CENTER FOR DRUG EVALUATION AND RESEARCH
`
`- Approval Package for:
`
`/
`
`APPLICA TI0N NUMBER:
`
`19-386/8001 and 8002
`
`Trade Name:
`Brevibloc Injection
`"Generic Name: Esmolol Hydrochloride
`
`Sponsor:
`Dupont Critical Care, Inc.‘
`V Approval Date: August 15, 1988
`
`Indicatibns:
`
`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
`
`APPLICATION NUMBER:
`19—386/8001 and 8002
`
`CONTENTS
`
`
`
`g—Reviews / Information Included in this NDA Review.=l
`
`
`
` Approval Letter
`
`
`
`A) rovable Letter
`
`Labeling
`
`
`Medical Review(s)
`
`Chemistry Review(s)
`
`
`
`Pharmacology Review(s)
`
`
`
`Statistical Review(s)
`
`Microbiology Review(s)
`
`Clinical Pharmacology/ Biopharmaceutics Review(s)
`
`
`Administrative/Correspondence Document(s) I
`.
`
`
`
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TI0N NUMBER:
`
`19-386/8001 and $002
`
`APPROVAL LETTER
`
`

`

`4
`
`..
`
`.
`noniw-wws-am
`Sr006
`
`-
`
`'
`
`*
`
`‘
`
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`.
`—
`km};
`MG l5 [988 ,
`
`DuPont Critical Care, Inc.
`Attention: Mr. John H. Haterman
`
`1600 Maukegan Rd.
`Haukegan,
`IL 60985
`
`Dear Mr. Waterman:
`
`.
`l988 supplemental new
`Please refer to your September l7, l987 and July 12,
`drug applications submitted under section 505(b)(1) of the Federal Food, Drug.
`and Cosmetic Act for Brevibloc (esmolol HCl) Injection.
`
`He also acknowledge receipt of your amendments to your Septanber l7
`supplemental application dated November l9, l987, March 10 and
`June l7,’30,'1988.
`The latter contained final printed labeling.
`
`- Your September 17 supplemental application provides for a new dosage form of
`Brevibloc (esmolol HCl) consisting of a lo mL_single use vial containing
`esmolol Hcl
`l0 mg/mL (total of 100 mg) suitable for direct intravenohs
`injection.
`
`Your July 12 supplemental application provides for final printed labeling
`revised to strengthen'the Overdosage and Dosage and-Administration sections_of
`the package insert for Brevibloc.
`
`-
`
`We have completed the review of these supplemental,applications and they are
`approved.r
`_
`,
`‘
`He remind you that you must comply with the requirements for'an approved RDA
`set forth under 2l CFR’3li.80.and 3l4.8l.
`'
`
`-
`
`i
`
`_
`
`'
`
`-
`
`3‘
`
`'
`
`_
`
`V
`
`‘
`
`Sincerely‘yours!
`I
`2
`.cc:
`'
`M" 75'
`mfifi'
`61' it w /
`_' HFD'B—T—Jo '
`_-
`Raymond J. Lipicky, H.D.
`"
`-HFD-110/CSO
`Director
`,
`_
`HFD~80IDDIR
`Division of CardiorRenal Drug Products
`_ l'
`1
`HFD-lOO
`.
`Office of Drug-Evaluation I
`--
`Eggggg (with abe mg)-
`Center for Drug Evaluation and Research
`HFD—llO/KBongiovanni/7/ll/88;8/l/88
`c1 b/7/ll/_88 {8/3/88/0850C W 83458
`MD: DCunningham/B/l/BB 15‘5"?“
`'
`RWolters/B/l/BB
`CResnick/8/l/88
`SChen/B/l/88.
`CGraham/S/l/BB
`NMorgenStern/B/Z/BS
`
`_
`
`»
`
`APPROVAL
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`’
`
`APPLICA TI0N NUMBER:
`
`19—386/S001 and 8002
`
`APPROVABLE LETTER
`
`

`

`m 19~39m~om
`/3~902
`
`AUG
`
`.1 c
`
`nuPant Cr1t1ca1 Care. Inc.
`~Attenfl'em Hr. Jehn H. Haterman
`'1669 wankegan Road
`Wankegan;
`IL 60985
`
`Eear Er. Waterman:
`
`'P1ease- rEfEr ta your January 21 1987 inpp1amanta1 new drug appl1cat1-ans
`s-ubm1tted under Se¢t1nn 505(-b)(1) of t—he Fadara1 Food, Drug, and Cosmet1c Act
`far Brev1E1aa (esma1o1 hydroeh1ar1de) Injection. We also acknow1edge rece1pt
`on March 3, 1-987 of yen-r supp1ementa1 new drug app11ea-t10n (5-692) dated
`Fehruury 13.1.987‘
`_
`
`This la-tfier E156 Eonf1rms year aa1y 21. 1981 ta1-cphena converéat1ea E1th
`'flr. flEry Eueh1er.
