CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Aggroval Package for:
`
`APPLICA TION. NUMBER:
`
`19-386/8007
`
`Trade Name:
`
`Brevibloc '
`
`Generic Name: Esmolol HCl Injection
`
`Sponsor:
`
`Dupont Critical Care Inc.
`
`Approval Date: May 11, 1989
`
`"Indications:
`
`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 I
`
`RESEARCH
`
`APPLICATION NUMBER: _
`19-386/8007
`
`CONTENTS
`
`
`
`
`
`Approval Letter
`
`A rovable Letter
`
`
`|=Rei7ieWs / Information Included in this NDA Review. i
`
`
`
`
`
`
`
`
`‘
`Labeling
`Medical Review(s)
`Chemistry Review(s)
`PharmacOlogy Review(s)
`Statistical Review(s)
`Microbiolo -y Review(s)
`Clinical Pharmacology/ Biopharmaceutics Review(s)
`Administrative/Correspondence Document(s)
`
`
`
`
`
`
`
`
`I -
`— ‘
`_
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`,
`
`. APPLICATION NUMBER:
`
`18-998/8038'
`
`APPROVAL LETTER
`
`

`

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`
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`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TI0N NUMBER:
`
`19-386/8007
`
`LABELING
`
`

`

`
`
`' NoA 19-386
`
`BREVIBLOC’ Inqscrron
`
`(ESMOLOL HYDROCHLORIDE)
`
`INSERT - A43113
`
`0
`
`'BR‘EVV'I‘I LDC” INJECTION
`(esmolol hydrochloride)
`E}
`II) It. Am til —¥::gt?l 2.5 I: Hill run IltItECT INHIIVEIIJIIS
`E
`I
`I’ll ITS ill USIIJII- SE MSAEE AND ADMINISI'IIM'IIIII SECTION].
`'
`lflml Single lieu VIII — lilo trip
`.
`DESCRIPTION
`BHEVIBLOC' (esmolol MCI) is a beta -seleclive (cardioselective) adrenergle receptor blocking agent with a very
`short duration at action (elimination hall-lite is approximately 9 minutes). Esmolol MCI is:
`'
`ture:
`til-Methyl p-lZ-hydroxy-fl-[isopropylamlncl propoxyl hydrodnnamate hydrochloride and has the lollowing struc-
`
`'tlifl
`'
`
`'
`
`|989
`:
`MAY 5
`CH,0.CCH,CH,-©—OCH2CHOHCHZNHCH(CH,),.HC|
`
`Esmolol Hct has the empirical lormlua c..H,.N0.cr and a molecular weight at 331.8. It has one asymmetric center
`and exists as an enantlomeric pair.
`-
`-
`Esmolol Hcl is a white to oil-white crystalline powder. It is a relativdy hydrophlllc compound whhh is very soluble
`propra
`cl.
`In watexnd lreely soluble in alcohol. its partition coelticlent (octanollwaterl at pH 7.0 is 0.42 compared to 17.0 let
`BREVIBLOC' (eemolol HCI) INJECTION Is a clear. colorless to light yellow. sterile. nonpyrogenlc solution tor intrave-
`nous lgtusioq‘ alter diiu ion
`
`
`
`
`
`
`
`
`
`
`
`
`W1} -
`offs
`-
`w
`.
`talnf I I 'rng ismolol HCI In 25% Propylene Glycol..USP, 2596 Alcohol. USP and
`r tor lnlection. USP; buttered with 17.0 mg Sodium Acetate. USP. and 0.00715 ml. Glacial Acetic Acid. USP.
`Wat
`Sodium hydroxide and/orhydroehlorlc acid added. as necessary. to adjust pH to 3.5-5.5.
`100 mg, 10 mL Single Dose Wal -— Each mL contains 10 mg esmolol Itcl and Water lor lngeetion. USP; buttered
`with 2.8 mg Sodium Acetate, USP. and 0.545 mg Glacial Acetic Acid. USP. Sodium hydroxi e and/or hydrochloric
`acid added. as necessary. to adjust pH to 4.5-5.5.
