringe while the maintenance infusion is being prepared.
This dosage form is prediluted to 250 mL to provide a ready-to-use, iso-osmotic solution of 10 mg/mL esmolol hydrochloride in sodium chloride. BREVIBLOC PREMIXED Injection (10 mg/mL) is provided in ready-to-use bags with two ports, a medication port and a delivery port.
Each bag is for single-patient use only
and contains no preservative. It is advised that once drug has been withdrawn from BREVIBLOC PREMIXED Injection, the bag should be used within 24 hours, with any unused portion discarded. The BREVIBLOC PREMIXED Injection contains esmolol hydrochloride at a concentration of 10 mg/mL. The initial loading dose can be removed from the medication port of the premixed bag. Please refer to SPECIAL HANDLING INSTRUCTIONS for Preparation for Intravenous Administration.
Missed Dose
This section is not applicable as BREVIBLOC Injection / BREVIBLOC PREMIXED Injection is an IV drug titrated by a physician.
Overdosage with BREVIBLOC (esmolol hydrochloride) can produce bradycardia, congestive heart failure, hypotension, bronchospasm, electromechanical dissociation, drowsiness, loss of consciousness, hypoglycaemia and cardiac arrest. Cases of massive accidental overdoses of BREVIBLOC (esmolol hydrochloride) have occurred due to dilution errors. Some of these overdoses have been fatal while others resulted in permanent disability. Bolus doses in the range of 625 mg to 3500 mg (12.5 - 70 mg/kg) have been fatal. Patients have recovered completely from overdoses as high as 1750 mg given over one minute or doses of 7500 mg given over one hour for cardiovascular surgery. The patients who survived appear to be those whose cardiovascular circulation could be supported until the effects of BREVIBLOC Injection / BREVIBLOC PREMIXED Injection resolved. The first step in the management of toxicity should be to discontinue the BREVIBLOC (esmolol hydrochloride) infusion. Then, because of its approximately 9-minute elimination half-life and based on the observed clinical effects, the following measures should also be considered:
General: BREVIBLOC Injection / BREVIBLOC PREMIXED Injection (esmolol hydrochloride) is a competitive antagonist of isoproterenol and hence larger doses of isoproterenol may be needed to reverse many of the effects of excessive dosage of BREVIBLOC. However, the complications of excessive isoproterenol should not be overlooked.
Bradycardia: Atropine or another anticholinergic drug.
Heart block (second or third degree): Isoproterenol or transvenous cardiac pacemaker.
Congestive heart failure: Conventional therapy such as diuretic and/or digitalis glycoside. In shock due to inadequate cardiac contractility: dopamine, dobutamine, isoproterenol.
Hypotension (depending on associated factors): Epinephrine, rather than isoproterenol, or norepinephrine may be useful in addition to atropine and digitalis.
Bronchospasm: Aminophylline or isoproterenol or other beta-2 agonists.
Hypoglycaemia: Intravenous glucose.
Mechanism of Action
BREVIBLOC Injection / BREVIBLOC PREMIXED Injection (esmolol hydrochloride) is a beta- adrenergic receptor blocking agent with predominant blocking effect on beta-1 receptors. It does not possess significant intrinsic sympathomimetic or membrane stabilizing activity. BREVIBLOC Injection / BREVIBLOC PREMIXED Injection, which is administered only intravenously, has a rapid onset and a short duration of action.
Pharmacodynamics
In human electrophysiology studies, BREVIBLOC (esmolol hydrochloride) 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. Studies in normal volunteers have confirmed the beta-blocking activity of BREVIBLOC (esmolol hydrochloride), showing reduction in heart rate at rest and during exercise, and attenuation of isoproterenol-induced increases in heart rate. Blood levels of BREVIBLOC (esmolol hydrochloride) have been shown to correlate with extent of beta-blockade. Bolus injections of 50 and 100 mg BREVIBLOC (esmolol hydrochloride), given intraoperatively during general anaesthesia, decreased heart rate by more than 20% within two minutes. Systolic blood pressure fell by 17% within five minutes. The effects lasted for up to ten minutes. When given 1.5 to 2 minutes before intubation, 100 and 200 mg bolus injections of BREVIBLOC (esmolol hydrochloride) attenuated the heart rate and blood pressure response to endotracheal intubation. No effects were detectable five minutes after the administration of BREVIBLOC Injection. The haemodynamics were studied during continuous intravenous infusions in patients with elevated heart rate and acute ischemic heart disease (e.g., unstable angina pectoris or acute myocardial infarction). Titrated infusions of BREVIBLOC (esmolol hydrochloride), from 0.05 to 0.3 mg/kg/min, lowered heart rate and blood pressure. There were small increases in the left ventricular end diastolic pressure and pulmonary capillary wedge pressure, but were not considered to be clinically significant. Cardiac index, however, decreased. Cardiac index returned to pretreatment levels within 30 minutes after discontinuation of the infusion. The relative cardioselectivity of BREVIBLOC Injection was demonstrated in mildly asthmatic patients. BREVIBLOC (esmolol hydrochloride) infusions (0.1, 0.2 and 0.3 mg/kg/min) produced no significant increases in specific airway resistance when compared to placebo. At 0.3 mg/kg/min, BREVIBLOC Injection (esmolol hydrochloride) produced slightly enhanced bronchomotor sensitivity to dry-air stimulus but was not considered clinically significant.