`Ha adv1sed you t.Eat fer Edm1n1strat1ve purposes. «a have;
`renumbered year January 21
`sn—pp1emanta1 app11-cation.
`E;
`Eh: EEEEEemenEul Eag11aat1aas previde fur :.
`1
`
`danuary 21. Isails~flfli
`
`_
`
`An add1£tona1 destfs farm 31 a 15 EL stkgfggEase
`
`v1e1 9f arev1b1oe 'Gsmo101 hydroeh1ar1dg
`IEJEEE1EE.
`
`February 13. 198118~962
`
`F1ua1 pr1ntad labc1ing rkvised as 1311.5ws:
`
`1.
`
`‘aextresa (5%} 1E Lactufiad R1ager‘s In:net1na* :111 he
`ndflad ta 1E3 11-51 of fairavaneus f1u1és 1ntn uhEEE
`Brav1btvc mg; Ea<d1iatefi.
`
`-
`
`'3;
`
`'ffi1s 33.3111: dating nae idmfiu1struu1aa Figfiuga his 56%
`EEEE. stadieé tutraepartttva1y aaE.EEElune-E1'fihe E.1EE
`,requ1red far t1nrasfan, any net be opt1ma1 fbr intEE«
`' -T3at1ve aae.‘ «111 he 1nEeEtEd as a fienrtfi paragriph
`
`
`[qu LED EEHEHIEERATIGH « Superventr1eu1av
`Taehyesrm1a.
`HE have«.mE1Etad tan rev1ew of these suupieEEEEET upy1faae1-Ens as :Ehmittad
`E ffi‘draft 14Eg11nge Befara tugs; supy1amuats may be EEprEvad. hawavar.
`1-E
`Ee-geaaaaav
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`r yaw ta submit .v1E.'EEE anEeE EErtaE 1abe1s and f1—na1
`
`
`“E
`. 1EEB11
`If Edd1§1onq1 informatian rai-attug he the safety or
`
`:EE
`‘ “ iii a? EE1§ Erag Eseamas EEE11EE1¢ -befhre we reee1ve the f1ua1
`.aEe11ag, rav1s1an oE EEEE 1a§a11ng mEy Ea Esqu1rad.
`
`'13ease snbm1t twa1ve eEp1es of the printed 1nEg1s and 1abe11ng seven of uh1eh
`.-a:Ee 1nd1v1dua11y mnunted an heavy we1ght papEr 9r 51m112r mater1—n1.
`
`

`

`Pa g: 2-
`
`Hith1n 10 days after the date of this letter. yen are required to amen-d these
`sup 1ementa1 app11catiens.. nat1fy us of ynur intent ta 1116 an amendmant, or
`fa1 6w one of your ether apt1ans under 21 CFR 314 110.1» the absence 9? sash
`a§t1on FDA may take 2611071 to w1thdraw these supglemental a‘pplieaflans.
`317117113113: (asmalm hydrotmoflde) Injection in 113 1111- Single 631: vials may not
`be 1123111137 marketed unti'l yen haw: been notified in 177771121119 that 121113
`supplemental 111171 1111:1911 is approved.
`
`Shea-I'd yea 1mm any quesuiws. p1 9191 contact:-
`
`1111. mama Henry
`Censunfir Safety Officer
`Ta} 2131101197
`(331) 4113-4731)
`
`smear-91y years -.
`
`1L4 7171/37
`
`111mm 4. Links-11y. NJ}...
`_ aviator
`1111713101: at 61111104131111 Drug Pies-dares};
`11111111 771‘ Drug Research and 119771“ ,7“
`Center far 11mins and 316101“:
`570’
`L!"
`
`$'
`
`
`
`HFN~IIGICSO
`HFN~713$G£h1_
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`HFH~snraa1R
`HFN~11E1I511¢1varsenl7l2l87
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`111111”71111151777777.7777
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`SHalvarsen/7/6/a7;7/27/s7; 7/23/87 ,A.1uax¢1~44m1'
`Rmelters/7/7/87: 7/27/8-7
`NMorgenstemfl/‘ZB/fi?
`7/.3 l/5’ 7
`
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`
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`
`1131/95‘
`
`APPROVABLE
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICATION NUMBER:
`
`19-386/8001 and S002
`
`LABELING
`
`

`

`
`
`Iia’bel In; 3
`
`him HerMRo'd. r
`n‘_a-_-a L'.: K2 in,
`
`'
`
`
`
`-_ BREVIBLO‘U I’NJ '
`(esmololhydrochloride)
`Ill lnl Milli! — 2.5 |: NOT FOR BIRECT INTRAVENOUS INJECTIONJMPIJL Mil
`988
`'
`illFustilli [SEE lidSAiiE Al'iil -AGMiNlSTIATION SEGTlOlII.