`.
`_
`CLINICAL PHARMACOLOGY
`BREVIELOC' (motel MCI) is a heta,—selective Imrdioselective) adrenergic remptor blocking agent with rapid
`onset. a very short duration'ol action. and no significant intrinsic sympathornlmetlcor membranestabilizing actlovgz
`at therapeutic dosages lts elimination hall-tile alter Intravenous intuslon is approximately 9 minutes. BHEVIBL
`inhibits the betaI receptors located chielly in cardiac muscle. but this preterentlal ettect Is not absolute and at
`higher doses It begins to Inhibit beta, receptors located chietty In the bronchial and vascularmusculature
`Phlnirecelrlnellcl and Heblnllrn
`.
`BHEVIBLOCO (esmolol MCI) is rapidly metabolized by hydrolysis otthe ester linkage. chlelly by the esterases in the
`growl of red blood cells and not by plasma cholinesterases or red cell membrane acetyleholinesterase Total body
`earance in man 'was found to be about 20 nglhr. whidr ls-greater than ardiac output; thus the metabolisn ol
`BREVIBLOC' is not limited by the rate at blood flow to metabolizing tissues such as the liver or altected by hepatic
`or'renal blood liow. BREVIBLOC° has a rapid distribution haiHiIe 01 about 2 minutes and an elimination hall-llte at
`about 9 minutes.
`
`Using an appropriate loading dose steady-state blood levels ol BHEVIBLOC' lor dosages lrom 50-300 mcglkglmin
`are obt'aln within five minutes. lSteady-state is reached In.‘abou130 minutes without the loading dose.) Study-
`state blood levels at BREVIBLOCO increase linearly over this dosage range and elimination kinetics are dose-
`lndependent over this” range. Steady-state blood levels are maintained during lnlusion but decrease rapidly alter
`termination ol the Inlusion. Because at its short hall-lite. blood levels at BHEVIBLOC' can be rapidly altered by In-
`creasing or decreasing the inlusion rate and rapidly eliminated by discontinuing the inlusion.
`Consistent with the high rate at blood:based metabolism of BREVIBLOC', less than 2% ol the drug is excreted un-
`changed in the urine. Within 24 hours or the end at inlusion. approximately 73-08% at the dosage has been 'accwnt-
`ed tor in the urine as the acid metabolite of BREVIBLOCG.
`Metabolism ol BHEVIBLOC' results in the lormation ol the corresponding tree acid and methanol. The acid metabo-
`lite has been shown in animals to have about tlISOOIh the activityot esmolol and in normal volunteers its blood
`levels do not correspond to the level at beta-blockade. The acid metabolite has an elimination hall-lite at about 17
`hours and Is excreted in the urine with a clearance approximately equivalent to the glorneruiar tiltration rate. Excre-
`tion at the acid metabolite is significantly decreased in patients withvrerial disease. with the elimination halt-tile in-
`creased to about ten-101d that ol normals. and plasma levels considerably elevated.
`Methanol blood levels, monitored in sublects receiving BREVIBtOC' (or up to 6 hours at 300 moglkglmin and 24
`hours at 150 mcgltrglmin, approximated endogenous levels and were less than 2% at levels usually associated with
`methanoltoxiclty.
`'
`_ boun .
`.
`-
`BRElgBLOCO has been shown to be 55% bound to human plasma protein. white the acid metabolite is only 10%
`
`

`

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`
`rbamacodyumics
`Clinical(pharmacology studies in normal volunteers have confirmed the beta blocking activity at BREVtBLOC° (es-
`molol H ll. showing reduction in heart rate at rest and during exercise. and attenuation ol isoproterenot-induced in-
`creases in heart rate. Blood levels of BREVIBLOC' have been shown to correlate with extent of beta blockade. Alter
`termination ol inlusion. substantial recovery lrom beta blockade is observed in 10~20 minutes.
