CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`' APPLICA TION NUMBER:
`
`19-386/5009
`
`CONTENTS
`
`
`
`Eeviews / Information Included in this NDA Review.
`
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`
`
`
`C
`
`'
`
`' A: proval Letter
`
`
`' A .rovable Letter
`
`
`
`
`
`Labelin
`’
`‘
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`
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`
`
`n
`r
`~Micr0bi010 Review 8
`
`
`
`I Clinical Pharmacolo 3 / Bio "n harmaceutics Review(s
`
`
`
`Administrative/Correspondence D0cument(s)
`'
`
`
`
`

`

`CENTER FOR DRUG EVALUATIONAND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
`19-386/8009
`
`V TradeName:
`
`Brevibloc Injection
`
`Generic Name: - Esmolol Hydrochloride
`
`Sponsor:
`
`Du Pont Merck Pharmaceutical Company
`
`Approval Date: October 21, 1991
`
`Indications:
`
`I
`
`Short—Term control Of heart rate in patients '
`with abnormally fast heart rhythms such as
`artrial fibrillation, atrial flutter or sinus
`tachycardia. ‘
`'
`’
`
`'
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICA TION NUMBER:
`
`19-386/8009
`
`APPROVAL LETTER
`
`

`

`“WE‘LL
`
`‘
`a“!
`
`I”
`
`’5.“'1er
`
`g: _/C DEPARTMENT OF HEALTH 8L HUMAN SERVICES
`
`
`
`Public Health Service
`
`NDA 19-386/8-009
`
`'
`
`The'Du Pont Merck PharmaceutiCaI Company
`Attention: Mr. Edward B. Adams
`
`Barley Mill Plaza, P27/2368
`Wilmington, DE 19880-0027
`
`Dear Mr. Adams:
`
`Food and Drug Administration
`Rockville MD 20857
`
`OCT 2 l 199'
`
`Please refer to your December 15,1989 supplemental new drug application submitted under
`section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act for Brevibloc (esmolol
`hydrochloride)
`Injection.
`,
`
`We also acknowledge receipt of your amendment dated September 25, 1991.
`
`The supplemental application provides for final printed labeling revised as follows:
`
`The statement, above the DESCRIPTION section, that the ampulIs not for direct
`1.
`intravenous injection has been made more prominent.
`
`2.
`
`Under the DESCRIPTION section, the following paragraph has been removed:
`
`1 g. 10 mL Ampul - Each mL contains 100 mg esmolol HCI in 10%
`Propylene Glycol, USP, 10% alcohol, USP and Water for
`injection, USP; buffered with 6.8 mg Sodium Acetate, USP, and
`0.00286 mL Glacial Acetic Acid,‘USP Sodium hydroxide and/or
`hydrochloric acid added, as necessary, to adjust pH to 3.5-5.5.
`
`Under the DESCRIPTION section, the phrase, "For intravenous infusion after
`3.
`dilution." has been deleted from the end of the fifth paragraph.
`'
`"
`
`Under the WARNINGS/Cardiac Failure section, the wording after the first
`4.
`two sentences has been changed to read:
`
`At the first sign or symptom of impending cardiac failure,
`BREVIBLOC should be withdrawn. Although withdrawal may be
`sufficient because of the short elimination half-life of
`BREVIBLOC, specific treatment may also ‘be considered. (see
`OVERDOSAGE.) The use of Brevibloc for control of ventricular
`response in patients with supraventricular arrhythmias should be'
`undertaken with caution when the patient is compromised
`hemodynamically or is taking other drugs that decrease any or all
`of the following: peripheral resistance, myocardial filling,
`myocardial contractility, or electrical impulse propagation in the
`
`