`”JG I 5 l -
`ill rill. Stella Um ml —' iflil up
`,
`DESCRIPTION
`BHEVlBL069'iesmolol HCl) is a beta,-seiectiire (cardioselective) adrenergic receptor blocking agent with a very
`short duration of action (elimination half-lite is approximately 9 minutes). Esmoiol HCI is:
`( :)-lllethyl p-t2-hydroxy-3-[isopropylaminoi propnxy] hydrocinnamale hydrochloride and has the loilowing struc-
`ture:
`'
`,
`'
`
`Epsom
`
`on.o,ccn.cn.@ocn.cnoncn.nncn(cn,t..Hot
`ESmaloi flat has the empirical lormiua CyalizaNDwI and a molecular weight of 3313. it has one asymmetric center
`and crisis as an enantiumerlc pair.
`‘
`Esmclol HCl is-a white to oil-white crystalline powder. It is a relaiitIely hydrophilic compound which is very soluble
`in water and ireeiy soluble in alcohol. its partition coefficient toctanotlwater) at pit 7.0 is 0.42 compared to 17.0 ior
`propranoiol.
`-
`ensvroLoco (esmolol iiCli INJECTION is a clear. colorless to light yellow. sterile. nonpyrogertic solution for intrave—
`nousiniuslon alter dilution
`'
`2.5 g. 10 mL Ampui — Each mL contains 250 mg esmolol list in 25% Propylene Glycol. USP. 25% Alcohol. USP and
`Water for injection. USP; buiiercd with t7.0 mg Sodium Acetate. USP. and 0.00715 mL Glacial Acetic Acid. USP.
`Sodium hydroxide and/or hydrochloric acid added. as necessary. to adiust pH to 3.5-5.5.
`ioo mg. to Mt 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 adiust pH to 4.5-5.5.
`-
`.
`.
`Bllllliilil PHARMACOIJJIIV
`-
`liliEVlBflle:o (esmolol
`lEICI) is a beta.-selectlve (cardioselective) adrenergic receptor blocking agent with rapid
`onset. a very short’duratmn of action. and 'no significant intrinsic sympaihoinimetic or membrane stabilizing activity
`at therapeutic dosages. its elimination half-lite alter intravenous iniusion is approximately 9 minutes. BlilEViBLOCo
`inhibits the beta, receptors located chiefly in cardiac muscle. but this preferential eltect is not absolute and at
`higher doses it begins to inhibit beta, receptors located chiefly in the bronchial and vascular musculature
`-
`Phrrrrrmlrluticr and Metabolic-
`.
`.
`-
`BREVIBLDC' (esmololHCl) is rapidly metabolized by hydrolysis of the ester linkage. chielly by. the esterases in the
`cytosot of red- blood cells and not by_plasma cholinesterasrs or red cell membrane acetylcholinesterase. Total body
`clearance in man was lound to beabout 20 nglhr. which is greater than cardiac output; thus the metabolism of
`. BREVIBLOC° is not limited by the rate of blood flow to metabolizing tissues such as the liver.or attested by hepatic
`a
`ut minutes.
`.
`orbgena; blood flow. BREVlBLOC° has a rapid distribution hall-Iiie at about 2 minutes and an eliminationhali-iile of
`Using an appropriate loading dose. steady-state blood levels of BREVIBLDC' lordosagos lrom 50400 mcglkglmin
`are obtained within five minutes. (Steady-stale is reached in about 30 minutes withwt the loading dose.) Steady-
`state blood levels at BHEVIBLOC° increase linearly over this dosage range and elimination kinetics are dose-
`independent over this range. Steady-stale blood levels are maintained during infusion but decrease rapidly alter
`termination of the infusion. Because at its shirt halt-life. blood levels of BREVlBLOCl’ can be rapidly altered by In-
`creasing ordecreasing the infusion rate andrapidly'eliminated by discontinuing the lnlusion.
`. Consistent with the high rate of blood-based metabolism oi.BRE\ilBLOC'. less than 2% of the drug is excreted un-
`changed in the urine.,Within 24 hours of the end of inlusiori. approximately 73—88% of the dosage has been account-
`’
`ed for in the urine as the acid metabolite of BREVIBLOC'.
`-
`Metabolism oi BHEVIBLOTJ' results in the formation of the corresponding free acid and methanol. The acid metabo-
`lite 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 hail-tile oi about 3.7
`hours and is excreted in the urine'with a clearance approximately equivalent to the glomeru'lar liltration'rate. Excre-
`'tion of the acid metabolite is significantly decreased‘in patients with renal disease. with the elimination hall—tile in-
`creased to about ten-fold that o normals; and plasma levels considerably elevated.