`in human electrophysioiogy studies. BHEVIBLOCO produced ellects typical of a beta blocker: a decrease in the
`heart rate. rncreasetn srnus cycle length. prolongation ol the sinus node recovery time, prolongation ol the AH inter-
`val during normal srnus rhythm and during atrial pacing, and an increase in antegrade Wenckebach cycle length.
`in patients undergoing radionuclide angiography, BBEVIBLOC’. at dosages oi 200 mcglkg/min. produced reduc-
`tions in heart rate. systolic blood pressure. rate pressure product. tell and right ventricular ejection traction and ar-
`diac index at rest. which were similar in magnitude to those produced by intravenous pmpranolol (4 mg). During ex-
`ercise. BHEVIBLOC" produced reductions in heart rate. rate pressure product and cardiac index which were also
`similar to those produced by propranoiol. but produced a signlticantty larger tall in systolic blood pressure In pa-
`tients undergoing cardiac catheterizatiott. the maximum therapeutic dose at 300 mcg/kglmin ol BBEVIBLOC° pro—
`duced similar ellects. and. in addition. there were small. clinically insignilicaht. increases in the toll ventricularend
`diastolic pressure and pulmonary capillary wedge pressure. At thirty minutes alter the discontinuation ul
`BHEVIBLOC‘ inlusion. all at the hemodynamic parameters had returned to pretreatment levels.
`The relative cardioselectivity ot BHEVIBLDC‘ was demonstrated in 10 mildly asthmatic patients. tnlusions ol
`BREVIBLOCO (100, 200 and 300 mcglkglmin) produced no Signilicant increases in specilic airway resistance com-
`pared to placebo At 300 mcglkglmin. BREVIBLOC' produced slightly enhanced bronchomotor sensitivity to dry air
`stimulus. These ellects were not clinically signllicant. and tiiiEVtBLOC‘1 was well tolerated by all patients. Six oi
`the patients also received intravenous propranoiol. and at a dosage ol 1 mg. two experienced significant. symp-
`tomatic bronchospasm requiring bronchodiialor treatment. One other propranoiol-treated patient also experienced
`dry air-induced bronchospasm. No adverse pulmonary ellects were observed in patients with COPD who received
`therapeutic dosages ol BHEVIBLOC" Ior treatment at supraventricular tachycardia (St palientsi or in perioperative
`settings (32 patients).
`Saprmrttricllar tachycardia
`In 'two multi'center. randorhiled. double-blind. controlled comparisons ol BREVIBLOC‘ (esmolol HCI) with placebo
`and propranoiol. maintenance doses at 50 to 300 mcglkglmin oi BREVIBLUC' were lound to be more ellective than.
`placebo and 'about as ellectlve as propranoiol. 3-6 mg given by bolus iniections. in the treatment oi supraventricuiar
`tachycardia. principally atrial tibriitation and atrial llutter. the majority at these patients developed their arrhyth-
`mias postoperativeiy. About 60-70% at the patients treated with BREVIELOC" had a desired therapeutic ellect
`(either a 20% reduction in heart rate. a decrease to heart rate to less than 100 bpm. or. rarely. conversion to NSR)
`and about 95% pl those who responded did so at a dosage of 200 mcglkglmin or less. The average ellective dosage
`ol HHEVIBLOC' was approximately 100-115 mcglkg/min in the' two studies. Other multicenter baseline-controlled
`studies gave essentially similar results. in the comparison with propranoiol. about 50% ot patients in both the
`BREVIBLOC' and propranoioi groups were‘on concomitant digoxin Response rates were slightly higher with both
`beta-blockers in the digoxin-lrealed patients.
`in all studies significant decreases at blood pressure occurred in 20-50% at patients. identitied either as adverse
`reaction reports by investigators. or by observation ol 5 slotic pressure less than 90 mmttg or diastolic pressure
`loss than 50 mmHg. The hypotension was symptomatic gnainly diaphoresis or dizziness) in about 12% oi patients.