`

`Page 2 - NDA 19-386/8-009
`
`myocardium. Despite the rapid onset and offset of Brevibloc's
`effects, several cases of death have been reported in complex
`clinical states where Brevibloc was presumably being used to
`control ventricular rate.
`
`. and
`.
`Under the PRECAUTIONS/General subsection, the phrase ".
`5.
`thrdmbophlebitis" has been replace With “.
`.
`. including thrombophlebitis" in the first
`sentence of the first paragraph; the sentence, “Extravasation of 20 mg/mL may lead to a
`serious local reaction and possible skin necrosis" has been added; the phrase, "or
`infusion into small veins or through a butterfly catheter“ has been added to the last
`sentence; and the following paragraph has been added at the end of this subsection:
`
`Care should be taken in the intravenous administration of
`
`BREVIBLOC as sloughing of the skin and necrosis have been
`reported in association with infiltration and extravasation of
`intravenous infusions.
`
`The wording about anaphylactic reactions has been move to the
`6.
`PRECAUTIONS/Drug Interactions subsection.
`In addition, the following paragraph
`has been added to this subsection.
`
`Caution should be exercised when considering the use of
`BREVIBLOC and Verapamil in patients with depressed myocardial
`function. Fatal cardiac arrests have ocCurred in patients receiving
`both drugs. Additionally, BREVIBLOC should not be used to control
`supraventricular tachycardia in the presence of agents which are
`vasoconstrictive and inotropic such as dopamine, epinephrine, and
`. norepinephrine because of the danger of blocking cardiac
`contraCtility when systemic vascular resistance is 'high.
`
`Under the ADVERSE REACTIONS/Central Nervous System.subsection, the
`7.
`sentence, "One brief (30 second) episodeof grand mal Seizure has been reported" has
`been replaced with the sentence, “Seizures were also reported in less than 1% of
`patients, with one death."
`
`Under the ADVERSE REACTIONS/Skin (Infusion Site) subsection, the
`8.
`phrase, "thrombophlebitis, and local skin necrosis from extravasation" has been added to
`the list of adverse reactions reported in less than 1% of patients.
`
`' Under the DOSAGE AND ADMINISTRATION/Dilution subsection the
`9.
`following paragraph has been deleted:
`
`1 g AMPUL - Aseptically prepare a 10 mg/mL infusion, by adding
`five 1 g ampuls to a 500'mL container, of a compatible
`intravenous solution listed below.
`(Remove overage prior to
`dilution as appropriate). This yields a final concentration of
`10 mg/mL.
`
`

`

`Page 3 - NDA 19—386/8—009
`
`Under. the DOSAGE AND ADMINISTRATION/100 mg vial subsection, the
`10.
`sentence, "When using the 100 mg vial, a loading dose of 0.5 mg/kg/min for a 70 kg
`patient would be 3.5 mL." has been added.
`
`Under the DOSAGE AND ADMINISTRATION/Supraventricular
`11.
`Tachycardia subsection, the second and third paragraphs have been revised and a table
`has been added as follows:
`
`To initiate treatment of a patient with supraventricular
`tachycardia, administer a loading infusion of 500 mcg/kg/min
`(0.5 mg/kg/min) over one minute followed by a four-minute
`If
`maintenance infusion of 50 mcg/kg/min (0.05 mg/kg/min).
`an adequate therapeutic effect is observed over the five minutes of
`drug adminstration, maintain the maintenance infusion dosage
`with periodic adjustments up or down as needed.
`If an adequate -
`therapeutic effect'Is not observed, the same loading dosage“Is
`repeated over one minute followed by an increased maintenance
`rate infusion of 100 mcg/kg/min (0.1 mg/kg/min).
`
`Continue titration procedure as above, repeating the original
`loading infusion of 500 mcg/kg/min (0.5-mg/kg/min) over
`1 minute. but increasing the maintenance infusion rate over the
`subsequent four minutes by 50 mcg/kg/min (0.05 mg/kg/min)
`increments. As the desired heart rate or blood pressure is
`approached, omit subsequent loading doses and titrate the
`maintenance dosage up or down to endpoint. Also, if desired,
`increase the interval between steps from 5 to 10 minutes.
`
`»Time
`0- 1
`1- 5
`
`5- 6
`6- 10
`1 0-1 1
`
`1 1 -1 5
`
`1 5 -1 6 '
`1 6 ~20
`20-(24
`
`.
`
`Loading Dose
`(Over 1 minute)
`
`.
`
`,
`
`-
`
`500
`
`500
`
`_
`
`*
`
`'
`
`_
`
`-
`
`0.5
`
`0.5
`
`'
`
`hrs.)
`.
`
`'
`
`,
`
`.
`
`'
`
`I
`
`-
`
`,
`
`,
`
`'Maintenanoe Dosage
`(over 4 minutes)
`
`50
`
`100
`
`1 50
`
`'
`
`,
`
`0.05
`
`0.1
`
`0.15
`
`‘0 .2
`" 20 0
`Maintenance dose titrated
`to heart rate or other
`
`clinical endpoint.
`'*As the desired heart rate or endpoint is approached, the loading infusion may be omitted and the
`maintenance infusion titrated to 300 mcg/kg/min (0.3 mg/kg/min) or downward as
`appropriate. Maintenance dosages above 200 mcg/kg/min (0.2 mg/kg/min) have not been
`shown to have significantly increased benefits. The interval between titration steps may be
`increased.
`
`