`.
`Methanol blood levels. monitored in subiects receiving BHEVIBLOC' for up to 6 haurs at 500 mcglkglmin and 24
`met an
`toxicity.
`-
`,
`houas at; 50 mcglkglmin. approximated endogenous levels and were less than 2% of levels usually associated with
`con .
`'
`'
`-
`gHEthLOGG has bee‘n'shown to be 55% bound to human plasma protein. while the acid metabolite is only 10%
`Phrncodyaanlcl
`.
`.
`Clinical pharmacology studies in normal volunteers have confirmed the beta blocking activity at BREVIBLOC' (es-
`molol HCi). showing reduction in heart rate at rest and during exercise. and attenuation at lsoproterenol-induced in-
`creases in heart rate. Blood leveisol BREVIBLOC' have been shown to correlate with extent of beta blockade Altef
`termination oi infusion. substantial recovery from beta blockade‘is observed in lit-20 minutes
`In human'electrophysiology studies. BREVIBLOC' produced elfccts typical of a beta blocker: a decrease in the
`heart rate, increase in sinus cycle length. prolongation ol the sinus node remvery lime. prolongation of the AH inier~
`val during normal sinus rhythm and during atrial pacing. and an increase in antegrade Wenckebach cycle length.
`in patients undergoing radionuclide angiography. BREVIBLOCO, at dosages at 200 mcglkglmin.
`reduced reduc-
`tions inheart rate. systolic blood pressure. rate pressure product. tell and right ventricular ejection raction and ar-
`diac index at rest, which were similar in magnitude to those produced by intravenous propranolol (4 mg). During ex-
`ercise. BHEVIBLDC° produced reductions. in bean rate. rate pressure product and cardiac index which were also
`similarto those produced by propraiioloi. but produced a significantly larger fall in systolic blood pressure. in pa-
`tients undergoing cardiac catheterizatio‘n. the maximum therapeutic ””5.” or soc llluylhglillln ul oncvrnuoc- plu-
`duwd similar effects. and, in addition. there were small. clinicallylnsignilimni. increases In the left ventricular and
`diastolic pressure and
`lmonary capillary wedge pressure. At thirty minutes alter the discontinuation of
`BREVIBLOC' iniusion. al of the hemddynamic parameters had returned to pretreatment levels.
`»
`The relative cardloseiectivity cl BREViBLOC‘ was demonstrated in 10 mildly asthmatic patients._lnlusions oi
`BREVIBLQC' (100. 200 and 300 mcglkglmin) produced no significant increases in specific airway resistance com-
`pared to placebo. At 300 mcglkglmin. BHEVlELOC° produced slightly enhanced bronchomotor sensmvity to dry air
`stimulus. These eflects were not clinically significant. and BHEVlBLOC' was well tolerated by all patients. Six oi
`the patients also received intravenous propranoicl. and at a dosage of 1 mg. two experienced significant. symp-
`toinatic bronchospasm Tequ'fino bronchodjiator treatment. One other propranolol-treated patient also experienced
`dry air-induced bronchospasm. No adverse pulmonary effects were observed in patients with coco who received
`therapeutic dosages'oi BREVIBLOC' tor treatment at supmventn'cular tachycardia l5t patients) or in periolleraiive
`settings (32 patients).
`
`

`

`"MM
`
`given with wartarin. but thisIs not likelyto bpctinlcallyimportant
`Whemd'gexinnew (esmoiol HGT) Were concomitantlyadministere‘d intravenously tonormal volunteers.
`ere wasa 10-20%"Increase l digoxin blood levels at some tir'ne points. Digoxin did not ailect BREVIBLOG' phar-
`acokingltlsjmmitfiveno morphine and BREVIBLOC' were concornllantly administeredIn normal subjects.
`ellect'on”morphine load I
`Is was seen. but BREVIBLOG‘| steady;-state blood levels were increased by 46%In
`mamesence ol morEhine. Ifloo er pharmaeokinetic parameters were changed.
`_on the duration oi succinyichoiine-induced neuromuscularbiockade was studiedIn pa-
`tgg‘tfi‘under oibg sfii.‘ éry. The onset oi neuromuscular blockade by:sucéinylcholine was unaiiected by
`BLOC“ but thedu dtion oi neuromuscular blockade was prolonged irorn 5minutes t08 minutes.
`Although the interactions observed in these studies do not appear to be oi major clinical impedance. BREVIBLOC'
`wa ar n.
`shorriildl be titrated with caution in patients being treated concurrently with digoxin. morphine, succinylchoiine or
`carotene-Isle. flute eeealc. lrepllrmeltcircrtjtlly
`Because oi its short erm usage no carcinogenicity. mutagenicity or reproductive periormance studies have been
`conducted with BREVlBLOC'.