`and therapy was discontinued in about 11% at patients. about hall at whom we‘resymptomatic. in comparison to
`p
`ranolol. hypotension was about three times as lrequeni with BHEVtBLCtCO, 53% vs.,t 7%. The hypotension was
`rap dly reversible with decreased inlusion rate or alter discontinuation ol therapy with BHEVIBLOCO. For both
`BREVIBLOCO and propranoiol. hypotension was reported less Irequentiy in patients receiving concomitant digoxin.
`INIIIEATIUNS ANU USAGE
`.
`’
`~
`II rarentrlcular Tachycardia
`B EVIBLDB' (esmolol HCI) is initiated lot the rapid control at ventricular rate in patients with atrial libriilation or
`atrial flutter in perioperative, postoperative. or other emergent circumstances where short term control ol ventricular
`rate with a short-acting agent is desirable. BREVIBLOC' is also indicated in noncompensatory sinus tachycardia
`where. in the physician's iudgement. the rapid heart rate requires specific intervention. BREVIBLOC" is not intended
`Ior use In dtronlc settings where transler to another agent is anticipated.
`-
`CONTIIAINIIIEATIUNS
`_
`.
`BHEVtBLOC' (esmolol HCI) is contraindicated rn patients with srnus bradycardia. heart block greater than lirst
`degree, urologenic shock orovert bean lailure (see Warnings).
`WARNINGS
`It almiu: In clinical trials 20-5096 oi patients treated with BHEVIBLOC' (asmdlol HCI) have experienced hypoten-
`s on. generally delined as systolic pressure loss than 90 mmHg and/or diastolic pressure less than 50 mmllg. About
`12% ol the patients have been symptomatic (mainly diaphoresls or dizziness). Hypertension-can occur at any dose
`but is dose-related so that doses beyond 200 meg/kglmln are not recommended. Patients should be closely moni-
`tored, especially il pretreatment blood pressure is low. Decrease oi dose or termination oi Inlusion reverses hypoten-
`sion. usually within 30 minutes.
`Cardiac Faltara: Sympathetic stimulation is necessary in supporting circulatory lunction in congestive heart Iailurc.
`and beta blockade notes the potential hazard ol lurther depressing myocardial contractility and precipitating more
`severe lailure. Continued depression at the myomrdium. with beta blocking agents were period oi time can. in
`some cases. lead to cardiac lallure. At the lirst sign or symptom cl impending cardiac lallure. the dosage should be
`reduced or BHEVIBLOC° should be withdrawn. Although this dosage adiustment or withdrawal may be sulliclant
`age.
`.
`because at the short elimination hall-tile ol BREVIBLOC'. specitic treatment may also be considered. (See Overdos-
`Iruclarpaaitc lilaum: Mitilit: with lluticllttsrtsitc ntsuse: :llltitto. ttt
`iEtlEltAL ltlti lEcElllE IE"
`aLoctreas. Because of its relative beta. selectivity and titratabiiity, BREVIBLOC" may be used with caution in pa-
`tients with bronchospastic diseases However. since beta. selectivity is not absolute. BREVtBLOC' should be care-
`luily titrated to obtain the lowest possible ellective dose. In the event at bronchospasm. the inlusion slrouid be tor-
`minated Immediately: a beta, stimulating agent may be administered ll conditions warrant but should be used with
`particular caution as patients already have rapid ventricular rate:
`»
`l
`titrlalu Naililu all Malina-la: BHEVIBLOC' should be used with caution-in diabetic patients requiring a beta
`blocking agent. Beta b
`ers may mask tachycardia occurring with hypoglycemia. but other manilestations such
`as dizziness and sweating may not be signilicantly allected.
`'
`PRECAUTIONS
`Eaaanl
`Inlusion concentrations of 20 mglmt. were associated with more venous irritation and thrombophlebitis than corr-
`wntrations at to mglmL Concentrations greater than to mgImL should. therelore. be avoided.