`

`Page 4 - NDA 19-386/8-009
`
`Under the DOSAGE AND ADMINlSTRATION/Supraventricular
`12.
`Tachycardia subsection, the phrase, "and caution should be taken to prevent
`extravasation" has been added to the sixth paragraph.
`
`Under the HOW SUPPLIED section the NDC labeler code has been revised from
`13.
`0094 to 0590,
`reference to the 1 g ampul has been deleted, and the company signature
`has been updated to reflect the Manati, Puerto Rico name and address.
`
`Dosages have been expressed as both mcg/kg/min and mg/kg/min (insteadof
`14.
`mcg/kg/min only)
`throughout
`the insert.
`
`We have completed the review of this supplemental application and it is approved.
`
`We remind you that you must comply with the requirements for an approved NDA set forth
`under 21 CFR 314.80 and 314.81.
`
`Sincerely yours,‘
`
`3.1 10/19/19;
`
`Raymond J. Lipicky, MD.
`Director,
`
`Division of Cardio-Renal Drug Products
`Office of Drug Evaluation l
`Center for Drug Evaluation and Research
`
`
`
`HFC-130/JAllen
`HFD-110
`HFD-110/CSO
`HFD-80
`
`HFD-'232 (with labeling)
`HFD-110/ZMcDonald/10/11»/91;10/15/913m 10/17/67]
`
`'
`
`-
`
`Sb/10/15/91.;10/17/91
`R/D: FtWolters/10/16/91
`SChen
`
`-
`
`NMorgenstern/10/15/91
`
`Approval Date: . December 31, 1986
`
`APPROVAL
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`19-386/8009
`
`LABELING
`
`