`
`Pregnancyballoon t:
`. Teratogenicity studies in rats at intravenom dosages oi BREVIBLOC. up to 3000 moglkglmin (ten times the maxi-
`mum human maintenance dosage) Ior 30 minutes daily produced no evidence ol maternal toxicity. embryotoxicity
`or teratogenicity. while a dosage oi to.000 mcg/kg/min produced maternal toxicity and lethality. In rabbits. intrave-
`nous dosages up to 1000 mcglkg/min tor 30 minutes daily produced no evidence of maternal toxicity, embryotoxlci-
`ty or teratogeniclty. white 2500 mcg/Irglmin produced minimal maternal toxicity and increased total resorptions
`There are no adequate and well controlled studies in pregnant women. BREVIBLOC' should be used during
`pregnancy only It the potential beneiit Iustiiies the potential risk to the lotus.
`lurclcn Nether:
`it is not known whether BREVIBLOC' is excreted in human milk however. caution should be exercised when
`BREVIBLDC° Is administered to a nursing woman.
`Pediatric lies
`The safety and eliectivenesc oi BREVIBLOC'In children have not been established.
`ADVERSE BEAETIOIS
`. Supnveelrlccler Techycerlle
`The lollowlng adverse"reaction rates are based on use at BREVIBLOC° tesmolol HGI] In almost 400 clinical trial pa-
`tients with supraventricular tachycardia In addition. over 600 patients have been' exposed in clinical studies oI
`other conditions. The most important adverse‘ eliecl has been hypotension (see Warnings). Most adverse ellects
`have been mild and transient.
`terrllrrllcellr - Symptomatic hypotension (diaphoresis. di'zziness) occurred in 12% oi patients.- and therapy was
`discontinued'In about “99 about hall oi whom were.symptomatic. Asymptomatic hypotension occurredIn about
`25% oi patients Hypotension resolved during BHEVIBLOC' lniusionIn 63% oi these patients and within 30 minutes
`alter discontinuation oi iniusion'In 80% at the remaining patients. Diaphoresis accompanied hypotenslon In 10% of
`patients Peripheral ischemia occurred in approximately 1% ol patients. Pallor. ilushing. bradycardla (heart rate
`ess than 50 beats per minute1.chesl pain. syncope. pulmonary edema and heart block have each been reported'In
`less than 1% ol patients. in two patients without supraventricular tachycardia but with serious coronary artery dis-
`ease (post interior myocardial inlarction or unstable angina). severe bradycardialslnus pause/asystole has devel-
`oped rcversible‘In both cases with discontinuation oi treatment.
`
`
`
`central llenrm Sate-I—— Dizziness has occurred'In 3% oi patients; somnolenceIn 3%. contusion headache. and agi-
`tattonIn about 2
`and iatigueIn about 1% oi patients. Paresthesia. asthenia. depression. abnormal thinking. anxi-
`ety. anorexia. and lightheadedness were reported‘In less than 1% ol patients One briel (30 second) episode oi grand
`mal seizure has been reported.
`Iceplnlery -— Bronchospasm. wheezing. dyspnea. nasal congestion. rhanchi. and rates have each been reported in
`tea than 1% at patients.
`intrcletcrtlnl - Nausea was reported In 7% oi patients Vomiting has occurred In about 1% at patients. Dyspepsia.
`constipation. dry mouth. and abdominal discomiort have each occurredIn less than 1% ofpatients. Taste perversion
`has also been'reported.
`Iltle lleirielee Still — lniusion site reactions including inflammation and lndura'lion were reported In about 8% ct pa-
`tierl’etsl1 Edema erytherna. skin discoloration. and burning at the lniusion site have each occurred in iossthan tit oi
`p'at
`ts.
`Miscelltncecc— Each oi the lotiowing has been re'ported'In less than 1% ol patients: urinary retention. speech disor-
`der. abnormal VIslon midscapular pain rigors and- lever.
`OIEIIIIOSAII‘IE
`Acute Toxicity
`.
`A low casas oi massive accidental overdosage oi BREVIBLOC' issmolol HCll have occurreddue to errors in dilution.
`. These intravenous boiusdoses ol BHEVIBLDC‘ oi 5000-6250 mayIkg over 1-2 minutes have produced hypotenslon.
`bradycardia drowsiness and loss or consciousness The etlectshave resolved within to minutes.In some cases
`with administration of a pres'sor agent.
`Because at its approximately 9-minute elimination hall-llle. the first step in the management of toxicity should be
`to discontinue the BREVIBLOC' iniusion. Then. based on the observed clinical etlects. the following general mea-
`sures shouid also be considered:
`lredyeerlle: intravenous administration at atropine or another anticholinergic dIIIg.
`Irceclespu-z Intravenous administration oi a beta2 stimulating agent and/or a theophyttlne derivative.