`Because the acid metabolite ol BREViBLOC° is primarily excreted unchanged by the kidney. BREVIBLOC' (esmolol
`HCI)‘ should be administered with caution to patients with impaired renal tunction. The elimination hall-tile ol the
`acid metabolite was prolonged ten—told and the plasma level was considerably elevated in patients with end-stage
`renal disease
`.'
`'
`'
`tin latcraclim
`.
`Catr'achotarnine-depteting drugs. ea. reserpine, may have an additive ellect when given with beta blocking agents
`Patients treated concurrently with BBEVIBLOCo and a catecholamine depletor should theretore be closely observed
`for evidence at hypotension or marked bradymrdia. which may result in vertigo. syncope. or postural hypotension.
`A study at interaction between BR EVIBLUC' and warlarin showed that concomitant administration at BREVIELOC'
`and warlarin does not alter wartarin plasma levels. BHEVIBLDC° concentrations were equivomtty higher when
`given with warlarin, but this is not likely to be clinically important.
`
`f.
`
`

`

`NDA 19—386
`
`BREVIBLOC"
`
`INJECTION
`
`(ESMOLOL HYDROCHLORIDE)
`
`INSERT - A43113
`
`
`
`AP i If
`
`When digoxin and BREViBLOG' ,(esmoioi Hill) were concomitantly administered intravenously to normal volunteers.
`there was a iii-20% increase in digoxin blood levels at some time points. Digoxin did not attect BREVIBLOC' phar-
`macokinehcs. When intravenous morphine and BHEVIBLOC' were concomitantly administered in normal subjects.
`no ellect on morphine blood levels was seen. but BREVIBLOC' steady-state blood levels were increased by 46% in
`the presence of morphine. No other pharmacokinetic parameters were changed.
`The eltect oi QHEVIELDC' on the duration ot.succinyidroiine-induced neuromuscular blockade was studied in pa-
`tietglrundg bin {surgery The onset oi ‘neuromuscutar blockade by succinyichoiine was unaltected by
`Eli _ IBLOC .
`t I qdprationoinetnomusduiar blockade was prolonged lrom 5 mlnutesto 3 minutes.
`Although the‘i traétiohs obsei'ved in'these‘sidoies do not appear to be at ’maior clinical impedance. BHEVtEILDC‘
`.wa a rn. .. u
`-
`“"
`shearid‘p‘e titrated.with‘ caution in patients béihg treated concurrently with digcxin. morphine. succlnyichoiine or
`Carcinogenesis. Mehgeusie. Impairment el Fertility
`Because at its short term usage no carcinogenicity. mutagenicity or reproductive periormance studies have been
`conducted with BHEVIBLOC'.
`
`Irngeaecyhteglory l:
`‘,
`-
`;
`'
`Teratogenrcity
`udtee in rats at intravenous dosages oi BREVIBLOC" up to 3000 mcglkglmin (ten times the maxi-
`mum human matntenance dosage) lor 30 minutes daily producedfino evidence oi maternal toxicity. unbryotoxicity
`or teratogenicity. while a dosage oi 10.000 mogilrglmin produced maternal toxicity and lethality. in rabbits. intrave-
`nous dosages up to 1000 mcgllrglmin tor 30 minutes daily produced no evidenceol matemal toxicity. ernbryotoxlci- .
`ty or teralogentcity. while 2500 moglkglmin produced minimal maternal toxicity and increased teta't resorptions.
`There are no adequate and well controlled studies in pregnant women. BHEVIBLOC' should be um during
`pregnancy only it the potential benefit justifies the potential risk to the lotus.
`iterate: letters
`it is not known whether BHEViBLOC' is excreted in human milk. however. caution should be exercised when
`BREVIBLOC‘ is administered to a nursing woman.