`

`
`
`.
`
`Reviewedbvt‘
`
`BREVIBLOC® INJECTION
`(esmolol hydrochloride)
`.
`10 mL Ampul—2.5 g
`10 mL Single Dose Vial—100 mg
`HQIJ'JN reg f‘otravenous injection. Ampul must be diluted prior to its infusion—see DOSAGE AND .-
`nntflrnrsfifih’én;
`:
`.
`.
`.
`_
`DESCRIPTION
`BREVIBLOC® (esmolol HCI) is a beta,-selective (cardioselective) adrenergic receptor blocking agent with a
`very short duration of action (elimination half-life is approxrmately 9 minutes). Esmolol HCI is:
`structure:
`-”
`(:)-Methy| p-lZ-hydroxy-3-(isopropylamino) propoxy] hydrocinnamate hydrochloride and has the following 1 .
`
`/
`/0 H q /
`
`;.
`
`l-
`
`‘-
`
`I
`5..
`
`,
`
`.
`
`_= “ .-. ,
`
`_
`
`.—r«'
`
`CH30200HZCH2@OCH2CH0HCH2NHCH(CH3)2-HCl
`'Esmolol HCl has the empirical formula C(5H25N0401 and a molecular weight of 331.8. It has one asymmetric
`center and exists as an enantiomeric pair.
`Esmolol HCI 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. lts partition coefficient (octanol/water) at pH 7.0 is 0.42 com-
`pared to 17.0 for propranolol.
`BREVIBLOC® (esmolol HCI) INJECTION is a clear. colorless to light yellow. sterile. nonpyrogenic solution. r-
`2.5 g. 10 mL Ampul—Each mL contains 250 mg esmolol HCI in 25% Propylene Glycol. USP. 25% Alcohol.
`USP and Water for lnjection. USP; buffered with 17.0 mg Sodium Acetate, USP. and 0.00715 mL Glacial Acetic
`_ Acid. USP. Sodium hydroxide and/or hydrochloric acid added. as necessary. to adjust pH to 3.5-5.5.
`100 mg. 10 mL Single Dose Vial—Each mL contains 10 mg esmolol HCI and Water for Injection. USP;
`buffered with 2.8 mg Sodium Acetate. USP. and 0.546 mg Glacial Acetic Acid. USP. Sodium hydroxide and/or
`hydrochloric acid added. as necessary. to adjust pH to 4.5-5.5.
`‘
`-
`'
`CLINICAL PHARMACOLOGY
`BlitlEVlBLOC® (esmolol HCl) is a betarselective (cardioselective) adrenergic receptor blocking agent with
`rapid onset. a very short duration of action. and no significant intrinsic sympathomimetic or membrane stabi-
`lizing activity at therapeutic dosages. Its elimination half-life after intravenous infusion is approximately 9 min—
`utes. BREVIBLOC® inhibits the betaI receptors located chiefly in cardiac muscle. but this preferential effect is
`lar muscu ature.
`not absolrite and at higher doses it begins to inhibit betaZ receptors located chiefly in the bronchial and vascu-
`Pharmacokinetlcs and Metabolism
`. BREVlBLOC® (esmolol HCI) 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 ng/hr. which is greater than cardiac output; thus the
`metabolism of BREVlBLOC® is not limited by the rate of blood flow to metabolizing tissues such as the liver or
`affected by hepatic or renal blood flow. BREVIBLOC® 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 BREVlBLOC® for dosages from 50-300
`mcg/kg/min (.05-0.3-mg/kg/min) are obtained within five minutes. Stead —state is reached in about 30 min-
`utes without the loading dose.) Steady-state blood levels of BREVI L0
`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 lev—
`els of BREVlBLOlZI® 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 BREVIBLOC‘D. less than 2% of the drug is excret-
`ed unchanged in the urine. Within 24 hours of the end of infusion. approximately 73—88% of the dosage has
`been accounted for in the urine as the acid metabolite of BREVlBLOC®.
`Metabolism of BREVIBLOC® results in the formation of the corresponding free acid and methanol. The 'acid