`terdlrc Flllrrc: intravenous administration oi a diuretic and/or digitalis glycoside. in shock resultingfrom inade-.
`considered.
`quate cardiac contractllity. intravenous administration oi dopamine. dobutamine isoproterenol. or amrlnone may be
`Synptcntle ltypotenlec- intravenous administration oi iiuids and/or pressor agents
`0:81:35,{"10 ADMINISTRATION
`l-iEI 2.59 AMPUL IS NOT FOR DIRECT INTRAVENOUS INJECTION. THIS DOSAGE FORMIS A CONCENTRATED
`Pogfilg)8&ng “magi filUST BE DILETEO PRIOR TO "'8 INFUSION BREVIBLOC' SHOULD NOT BE ADMIXED
`B
`O ATE BREVIB OC' SHOULD NOT BE MIXED WITHOTHER DRUGS PRIOR TO DILUTION IN
`A SUITABLE lNTHAVENOUS FLUID. (See Compatibility Section below.)
`Illlliu: Aseptimlly prepare a 10 mgImL lniusion. by adding two 2.5 g ampuls to a 500 mL container. or one 2.5 g
`ampul to a 250 mL container. at a compatible intravenous solution listed below. (Remove average prior to dilution as
`appropriate). This yields a llnal mncentration oi IO mgImL The diluted solution is stable tor at least 24 hours at
`room temperature. Note: Concentrations oi BREVIBLOC° greater than to mg/mL are likely to produce irritation on
`ra v n
`....— .__.-.' r.--
`footigie'd infusion (see Precautions). BREVIBLOCo has.however, been well tolerated when administeredvia a cen-
`am.— pm ...._..,
`
`2T
`
`;
`
`one not"
`
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`.
`_
`Supraltaatrlcuiar Tachycardia
`In two multicenter, randomized, double-blind. controlled comparisons oi BREVIBLUC° (Ismaiol ilCll wrth placebo
`and propranoiol. maintenance doses of 50 to 300 mcg/kglmin ol flHEVlBLOC' were found to be more ettective than
`placebo and about as ellective as propr‘anoiol.'3-G mg given by bolus injections. in the trwtment oi supraventricuiar
`tachycardia. principally atrial iihriliation and atrial llulter. The majority at these patients developed their arrhyth-
`mias postoperativeiy. About 60JO‘il ol the patients treated with BREVIBLOG° had a desired therapeutic ellcct
`(either a 20% reduction in heart rate. a decrease in heart rate to less than 100 bpm. or. rarely. conversion to NSRl
`and about 95% at those who responded did so at a dosage at 200 mcg/kglmin or less. The average ellective dosage
`ol BREVIBLOCo was approximately loo-t l5 mcglkglrnin in the two studies. Other mullicenter baseline-controlled
`studies gave essentially similar results in the comparison with propranoloi. about 50% oi patients in both-the
`BREVIBLOCO and propranoloi groups were on concomitant digoxin Response rates were slightly higher with both
`beta-blockers in the digoxio-treoted patients.
`»
`in all studies significant decreases 0! blood pressure occurred in 20-50% at patients. identitied either as adverSe
`reaction reports by investigators. or by observation at 5 static pressure loss than 90 mmHg or diastolic pressure
`less than 50 mmHg. The hypotension was symptomatic gnainly diaphorasis or dizziness) in about 12% ct patients.
`and therapy was discontinued in about 11% ct patients, about hall at whom were symptomatic: in comparison to
`propranoiol. hypotension was about three times as lrequent with BREVIBLOCO, 53% vs. 17%. The hypotension was
`rapidly reversible with decreased inlusion rate or alter discontinuation 'ol therapy with BHEVIBLOC'. For both
`BHEVlBLOC' and propranoiol. hypotension was reported less lreoumlly in patients receiving concomitant digoxin.
`INDIGATIONSANII USAGE
`'
`.
`'
`Sir
`ventricular Tachycardia
`.
`B EVlBLOC' lasmoloi MCI) is indirzted tor the rapid control oi ventricular rate in patients with atrial iibriilatlon or
`atrial flutter in perioperative. postoperative. or other emergent circumstances where short term control at ventricular
`rate with a short-acting agent is desirable. BREVlflLOC‘ is also indicated in noncompensatory sinus tachycardia
`where. in the physician's judgement. the rapid heart rate requires specific intervention. BREVlBLOC' is not intended
`tor use in chronic settings wheretransler to another agent is anticipated.
`'
`.
`conrnanrorcnrtons
`_
`allevtetocn lesmoioi HCl] is contraindicated in patients with sinus bradycardia. heart block greater than lust
`degree, cardiogenic shock or overt heart laiiure (see Wamingsi'.