`tuner: use '
`The salety and etiectiveness ol BHEVIBLOC' in children have not been established,
`novertse nencrrorts
`_
`Seprmnbtcnlar Tachycardia
`The tollqwing adverse reaction rates are based on use at BBEVlBLOC' iecmoioi MCI) in almost 400 clin'iiat trial pa-
`tients with supraventricular tachycardia. in addition. over 600 patients have been exposed in clinical studies at
`other conditions. The most important adverse ellect has been hypotenslon (see Warnings). Most adverse eliects
`have been mild and transient.
`'
`'
`tiarllmgeeier - Symptomatic hypotension (diaphoresis. dizzinss) occurred in mt ol patients. and therapy was
`discontinued in about 11%, about hail oi whom were symptomatic Asymptomatic rhypotenslon occurred in about
`25% ct patients Hypotension resolved during BREVIBLOCO iniuslon in 6:!" ol these patients and within 30 minutes
`after discontinuation oi inluslon in 80% oi the remaining patients. Diaphoresis accompanied hypotension in 10% at
`patients Peripheral ischemia occurred in approximately 1% oi patients Pailor. tlushing. bradycardla (heart rate
`less than 50 beats per minute). chest pain. syncope. pulmonary edema and heart block have each been reported in
`less than til ct
`tientsin two patients without supraventricu ar tachycardia but with serious coronary artery dis-
`ease (post inie
`myocardial lnlarction or unstable angina). severe bradycardialsinus pauselasystole has devel-
`oped. reversible in both eases with discontinuation or treatment.
`'
`Central ileum l
`tear — Dizziness has occurred in 3% ct patients; somnoience in 3%. contusion. headache. and agi-
`tation in about 2 . and tatigue in about lit at patients. Paresthesia, asthenia. depression. abnormal thinking. anxi-
`ety. anorexia. and ilghtheadedness were reported in less than iii 0! patients One brlel (30 second) episode= ol grand
`mal seizure has been reported.
`'
`nerplretrry — Brmchospasm. wheezing, dyspnea. nasal congestion. rhonchi, and rates have each been reported in
`less than 1% cipatients.
`Eulreleluuul -' Nausea was reported in7ii of patients. Vomiting has occurred in about lit at patients. Dyspepsia.
`constipation. dry mouth. and abdominal discbmtort have 'each occurred in less than 1% ol patients. Taste perversion
`has also been reported.
`.
`'
`Skin ileiulen altri — tniusion site reactions including inflammation and induration were reported in about 8% ol pa-
`tients. Edema. erythema. skin discoloration. and burning at the intusion site have each occurred in less than 1% of
`patients
`‘
`Itiecellmm -— Each ol the lottowlng has been reported in‘less than 1% ct patients: Urinary retenUon. speech disor-
`der. abnormal vision. midscapuiar pain. rigors, and lever.
`’
`.
`OVEROOSABE
`'
`,
`Acute anlci
`A low casestc'rt massive accidental overdosage oi BHEViBLOC' (esmolol HCl) have occurred due to errors in dilution.
`These intravenous bolus doses at BREVIBLOCO at 5000—6250 meg/kg over 1-2 minutes have produmd hypotension.
`bradycerdia. drowsiness and toss oi consciousness the etlects have resolved within to minutes.” in some cases
`with administration at a pressor agent.
`Because oi its approximatelyre-minute elimination hall-lite. the first step in the management at toxicity should be
`to discontinue BREVlBLOC° iniuslon. Then. based on the observed clinical clients. the lottowlng general measures
`should also be considered:
`'
`lrelycerdie: intravenous administration oi atropine or another anticholinergr'c drug.
`Irensnupnn: intravenous administration at a beta, stimulating agent andlor a theophy'itine derivative.
`cardiac Failure: intravenous administration ot a diuretic andlor digitalis giyooside. in shock resulting tram inade-
`quate cardlc oontractitity. intravenous administration at dopamine; dobutamine. isoproterenot. or amrinone may be
`considered.
`'
`.