Pharmacokinetics
Following bolus injections of BREVIBLOC (esmolol hydrochloride) to healthy volunteers, the distribution and elimination half-lives averaged 1.4 and 10.9 minutes respectively. The blood concentrations of BREVIBLOC (esmolol hydrochloride) were below quantifiable limits within 10 minutes.
Distribution: Following a loading infusion of 0.5 mg/kg/min over one minute, BREVIBLOC (esmolol hydrochloride) infusions of 0.050 to 0.3 mg/kg/min reach steady-state blood levels within five minutes with corresponding blood levels from 1.56 x 10-4 to 9.93 x 10-4 mg/mL. Steady-state blood levels increase linearly with dose over the dose range of 0.05 - 0.3 mg/kg/min. If a loading dose is not used, approximately 30 minutes are required to reach steady- state blood levels. Fifty-five percent of the amount in blood is bound to plasma proteins while the acid metabolite is only 10% bound. After cessation of the infusion, the blood levels of BREVIBLOC (esmolol hydrochloride) decrease rapidly with an elimination half-life of nine minutes.
The total body clearance of BREVIBLOC (esmolol hydrochloride) is about 20 L/hr/kg. Since this is greater than cardiac output, the metabolism of BREVIBLOC (esmolol hydrochloride) is not limited by the rate of blood flow to metabolizing tissues such as the liver. The central and total volume of distribution were found to be 1.9 L/kg and 3.3 L/kg, respectively.
Esterases in the red blood cell cytosol hydrolyse the ester link of BREVIBLOC (esmolol hydrochloride) resulting in the formation of the corresponding free acid and methanol. This acid metabolite, which shows approximately 1/1500th the beta-blocking activity of esmolol in animal studies, 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. Excretion of the acid metabolite is significantly decreased in patients with renal disease, with elimination half-life increased to about ten-fold that of patients with normal renal function, and plasma level was considerably elevated.
After several hours of infusion, at rates up to 0.3 mg/kg/min, methanol blood levels approximated endogenous levels (<10 mg/mL) and were less than 2% of levels usually associated with methanol toxicity. Less than two percent of BREVIBLOC (esmolol hydrochloride) is excreted unchanged in urine. After 24 hours, approximately 73 - 88% of the dose is recovered in the urine as the acid metabolite.
Special Populations and Conditions
: The safety and effectiveness of BREVIBLOC (esmolol hydrochloride) in children have not been established.
The safety and effectiveness of BREVIBLOC (esmolol hydrochloride) in elders have not been established.
No data is available.
No data is available.
The pharmacokinetics of BREVIBLOC Injection / BREVIBLOC PREMIXED Injection and of its major metabolite are unaltered in patients with hepatic cirrhosis.
In patients with end-stage renal disease, on haemo- or peritoneal dialysis, the pharmacokinetics of BREVIBLOC (esmolol hydrochloride) were unchanged except for an increase in the volume of distribution in patients on peritoneal dialysis. The elimination half-life of the acid metabolite is increased about ten times in patients with renal disease.
No data is available.
Vial: Store at 15 @C to 25 @C. Premixed Bag: Store at 15 @C to 25 @C. Protect from freezing. Avoid excessive heat.
CAUTION: When using BREVIBLOC PREMIXED Injection (10 mg/mL), 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 introduce additives to BREVIBLOC Injection / BREVIBLOC PREMIXED Injection. TO OPEN BREVIBLOC PREMIXED BAG: 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 inner bag firmly. If leaks are found, discard solution as sterility may be impaired. Do not use unless the solution is clear, colourless to light yellow, and the plastic protector on the delivery port is intact. Do not use if the solution is cloudy or a precipitate is present.