`metabolite has been shown in animals to have about 1/1500th the activity of esmolol and in normal volunteers
`its blood levels do not correspond to the level of beta-blockade. The acid metabolite has an elimination half-
`lite 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 significantty decreased in patients with renal disease. with the
`elimination half-life increased to about ten-fold that of normals. and plasma levels considerably elevated.
`Methanol blood levels. monitored insubjects receiving BREVIBLOC® for up to 6 hours at 300 mcg/ kg/min
`(0.3 mg/kg/min) and 24 hours at 150 mcg/kglmin (Giggmglljtglmln). approximated endogenous levels and
`were leSS than 2% of. levels usually associated with met
`riot ’t’berity.
`10% oun .
`‘
`BREVtI).BL0(t;.‘® has been shown to be 55% bound to human plasma protein. while the acid metabolite is only
`Pharmacodynamlcs
`-
`Clinical harmacology studies in normal volunteers have confirmed the beta blocking activity of BREVIBLOC‘s
`(esmolo HCI). showmg reduction in heart rate at rest and during exercise. and attenuation of isoproterenol—
`induced increases in bean rate. Bloodlevels of BREVIBL00® 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.
`In human electrophysiology studies. BREVlBLOC® produced effects ty ical of a beta blocker: a decrease in the
`heart rate. increase in sinus cycle length. prolongation of the sinus no. e recovery time. prolongation of the AH
`:nterv'al during normal sinus rhythm and during atrial pacing.,and an increase in antegrade Wenckebach cycle
`engt .
`In patients undergoing radionuclide angiography. BREVIBLOCB. at dosages of 200 meg/k Imin (gt-2.9
`mgflkg/min).iproduced reductions in heart rate, systolic blood pressure. rate pressure product. le
`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. BBEVIBLOCO produced reductions in heart rate. rate pres-
`sure product and cardiac index which were also Similar to those produced rig! propranolol. but produced a sig-
`nificantly lar er fall in systolic blood pressure. inpatients undergoin ca iac catheterization, the maximum
`AD
`therapeutic use of 300 mcg/kg/min
`g‘lkg/rijin) of_BREVlBL
`produced similar effects, and. in addi-
`tion. there were small. clinically Insignificant. increases in the left ventricular end diastolic ressure and ul-
`monary capillary wedge pressure. At thirty minutes after the discontinuation of BREVlBLO
`infusion. at of
`the hemodynamic parameters had rammed to pretreatment level
`.
`“
`-
`The relative cardioselectivity of BREVIBLOQD was demonstrated in 10 mildly asthmatic patients. Infusions of
`BREVIBLOC‘D [100. 200 and 300 mcg/kg/min (0.1. 0.2 and 023m _. glrninjq groduced no si nificant increases
`in specific airway resistance compared to placebo. At 300 mp
`glmin '(0. mg/Kglmin). REVIBLOC‘D pro-
`duced slightly enhanced bronchomotor sensitivity to dry air stimulus. These effects Were not clinically signif-
`cant. and BREVIBLOC® was well tolerated by all patients. Six of the patients also received intravenous propra-
`nolol. 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 broo-
`chospasm. No adversregulmonary effects were observed in patients with COPD who received therapeutic
`dosages of BREVIBLO
`for treatment of supraventricular tachycardia (51 patients) or in perioperative set-
`tings (32 patients).
`
`.
`
`,
`
`