`Shortened: Hypateealn: Intravenous administration otttuids andlor pressor agents.'
`
`'4“—
`
`f
`'
`
`r
`
`~
`
`
`
`

`

`'fd
`
`'
`
`-
`NDA 19—386
`
`,
`
`inhaling: mm
`' NzI°3tw .RI‘I.'
`(:
`”A ° “L... 0 d Mil.“
`Reviewed by:
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`2.5 g AMPULS ARE nor FDR ornecr lNTRAVENDUS INJECTION. mess DOSAGE roams ARE
`
`'
`
`ItiJECTION
`BREVJBLQC"
`.
`_
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`“ll 2.! "Pill
`I
`‘
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`ousnourro coutursredrtorr
`CONCENTRATED. PDTENT DRUGS WHICH MUST BE OILUTED PRIOR TO INFUSION. BREVIBLDC' SHOULD NOT BE
`ADMIXED WITH SODIUM BICARBONATE. BREVIELDC" SHOULD NOT BE MIXED WITH OTHER DRUGS PRIOR TO
`DILUTION IN A SUITABLE INTRAVENOUS FLUID. (See Compatibility Section. below.)
`lll
`.
`_
`'T'l'u gillL'aébi—éttltait n e 2155'
`
`
`1mm LLAsepticaily prepare a it) mgImL inlusion. by adding two 2.5 g ampuls to a 500 mL container. or one
`2.5 g ampul ioa 250 mL container. at a compatible intravenous solution listed below. (Remove average prior to dilu-
`tion as appropriate). This yields a iinal concentration at to mglm L.
`The diluted solution is stable tor at least 24 hours at room temperature. Note: Concentrations oi BHEVIBLDC' great-
`er than 10 mgImL are likely to produm irritation on continued inlusion (see Precautions). BREVIBLOC' has. howev-
`er. been well tolerated when administered via a central vein.
`lilti- till
`This
`sage lorm is prediluted to provide a ready-lo—use t0 mglmt concentration recommended for BREVIBLOC'
`intravenous administration. It-may be used to administer the appropriate BREVIBLOC' loading dosage inlusions by
`hand—held syringe while the maintenance inlusion Is being prepared.
`Supmellrlclitr tachycardia
`in the treatment at supraventricular tachycardia. responses to BREVIBLDC¢i usually (over 95%) occur within the
`range oi 50 to 200 mcg/kg/min. The average elleclive dosage Is approximately lilo mcgtkg/min although dosages
`as low as 25 moglirglmln have been adequate In some patients; Dosages as high as 300 mcgllrg/ min have been
`used. but these provide little added eiiect and an Increased rate ol adverse eiiects. and are not recommended.
`Dosage oi BHEVIBLDC' in supraventricuiar tachycardia must be individualized by titration in which each step con—
`sists oi a loading dosage lollowed by a maintenance dosage
`-
`To initiate treatment of a patient with supravenlricular tachycardia. administer a loading dosage inlusion oi 500
`moglkglmin oi BREVIBLDC' ior one minute lollowed by a 4 min maintenance inlusion at 50 mcglkglmln. ii an ade-
`quate therapeutic eiiect is not observed within live minutes. repeat the same loading dosage and tollow with a main-
`tenance inlusion increased to too mcglkglmin.
`-
`Continue titration procedure as above. repeating loading inlusion (500 mcglkg/min tor l minute), Increasing main-
`tenance inlusion by increments at 50 moglkgl min (ior 4 minutes). As the desired heart rate or a salety end-point
`(eg.. lowered blood pressure) is aépproached. omit the loading inlusion and reduce incremental dose in maintenance
`mm to minutes.
`inlusign Ivor)“ 5t) mcglkglmin to 5 mcg/kglmin or lower. Also. it desired. increase interval between titration steps
`This specilic dosage regimen has not been studied intraoperatively and. because oi the time required ior titration.
`may not be optimal tor intraoperative use.