(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.
BREVIBLOC Injection / BREVIBLOC PREMIXED Injection is provided in two different presentations, BREVIBLOC Injection in 10 mL vial and BREVIBLOC PREMIXED Injection in 250 mL bag. It is a clear, colourless to light yellow, sterile, nonpyrogenic, iso-osmotic solution of esmolol hydrochloride in sodium chloride.
Composition:
| Dosage form: | VIALS | PREMIXED BAGS |
| Concentration: | 10 mg/mL | 10 mg/mL |
| Volume: | 10 mL | 250 mL |
Esmolol Hydrochloride 10 mg/mL Sodium Acetate Trihydrate, USP 2.8 mg/mL Sodium Chloride, USP 5.9 mg/mL Glacial Acetic Acid, USP 0.546 mg/mL Sodium Hydroxide, as needed to adjust pH to: 4.5 - 5.5 Hydrochloric Acid, NF, as needed to adjust pH to: 4.5 - 5.5 Water for injection, USP q.s. The calculated osmolarity of BREVIBLOC Injection / BREVIBLOC PREMIXED Injection is 312 mOsmol/L.
Packaging:
BREVIBLOC Injection (esmolol hydrochloride) for direct intravenous injection is supplied in 10 mL amber glass vials at a concentration of 10 mg/mL (100 mg/10 mL), in boxes of 25 vials.
BREVIBLOC PREMIXED Injection (esmolol hydrochloride) for direct intravenous injection is supplied in 250 mL non-latex, non-PVC INTRAVIA bag with two PVC ports. The INTRAVIA bag is 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 PREMIXED Injection is supplied in boxes of 10 bags.
PART II: SCIENTIFIC INFORMATION
Proper name: Esmolol hydrochloride Chemical name: (+-)-Methyl p-[2-hydroxy-3-(isopropylamino) propoxy] hydrocinnamate hydrochloride Molecular formula and molecular mass: C16 H26 NO4 Cl, 331.8 Structural formula: Physicochemical properties: White to off-white powder Solubility: Water: greater than 100 mg/mL; Alcohol: freely soluble pKa: 9.5 pH: 4.5 - 5.5 (10 mg/mL) Partition Coefficient: octanol/water at pH 7.0 is 0.42 compared to 17 for propranolol
Animal data
BREVIBLOC Injection / BREVIBLOC PREMIXED Injection (esmolol hydrochloride) has a very short duration of pharmacological action in vivo because of its rapid metabolic inactivation. In animal studies it has been shown that this rapid inactivation occurs by hydrolysis of the methyl ester functionality in BREVIBLOC (esmolol hydrochloride) to the corresponding carboxylic acid (ASL-8123) via blood and tissue esterases. The drug must be administered by the intravenous route and continuous infusion is required to achieve a prolonged pharmacological response. The following studies defined the pharmacokinetics of BREVIBLOC Injection / BREVIBLOC PREMIXED Injection and ASL-8123 in humans and provided the basis for the dosage regimen developed.
Human Studies
Please refer to Part I: HEALTH PROFESSIONAL INFORMATION - ACTION AND CLINICAL PHARMACOLOGY section.
Acute Toxicity:
| SPECIES | SEX | ROUTE | LD50 (mg/kg) | 95% C.I. (mg/kg) |
| Mouse | M/F | I.V. * | 92.9 | 86.6 - 100.2 |
| Rat | M/F | I.V. * | 70.9 | 59.0 - 82.0 |
| Rabbit | M/F | I.V. * approx. | 40 | - |
| Dog (Beagle) | M/F | I.V. * | 31.6 | 26.3 - 38.0 |
| Rat | M/F | I.V. * * | 66.7 | 62.8 - 70.8 |
| Rat | M/F | Oral | 8.9 g/kg | 8.3 - 9.6 g/kg |
* Esmolol in saline
* * 10% esmolol in formulation containing propylene glycol, alcohol and sodium acetate buffer.
After intravenous administration, all deaths occurred within approximately 10 minutes of dosing. Pharmacotoxic signs included dyspnea, prostration, convulsions, vocalizations (dogs), papillary constriction (rabbits), progressing to papillary dilation (rabbits and dogs) and less frequently, hyperpnea, hypokinesia, tremors, and sedation. All signs were absent within one hour after dosing and no delayed toxicity was observed during the two-week observation period. After oral administration, similar pharmacotoxic signs were observed, but deaths occurred for up to two days after dosing.