`MflfllflGS
`llypatanian: In clinical trials 20-50% oi patients treated with BREVIBLOC' (esmolol HCi) have experienced hypoten-
`sron. generally delined as systolic pressure less than 90 mmilg and/or diastolic pressure less than 50 mmHg. About
`12% ot the patients haw been symptomatic (mainly diaphoresis or dizziness). Hypotension can occur at any dose
`but is dose-related so that doses beyond 200 mcg/kglmln are not recommended. Patients should be closely moni-
`tored. especially "pretreatment blood pressure is low. Decrease ot dose or termination of inlusion reverses hypoten-
`slon. usually within 30 minutes
`'
`cardiac Faitara: Sympathetic stimulation is necssary in supporting circulatory lunction in'congestive heart laiiure,
`and beta blockade carries the potential hazard ol lurther depressing myocardial contractility and precipitating more
`severe laiiure. Continued depression at the myocardium with beta blocking agents over a period oi time can. in
`some cases, lead to cardiac laiiure. At the first sign or symptom at impending cardiac laiiure. the dosage should be
`reduced or BHEVIBLOC' should be withdrawn. Although this dosage adjustment or withdrawal may be suilicient
`aoe- -
`'
`.
`because at the short elimination hall-lite at BHEVlBLOG'. specilic treatment may also be considered. (See Overdos-
`lreacirnxpaatie plream: PATiEllT: Willi MillicllltSMSTii: UISEASES Siltltiltl. II GEilElul.
`tilt! RECEIVE IETA
`IltliilEli. Because oi its relative beta. selectivity and titratability. BREVIBLOC' may be used with motion in pa-
`tients with bronchospastic diseases. However. since betal selectivity is not absolute, BliEVlBLOC° should be care-
`luily titrated to obtain the lowest possible eliectivc dose. in the event at bronchospasm. the inlusion should be ter-
`minated immediately; a beta, stimulating agent may beadministered it conditions warrant bul'shouid be 'used with
`particular caution as patients already have rapid ventricular rates.
`liahaln lalillaa .a ll «ulna-la: BREVIBLOC' should be used with caution in diabetic patients requiring a beta
`blocking agent. Beta b ockers may mask tachycardia occurring with hypoglycemia. but other manitestatlons such
`as dizziness and sweating may not be significantly aliected.
`PRECAUTIMIS
`.
`.
`General
`inlusion concentrations oi 20 org/mi, were associated with more venous irritation and thrombophiebitis than con-
`centrations 0110 mglmL. Concentrations greater than 10 mg/mL should, therelore. be avoided.
`.
`7
`.
`Because the acid metabolite oi BHEViBLOC° is primarily excreted unchanged by the kidney. BREVlBLOC' lesmolol
`HCl) should be administered with caution to patients with impaired renal lunction. The elimination hail-tile ol the
`acid metabolite was prolonged ten-laid and the plasma level was considerably elevated in patients with end-stage
`renal disease
`-
`'
`.
`'
`llraa lateractlaaa
`Catecholamlne-depleting drugs, e.g., reserpine. may have an additive ellect when given with beta blocking agents
`Patients treated concurrently with BREVIBLOC‘ and a catechoiamine deptetor should theretore be closely observed
`tor evidenm ol hypotension or marked bradycardia. which may result in vertigo. syncope. or postural hypotenslon.
`A study of interaction between BREViBLOC' and warfarin shower: that concomitant administration at BHEVtBLOC'
`and wartarln does not alter wartarin plasma levels BREVIBLOC‘ concentrations were equivocaliy higher when
`
`.
`
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`(ofI
`This tfosagle low is prediluted to provide a ready--to'-use I0 trig/ml. concentration recommended tor Brevibioc‘III-
`travenous administration. it may be used to administer the appropriate Brevibioc' loading dosage intusions by
`hand—held syringe while the maintenance inlusion'Is being prepared.
`Soprattantrlciiar tachycardia
`In the treatment ot supraventricular tachycardia responses to BREVIBLOC' usually (over 9596) occur within the
`range ol 50 to 200 mcglkglrnin. The average ellective dosage'Is approximately 100 mcg/kglmin although dosages
`as low as 25 moglkg/min have been adequatell_l some patients. Dosages as high as 300 mcg/lrglmin have been
`used. but those provide ltttie added eltect and 'an increased rate oi adverse 'eItects. and are not recommended.
`Dosage ct BREVIBLOCoIn supraventricular tachycardia must be individualized by titration .in which each step _con-
`. sisls at a loading dosage Iollowed by a maintenance dosage.
`To initiate treatment at a patient with supraventricular tachycardia. administer a loading dosage iniusion at 500
`mcglkglmin oi BREVIBLIJIID tor one minute lollowed by a 4 min maintenance iniusion III 50 mcglkglmin. ll an ade-
`quate therapeutic ellectIS not observed within live minutes repeat the same loading dosage and Iolicw with a main-
`tenance iniusion increased to 100 mcglkglmin.