`

`Supraventricular Tachycardia
`In two multicenter. randomized. double-blind. controlled comparisons of BREVIBLOCG’ (esmolol HCI) with
`placebo and propranolol. maintenance doses of 50 to 300 mcg/kg/min (0.05 to 0.3 mg/kg/mrn)j:'of
`BREVlBLOC® 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 atri-
`al flutter. The majority of these patients developed their arrhythmias postoperatively. About 50-70% of the
`patients treated with BREVIBLOC® had a desired therapeutic effect (either a 20% reduction in heart rate. a
`decrease in heart' rate to less than 100 bpm, or. rarely. conversion to NSR; and about 95% of those who
`
`responded did so at a dosage of 200 mcg/kg/min (0.2 mglkgfmin)‘ or less. he average effective dosage of
`BREVIBLOC® was approximately 100-115 mcg/kg/min Oil.
`'5 mg/kg/minjfn the two studies. Other multi-
`center baseline—controlled studies gave essentially simi ar results. in the comparison with propranolol. about
`50% of patients in _both the BREVIBLOC® 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 dia—
`stolic pressure less than 50 mmHg. The hypotension was symptomatic (mainly diaphoresis or dizziness) in
`about 12% of patients. and therapy was discontinued in about 11% of patients. about half of whom were
`symptomatic.
`In comparison to propranolol. hypotension was about three times as frequent with
`BREVIBLOC®. 53% vs. 17%. The hypotension was rapidly reversible with decreased infusion rate or after dis—
`continuation of therapy with BREVIBLOC‘E. For both BREVIBLOC® and propranolol, hypotension was reported
`less frequently in patients receivrng concomitant digoxin.
`INDICATIONS AND USAGE
`_
`Supraventrlcular Tachycardia _
`BREVIBLOC® (esmolol HCI) is Indicated for the rapid control of ventricular rate in patients with atrial fibrilla-
`tion or atrial flutter in perioperative. postoperative. or other emergent circumstances where short term control
`of ventricular rate with a short-actrngagent lS desrrable. BREVIBLOC® is also indicated in noncompensatory
`sinus tachycardia where. in the physicianfis judgement. the rapid heart rate requires specific intervention. BRE-
`VlBLOC® is not intended for use in chronic settings where transfer to another agent is anticipated.
`CONTRAINDICATIONS
`BREVII‘JLDC® (esmolol HCI) is contraindicated in patients with sinus bradycardia. heart block greater than first
`degree; cardiogenic shock or overt heart failure (see WARNINGS).
`WARNINGS
`'
`
`Hypotenslon: in clinical trials 20-50% of patients treated with BREVIBLOC® (esmolol HCI) have experienced
`hypotension. generall defined as systolic pressure less than 90 mmHg and/or diastolic pressure less than 50
`mmHg. About 12% o the patients have been symptomatic mainly dia horesis or dizziness). Hypotension can
`occur at any dose but is dose-related so that oses beyon 200 mcg g/min (0.2 mg/kg/min? are not recom-
`mended. Patients should be closely monitored. especially if pretreatment blood pressure is ow. Decrease of
`dose or termination of infusion reverses hypotension. usually within 30 minutes.
`Cardiac Failure: Sympathetic stimulation is necessary in supporting circulatory function in congestive heart
`failure. and beta blockade carries the potential hazard of further depressing myocardial contractility and pre-
`cipitating more severe failure. Continued depression of the myocardium with beta blocking agents over a peri-
`
`od of time can. in some cases. lead to cardiac failure. At the first sign or symptom of_impend_ing cardiac fail-
`
`.
`4
`‘er
`étza‘useeof'tli‘e short eliminar
`
`o Enoosnc
`The useret
`
`
`
` “ta
`Bronchos astlc Diseases: PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD.
`lN GENERAL. NOT
`RECEIVE ETA BLOCKERS. Because of its-relative beta1 selectivity and titratahility. BREVIBLGC'D may be used
`with caution in patients with bronchospastic diseases. However, since beta, selectivity is not absolute. BREVl-
`BLOC® should be carefully titrated to obtain the lowest possible effective dose. In the event of branches asm.
`the infusion should be terminated immediately; a betaz stimulating agent may be administered if con itions
`warrant but should be used with particular caution as patients already have rapid ventricular rates.
`Diabetes Mellitus and fly oglycemla: BREVIBLOC° should be used with caution in diabetic patients requir-
`ing a beta blocking agent.
`eta blockers may mask tachycardia occurring with hypoglycemia. but other mani-
`festations such as dizziness and sweating may not be significantly affected.
`PRECAUTIONS
`General
`,
`
`Infusion concentrations of 20 mglmL were associated with more serious venous irritation. includingthrom-
`bophlebitis, than concentrations of 10 mg/mL. Extravasation of 20 mfimfiy teed to a senrflisfg .. geaction
`and possible skin necrosis. Concentrations greater than 10 mg/mL :.
`tisrfiii Ififfi‘sfiifilfirfl‘s‘m 'rb’tigh a -
`, butterfly catheter should be avoided..-
`Because the acidmetabolite of BREVIBLOC° is primarily excreted unchanged by the kidney. BREVIBLOC®
`‘(esmolol HCI) should. be administered with caution to(patients with impaired renal function. The elimination
`half-life of the acid metabolite was prolonged ten-fol
`and the plasma level was considerably elevated in
`patients with end—stage renal disease.
`'
`ting _l_ BR (th (29. $1942! hing of the skin and necrosis
`Ca ,
`ould,
`ta
`rinth
`tray. nous adm‘g
`re fiaagieebgfiassetiéneehmrma’nihghm a“ tea rt emails infusions.
`
`
`Drug Interactions
`Catecholamine-depletin drugs. e.g.. reserpine. may have an additive effect when given with beta blocking
`agents. Patients treate
`concurrently with BREVIBLOC° and a catecholamine depletor should therefore be
`closely observed for evidence of hypotension or marked bradycardia. which may result in vertigo. syncope. or
`postural hypotension.
`
`A sttédg of interaction between BREVIBLOC° and warfarin showed that concomitant administration of BREVI-
`BLO
`and warfarin does. not alter warfarin plasma levels. BREVIBLOC® concentrations were equivocally
`higher when given with warfarin. but this is not likely to be clinically important.
`'
`to normal vol-
`When digoxin and BREVIBLOC° (esmolol HCI) were concomitantly administered imravenousl
`unteers. there was a 10-20% increase in digoxin blood levels at some time
`ints. Digoxin d' not affect BRE-
`VIBLOC° pharmacokinetics. When intravenous morphine and BREVIBLO
`were concomitantly administered
`in normal subjects. no effect on morphine blood levels was seen. but BREVIBLOCG steady-state blood levels
`were increased by 46% in the presence of morphine. No other pharmacokinetic parameters were changed.
`The effect of BREVIBLOC° on the duration of succinylcholine-induced neuromuscular blockade was studied in-
`gatients undergoing surgery. The onset of neuromuscular blockade by succinylcholine was unaffected by
`REVIBLOOE, but the duration of neuromuscular blockade was prolonged from‘5 minutes to 8 minutes.
`Although the interactions observed in these studies do not appear to be of major clinical importance. BREVI-
`
`