Long-Term Toxicity:
| SPECIES/ STRAIN | SEX M F | DOSAGE | ROUTE | DURATION OF DOSING | TOXICITY SIGNS |
| Rat (CD) | 30 30 | 0, 12, 18, 27, 40, 60 mg/kg | Single IV dose/day | 7 Days | 12, 18, 27 mg/kg: reduced activity, sedation, respiratory depression, hyperactivity: 40, 60 mg/kg: dyspnea, prostration convulsions, tremors, ataxia, hyperpnea, unconsciousness. Deaths (all within 5 min. of dosing): 3 (60 mg/kg), 2 (40 mg/kg). |
| Rat (CD) | 60 60 | 0 (Vehicle), 5, 20, 40 mg/kg | Single IV dose/day | 14 Days | 20 and 40 mg/kg: reduced motor activity, ataxia, respiratory distress (1/2 to 5 min. post-dose). 40 mg/kg: involuntary twitching pale eyes, pale skin, prostration. Deaths: 1 (control) 5 (40 mg/kg). |
| SPECIES/ STRAIN | SEX M F | DOSAGE | ROUTE | DURATION OF DOSING | TOXICITY SIGNS | |
| Dog (Beagle) | 6 | 6 | 0, 50, 100, 200, 500, 1000 m g/kg/min | Continuous IV Infusion | 5 Days | 100 m g/kg/min: sedation and diarrhea. 500 m g/kg/min: head tremors and muscle rigidity. 1000 m g/kg/min: ataxia, head tremors, muscle rigidity, salivation, emesis, unsteady gait, disorientation, convulsions, prostration, vocalization, ptosis. No deaths during dosing. Slight decrease in body weight in all groups including controls. Gross pathology: haemorrhagic spots on kidneys of 4 treated dogs. No drug-related histopathological changes. |
| Dog (Beagle) | 6 | 6 | 0 (Saline), 400, 800 m g/kg/min | Continuous IV Infusion | 7 Days | 800 m g/kg/min: head tremors. Deaths: 1 (800 m g/kg/min) on Day 7 due to overdose of anaesthesia. |
| Dog (Beagle) | 12 | 12 | 0 (Vehicle), 100, 400, 800, m g/kg/min (Infusion solution = 10 mg/mL) | Continuous IV Infusion (10 mg/mL) | 14 Days | 800 m g/kg/min: sporadic decreased activity or emesis in 4 dogs. One male exhibited prostration, salivation, non- response to stimuli, disorientation, ataxia and decreased muscle tone. Only high-dose males had a significant loss of weight (5%). BUN slightly elevated in high-dose females. No drug-related macroscopic/microscopic changes, organ weights differences observed (except for liver weights in high-dose males). |
The acid metabolite of esmolol administered intravenously in mice as a bolus in normal saline had an LD50 of 452 mg/kg (95% C.I. : 417 - 488 mg/kg). Pharmacotoxic signs were similar to those of esmolol.
Teratology and Reproduction Studies
Intravenous administration of esmolol at dosages between 1.0 and 3.0 mg/kg/min in rats and 0.5 to 1.0 mg/kg/min in rabbits for 30 minutes daily during organogenesis produced no detectable maternotoxic, embryotoxic or teratogenic effects. Administration of esmolol at 10 mg/kg/min to rats and 2.5 mg/kg/min to rabbits produced maternotoxicity and embryotoxicity. No teratogenic effects were observed, however, at these high dosages.
Vascular Irritation Studies
Venous irritation of esmolol formulation was studied by infusing the drug into the jugular vein of dogs for up to 72 hours. Formulations containing 10 mg/mL of esmolol were generally well tolerated for up to 24 hours, at infusion rates of 0.5 mg/kg/min without serious irritation. Thrombophlebitis, erythema and inflammation occurred during longer infusions as with undiluted drug formulation. Drug vehicle or diluent contributed little to the irritation observed.