`Continue titration procedure as above. repeating loading iniusion I500 mcglkglmin Iar I minute}. increasing main-
`tenance iniusion by increments at 50 mcg/Irg/ min tier 4 minutes). As the desired heart rate or a saiety end-point
`(one lowered blood pressurel is approached omit the loading iniusion and reduce incremental doseIn maintenance
`iniusion from 50 mcglkglmin to 25 mcg/kglmin or lower. Also. it daired. increase interval between titration steps
`Iran 5 to lo minutes.
`
`This specific dosage regimen has not been studied intraoperaliveiy and. because at the time required tor titration.
`may not be optimal Ior intraoperative use.
`Maintenance dosages above 200 mcg/kglmin have not been shown to have signlticantiy increased benelits. and the
`saiety ot dosages above 300 mcglkglmin has not been studied.
`In the event oi an adverse reaction, the dosage ol BREVIBLDCO may be reduced or discontinued. It a local iniusion
`site reaction develops. an alternative lnlusion site should be used. The use at butteriiy needles should be avoided.
`Abrupt cessation of BREVIBLOC°In patients has not been reported to produce the withdrawal ellects which may
`occur with abrupt withdrawal ol beta blockers Iotiowing chronic use in coronary artery disease (CAD) patients. How-
`ever, caution should still be used‘in abruptly discontinuing inlusions ol BREVIBLOC' in CAD patients.
`Alter achieving an adequate control ot the heart rate and a stable clinical slattis in patients with supra‘ventricuiar
`tachycardia. transition to alternative antiarrhythmic agents such as propranotol. digoxin. or verapamil may beac-
`comptished. A recommended guideline tor such a transitionIs given below but the physician should caretulty con—
`sider the labeling instructions tor the alternative agentselected.
`.
`.
`Alternative mat
`bum
`,
`,
`Propranolol hydrochloride
`10-20 mg o 4-6 h
`Digcxin _
`0.125415 mg q 6 h (pp. or l.v.)
`Verapamil
`80 mg q 6h
`The dosage ot BREVIBLDC' should be reduced as lollows:
`I. Thin woules tollowing the Iirst dose oI the alternative agent. reduce the inltslon rate'of BREVIBLDC' by one-
`hall 5
`2. Following the second dose at the alternative agent. mmitor the patient's response and iI satislactory control ls
`maintained tor the tirst hour. discontinue BREVIBLDC'
`
`.
`
`The use at intusions ct BHEVIBLOCO up to 24 hours has been well documented. in addition. limited data trom 24-48
`hrs IN=4B) indiwte that BREVIBLDC'P'Is'Well tolerated up to 48 hours.
`.
`burg/alimllyly'litl curl-III Ila-d lanai-aorta Hulda
`'
`IBLDC' (amulet HCI
`iNJECTlON was tested tor compatibility with ten commonly used intravenous fluid; at
`a linal concentration at 10 mg osmoiot _HCI per mL BREVIBLDCO INJECTION was lound to be compatible with' the
`toilowing solutions and was stable Ior at least 24 hours at controlled room temperatureor under refrigeration '
`Dextrose (5%) Injection. USP
`-
`Dextrose (550'In Lactated Hinger'5 injection
`Dextrose (590'In Ringer's in action
`Dextrose (5%) and Sodium hloride (O.45%) Injection. USP
`Dextrose (5%) and Sodium Chloride (I1.990- lnjection. USP
`Lac'lated Ringer's in ectidn USP
`"
`Potassium Chloride 40 mEeither) In Dextrose (5%) Injection USP
`Sodium Chloride I0.45%) Injection. USP
`Sodium Chloride (0.9%) iniection. USP
`'
`BREVIBLDC' INJECTION was NOT compatible with Sodium Bicarbonate (5%) Injection. USP.
`Itato: Parenteral drug products should be inspected visually Ior particulate matter and discoloration prior to admin-
`lstration. whenever solution and container permit.
`HOW Slll'Pll in
`N00 0094—0015-7t100 mg —- 10 mL vial. Box at 20
`Not: 0094-0025-13. 25 g -— to mLamput. Box at 10
`STORE AT CONTROLLED ROOM TEMPERATURE (ST-86F I5‘-3011). Freezing does not adversely allect the prod-
`uct. but exposure to elevated temperature: should be avoided.
`Ilu Punt Pharmaceuticals
`E. l du Pontda Nemours and Company
`Vinirnlngton.0elaware19898
`-----
`Date: May.1988
`‘
`
`_
`. M3049.
`
`.
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`'
`
`RESEARCH
`
`'
`
`APPLICA TI0N NUMBER:
`
`19-386/8001 and 8002
`
`MEDICAL REVIEW
`
`

`

`DIVISIO