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`BLOC® should be titrated with caution in patients being treated concurrently with digoxin. morphine. succinyi-
`choline or warfarin.
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`Carcinogenesis. Mulagenesis. Impairment of Fertility
`.
`Because of its short term usage no carcrnogenrcity. mutagenrcity or reproductive performance studies have
`been conducted with BREVIBLOC®.
`Pregnancy Category c
`Teratogenicity studies in rats at intravenous dosages of BREVIBLOC® up to 3000 mcg/kg/min (3 mglkg/min)
`(ten times the maxrmum human maintenance dosage) for, 30 minutes daily produced‘no e '
`nce of maternal
`toxicity, embryotoxicity or teratogenicity. while a dosage of 10.000 mcg/kg/min (10111
`" 1) produced
`
`maternal toxicity and lethality. in rabbits. intravenous dosages up to 1000 mcg/kg/min (1»: g/kg/mrn) for 30
`minutes daily produced no evidence of maternal toxicity. embryotoxicity or teratogenicity. white 2500
`mcg/kg/min (2.5 m'g/kg/min) produced minimal maternal toxicity and increased fetal resorptions.
`There are no adequate and well controlled studies in pregnant women. BREVIBLOC® should be used during
`pregnancy only if the potential benefit justifies the potential risk to the fetus.
`Nursing Mothers
`it is not known whether BREVIBLOC® is excreted in human milk. however. caution should be exercised when
`BREVIBLOC® is administered to a nursing woman.
`Pediatric Use
`The safety and effectiveness of BREVIBLOc® in children have not been established.
`ADVERSE REACTIONS
`Suprairontricular Tachycardia
`The following adverse reaction rates are based on use. of BREVIBLOC® (esmolol HCI) in almost 400 clinical
`trial patients with supraventricular tachycardia. In addition. over 600 patients have been exxosed in clinical
`studies of other conditions. The most important adverse effect has been hypotension (see W RNINGS). Most
`"adverse effects have been mild andtransient.
`CardiovascuIan—Symptomatic hypotension diaphoresis, dizziness) occurred in 12% of patients. and therapy
`was discontinued in about 11%. about half 0 whom were 5 mptomatic. Asymptomatic hypotension occurred
`in about 25% of patients. Hypotension resolved during BR VIBL00® infusion in 63% of these patients and
`within 30 minutes after discontinuation of infusion in 80% of the remaining patients. Diaphoresrs accompa-
`nied hypotension in 10% of patients. Peripheral ischemia occurred in approximately 1% of patients. Pal or
`flushing. bradycardia (heart rate less than 50 beats per minute). chest parn. syncope. pulmonary edema and
`heart block have each been reported in less than 1% of patients. In two patients without supraventricular
`tachycardia but with serious coronary artery disease ( ost inferior myocardial infarction or unstable angina),
`severe bradycardia/sinus pause/asystoie has develope . reversible in both cases with discontinuation of treat-
`ment
`
`_
`
`Central Nervous System — Dizziness has occurred in 3% of patients; somnolence in 3%. confusion.
`headache. and agitation in about 2%. and fati ue in about 1% of patients. Paresthesia. asthenia. depression.
`abnormal thinking, anxiety. anorexia. and ligh eadedness were reported in less than 1% of patients. Seizures
`were also reported in less than 1% of patients. with one death;
`Respiratory — Bronchos asm. wheezing. dyspnea. nasal congestion. rhonchi. and rates have each been
`reported in less than 1% 0 patients.
`,
`' Gastrointestinal — Nausea was reported in 7% of_ patients. Vomiting has occurred in about 1% of patients.
`Dyspepsia. constipation. dry mouth. and abdominal discomfort have each occurred in less than 1% of
`patients. Taste perversion has also been reported.
`Skin (Infusion Site) — infusion site reactions including inflammation and induration were reported in about
`8% 0 patients. Edema. erythema. skin discoloration. bumln at the infusion site. thrombophlebitis.‘ and local
`skin necrosis from extravasatlon have each occurred in less an 1% of patients.
`Miscellaneous — Each 'of the following has been reported in less than 1% of patients: Urinary retention.
`speech disorder. abnormal vision. midscapular pain. rigors. and fever.
`OVEROOSAGE
`.
`‘
`Acute Toxicity
`A few cases of massive accidental overdosa e of enevreLoce aesmoiol HCI) have occurred due-to errors in
`e effects have
`dilution. These intravenous bolus-doses of B EVIBLOCO of 5
`. 250 meg/kg ($6525 mglkfl?‘ over 1'-2 min-
`utes have produced hypotension. bradycardia. drowsiness and loss of consciousness.
`resolved within 10 minutes, in some cases with administration of a pressor agent
`Because of itsapproximately 9-minute elimination half-life. the first step in the management of toxicity should
`be to discontinue the BREVIBLOCO infusion. Then. based on the observed clinical effects. the following gener-
`al measures should also be considered:
`»
`>
`-
`'
`Bradycardle: intravenous administration of atropine or another antlcholinergic drug.
`Bronchospasmi intravenous administration of a beta: stimulating agent and/or a theophylline derivative.
`Cardiac Fallon: intravenous administration of a diuretic and/or digitalis g coside. in shock resulting from
`inadequate cardiac contractility. intravenous administration of dopamine. do utamrne. isoproterenol. or amri-
`none may be considered.
`Symptomatic Hypotenslon: intravenous administration of fluids and/or pressor agents.
`ggsfiIE’UALND ADMINISTRATION
`THE'2.5Tg AMPUL IS NOT FORDIRECT INTRAVENOUS INJECTION. THIS DOSAGE FORM IS A CONCENTRAT-
`ED. PO NT DRUG WHICH MUST BE DILUTED PRIOR TO ITS INFUSION. BREVIBLOOo SHOULD NOT BE
`ADMIXED WITH SODIUM BICARBONATE. BREVIBLOCO SHOULD NOT BE MIXED WITH OTHER DRUGS
`PRIOR TO DILUTION IN A SUITABLE INTRAVENOUS FLUID. (See Compatibility Section below.)
`-
`'
`Dilution: Aseptical
`pre
`re a 10 mg/mL infusion. by adding two 2.5 g ampuls to a 500 mL container. or one
`2.5 g ampul to a 2 0 m container. of a compatible rntravenous solution listed below. (Remove overa e prior'
`to drlutlon as appmprtate). This yields a final concentration of 10
`mL The diluted solution is stab . for at
`least 24 hours at room temperature. Note: Concentrations of BREVIB 000 meter than 10 mg/mL are lrkely to
`produce irritation on continued infusion (see PRECAUTIONS). BREVIBLO
`has. however. been well tolerated
`when administered via a central vein.
`100 mg VIAI.
`,
`This dosage form is prediluted to provide a ready-to-use 10 mg/mL concentration recommended for BREVI-
`BLDCO intravenous administration. It may be used to administer the appropriate BREVIBLOCo loading dosage
`infusions by hand-held syringe while the maintenance infusion is being prepared.
`
`wrrenrrsmiti‘iifiiifimomt ‘
`dose of 0.5 mg/Itg/min for a 70 kg patiem would be 35 mL
`
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`