Abrams J, Allen J, Allin D, Anderson J, Anderson S, Blanski L, Chadda K, Dibianco R, Favrot L, Gonzalez J, Horowitz L, Laddu AR, Lee R, MacCosbe P, Morganroth J, Narula O, Singh B, Singh J, Steck J, Swerdlow C, Turlapaty P, Waldo A. Efficacy and Safety of Esmolol vs Propranolol in the Treatment of Superventricular Tachyarrhythmias - a Multicenter Double-Blind Clinical Trial. Amer Heart J 1985; 110:913-922. Achari R, Drissel D, Matier WL, Hulse JD. Metabolism and Urinary Excretion of Esmolol in Humans. J Clin Pharmacol 1986; 26:44-47. Anderson S, Blankski L, Byrd RC, Das G, Engler R, Laddu A, Lee R, Rajfer S, Schroeder J, Steck J, Sung R, Turlapaty P, Williams D, Wilner G, Zoble R. Comparison of the Efficacy and Safety of Esmolol, a Short_Acting Beta-Blocker, with Placebo in the Treatment of Superventricular Tachyarrhythmias. Amer Heart J 1986; 111:42-48. Byrd R, Sung RJ, Marks J, Parmley WW. Safety and Efficacy of Esmolol (ASL-8052: an Ultrashort-Acting Beta-Adrenergic Blocking Agent) for Control of Ventricular Rate in Supraventricular Tachycardias. J Amer Coll Cardiol 1984; 3:394-399. Gold, MI Brown M, Coverman S, Herrington C. Heart Rate and Blood Pressure Effects of Esmolol After Ketamine Induction and Intubation. Anesthesiology 1986; 64:718-723. Gray RJ, Bateman TM, Czer LSC, Conklin CM, Matloff JM. Esmolol - A New Ultrashort Acting Beta-Blocking Agent for Rapid Control of Heart Rate in Postoperative Supraventricular Tachyarrhymias. J Amer Coll Cardiol 1985; 5:1451-56. Gray RJ, Bateman TM, Czer LSC, Conklin C, Matloff JM. Use of Esmolol in Hypertension After Cardiac Surgery. Amer J Cardiol 1985; 56:49F-56F. Greenspan AM, Scott R, Spielman SR, Horowitz LN, Senior S, Steck J, Laddu A. Electrophysiology of Esmolol. Amer J Cardiol 1985; 56:19F-26F. Iskandrian AS, Hakki AH, Laddu AR. Effects of Esmolol on Cardiac Function: Evaluation by Noninvasive Techniques. Amer J Cardiol 1985; 56:27F-32F. Kloner RA, Kirshenbaum J, Lange R, Antman EM, Braunwald E. Experimental and Clinical Observations on the Efficacy of Esmolol in Myocardial Ischemia. Amer J Cardiol 1985; 56:40F-48F. Menkhaus PG, Reves JG, Kissin I, Alvis JM, Govier AV, Samuelson PN, Lell WA, Henling CE, Bradley E. Cardiovascular Effects of Esmolol in Anesthetized Humans. Anesth Anal 1985; 64:327-334. Murthy VS, Hwang TF, Sandage BW, Laddu AR. Esmolol and the Adrenergic Response to Perioperative Stimuli. J Clin Pharmacol 1986; 26(Suppl A):A27-A35. Murthy VS, Patel KD, Elangovan RG, Hwang TF, Solocheck SM, Steck JD, Laddu AR. Cardiovascular and Neuromuscular Effects of Esmolol During Induction of Anesthesia. J Clin Pharmacol 1986; 26:351-57. Reves JG, and Flezzani P. Perioperative Use of Esmolol. Amer J Cardiol 1985; 56-57F-62F. Sinetos AL, Hulse J, Pritchett ELC. Pharmacokinetics and Pharmacodynamics of Esmolol Administered as an Intravenous Bolus. Clin Pharmacol Ther 1987; 41:112-7. IMPORTANT: PLEASE READ
PART III: CONSUMER INFORMATION
Pr
BREVIBLOC Injection (esmolol hydrochloride)
Pr
BREVIBLOC PREMIXED Injection (esmolol hydrochloride)
This leaflet is part III of a three-part "Product Monograph" published when BREVIBLOC Injection / BREVIBLOC PREMIXED Injection was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about BREVIBLOC Injection / BREVIBLOC PREMIXED Injection. Contact your doctor or pharmacist if you have any questions about the drug.
ABOUT THIS MEDICATION
What the medication is used for:
BREVIBLOC is used to manage rapid heart rates and high blood pressure during surgical operations when there is a risk for heart attacks.
BREVIBLOC is also used to rapidly control the heart rate in patients with rapid or irregular heart rhythm.
What it does:
BREVIBLOC is classified as a beta-adrenergic receptor blocking agent which blocks the actions of the involuntary nervous system
which effects the heart. It is quick acting and has a short duration of action.