`

`Supraventricular Tachycardia
`In the treatment of supraventricuiar tachycardia responses to BREVIBLOG® usually (over 95%) occur within ..
`the range of 50 to 200 mcg/kg/min (0.05 to 0.2 mg/kgl'min) The average effective dosage is approximately
`100 mcgg/Irg/min (0.1 mg/kglmin) although dosages as low as 25 meg/kg/min ((1(125 mglIgg/min) have been
`adequateIn some patients. Dosages as high as 300 mcg/kg/min (0.3 'Ing/kglmin)have been used. but tifese _
`provide little added effect and an increased rate of adverse effects. and are not recommended. Dosage of BRE-
`VIBLOC®In supraventricular tachycardia must be individualized by titration in which each step consists of a
`loading dosage followed by a maintenance dosage.
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`(I ’ cglkg/Inin (V
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`sequen_-four minutes
`
`This specific dosage regimen has not been studied intraoperatively and. because of the time required for titra-
`tion. may not be optimal for intraoperative use.
`The safety of dosages above 300 mcg/kg/min (0.3. mg/kg/rhin)‘ has not been studied.
`In the event of an adverse reaction. the dosage of BREVIBLOC® may be reduced or discontinued If a local
`infusion site reaction develops an alternate infusion site should be used and caution should be taken to pre—
`vent extravasation. The use of butterfly needles should be avoided.
`
`Abrupt cessation of BREVIBLOC®'In patients has not been reported to produce the withdrawal effects which
`may occur with abrupt withdrawal 0 beta blockers following chronic use in coronary artery disease (CAD
`patients. However. caution should still be used in abruptly discontinuing infusions of BREVIBLOCG'In CA
`patients.
`After