When it should not be used:
BREVIBLOC Injection / BREVIBLOC PREMIXED Injection is not for use in chronic settings.
BREVIBLOC should not be used in patients:
With low blood pressure,
With a slow heart rate,
With a disease in the natural pacemaker (conduction system) of the heart,
Who are using medications to manage heart conditions or maintain their blood pressure (see Note),
With heart failure,
With shock caused by a decreased heart output.
Do not take BREVIBLOC Injection / BREVIBLOC PREMIXED Injection if you are allergic to esmolol hydrochloride or any of the nonmedicinal ingredients (see the section What the important nonmedicinal ingredients are).
Note: Your physician will determine if BREVIBLOC should be administered. This medication is only administered by a physician familiar with its effects.
What the medicinal ingredient is:
Esmolol Hydrochloride
What the important non-medicinal ingredients are:
Glacial Acetic Acid USP, Hydrochloric Acid NF, Sodium Acetate Trihydrate USP, Sodium Chloride USP, Sodium Hydroxide,
Water for Injection, USP
What dosage forms it comes in:
100 mg/10mL (10 mg/mL) vial
2,500 mg/250mL (10 mg/mL) Premixed Bags
WARNINGS AND PRECAUTIONS
Serious Warnings and Precautions
DURING THE ADMINISTRATION OF BREVIBLOC INJECTION / BREVIBLOC PREMIXED INJECTION
PATIENTS SHOULD BE CAREFULLY MONITORED, WITH PARTICULAR ATTENTION TO HEART RATE AND
BLOOD PRESSURE.
BEFORE you use BREVIBLOC Injection / BREVIBLOC PREMIXED Injection talk to your doctor if:
You have a heart condition or low blood pressure
INTERACTIONS WITH THIS MEDICATION
Talk to your doctor if you are taking any of the following medications:
Verapamil, Reserpine, Digoxin, Morphine (opioids), Succinylcholine or Warfarin
PROPER USE OF THIS MEDICATION
Usual dose:
Your physician will decide what dose of BREVIBLOC Injection /
BREVIBLOC PREMIXED Injection you will receive. The dose will vary depending on your age, weight, and the type of operation that you are having.
The safety and effectiveness of BREVIBLOC Injection / BREVIBLOC PREMIXED Injection in children have not been established.
Do not introduce additives to BREVIBLOC Injection / BREVIBLOC PREMIXED Injection.
SIDE EFFECTS AND WHAT TO DO ABOUT THEM
Side effects may include sleepiness, headache or fatigue.
If skin inflammation or hardening at the injection site occurs, contact your doctor or pharmacist.
REPORTING SUSPECTED SIDE EFFECTS
To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on
serious and unexpected side effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:
By toll-free telephone: 866-234-2345 By toll-free fax: 866-678-6789
Online: www.healthcanada.gc.ca/medeffect By email: CanadaVigilance @hc-sc.gc.ca
By regular mail:
Canada Vigilance National Office Marketed Health Products Safety and Effectiveness Information Bureau Marketed Health Products Directorate Health Products and Food Branch Health Canada
Tunney's Pasture, AL 0701C Ottawa ON K1A 0K9
NOTE: Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.
| SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM | ||||
| Symptom / effect | Talk with your doctor or pharmacist | Stop taking drug and call your doctor or pharmacist | ||
| Only if severe | In all cases | |||
| Very Common | Low blood pressure (with dizziness lightheadedness or excessive sweating) | 3 | ||
| Common | Slow heart rate | 3 | ||
| Abnormal heart rate and shortness of breath | 3 | |||
| Dizziness | 3 | |||
| Confusion | 3 | |||
| Agitation | 3 | |||
MORE INFORMATION
This is not a complete list of side effects. For any unexpected effects while taking BREVIBLOC Injection / BREVIBLOC PREMIXED Injection, contact your doctor or pharmacist.
HOW TO STORE IT
For vial, store at 15degC to 25degC.
For premixed bag store at 15degC to 25degC. Protect from freezing. Avoid excessive heat.
This document plus the full product monograph, prepared for health professionals, can be obtained by contacting the sponsor, Baxter Corporation, at:
1-800-4-BAXTER (1-800-422-9837)
This leaflet was prepared by Baxter Corporation, Mississauga, Ontario L4Z 3Y4
Brevibloc, Brevibloc Premixed and IntraVia are trademarks of Baxter International Inc.
Last revised: June 10, 2008