`Maintenance dosages above 200 mcglkglmln have not been shown to have signiiiantly increased benefits, and the
`salety oi dosages above 300 mcg/kglmin has not been studied.
`in the event oi an adverse reaction. the dosage'oi BHEVIBLOC' may be reduced or discontinued. il a local inlusion .
`site reaction develops. an alternative inlusion site should be used. The use oi buttertly needles should be avoided.
`Abrupt cessation oi BREVIRLDC' inpatients has not been reported to pmduce the withdrawal'eilecls which may
`occur with abrupt withdrawal oi beta blockers ioilowlng chronic use in coronary artery disease (CAD) patients. How-
`ever. mutton should still be used ln'abruptty discontinuing intusions nl BREVIBLOC' in CAD patients.
`After achieving an adequate control at the heart rate and a stable clinical status in patients with supravenlrlcular
`tachycardia. transition to allemative antiarrttylhmic agents such as propranolot. digoxin. or verapamll, may be ac-
`complished. A recommended guideline lor such a transition is given below but the physician should careiuily con-
`sider the labeling Instnrctions lor the alternative agertl selected:
`Alternative Melt
`bum
`Propranotoi hydrochloride
`10-20 mg o 4-5 h
`Dlgoxln
`0125-05 mg q 6 h [p.o. or iv.)
`Verapamll
`_
`80 mg q 6 h
`The dosage oi anal/romeo should be reduced as lollows:
`i.‘ Eh sanguine; lollowlng the iirst dose of the alternative agent. reduce the inlusion rate oi BREIIBLOC‘ by one-
`a Following the second dose at the allemative agent. monitor the patient's response and ii satlstactory control is
`maintained tor the first hour. discontinue BREVIBLOCO.
`-
`The use of lnluslons ol BREVIBLOC' up 'to 24-hours has been well documented; in addition. limited data tram 2MB
`hrs (N=48) indicate that BHEVIBLOC' ts well tolerated up to 48 hours.
`itntl Iltllilly with Ciro-all tired intravenous Field:
`_
`Bit '
`IBLOC' (esmolol HCI
`lNJEcilON was tested ior compatibility with ten commonly used intravenous tlulds at
`a (that concentration at it) mg esmolol Hcl per mL. BREVIBLOC° lNJECTiON was lound to be compatible with the
`totiowlrtg solutions and was stable lorat least 24 hours at controlled room temperature or under reirlgaratlon:
`Dextrose 5%) injection. USP
`.
`Dextrose 5%) ln Lactated Ringer's inlection
`Dextrose 5%: inRingerslnlection
`-
`Dextrose 5% and Sodium Chloride (0.45%) injection. USP
`Dextmse 5% and Sodium Chlodde (0.9%) injection. USP
`tactated Ringer's in'ection. USP
`Potassium Chloride I40 mquliler) in Dextrose (5%) intention. USP
`Sodium Chloride 0.45%] intention. USP
`Sodium Chloride 0.9%) injection. USP
`BREVIBLOC' lNJECTIDN was NOT compatible with Sodium Bicarbonate (5%) injection. USP.
`Ilia: Parenteral dntg products should be inspected visually ior particulate matter and discoloration prior to adminis-
`tration. wheneversolulion and container. permit.
`How surrt‘reu
`--0015-7|'100mg — lU'mL vial.Box at 20
`
`‘r
`'
`.
`is?
`
`“
`'o —W%E§€b
`STORE AT CONTROLLED ROOM TEMPERATURE (SET-85?. 15'-30'C). Freezing does not adversely ailect the prod-
`uct. but exposure to elevated temperaturs should be avoided.
`
`i
`
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`

`

`NDA 19—386
`
`BREVIBLOC‘
`
`INJECTION
`
`(ESMOLOL HYDROCHLORIDE)
`
`1 GRAM AMPUL LABEL - A41201
`
`MAY 1
`
`i
`
`1989
`
`. ~ "mums -
`
`fiwwww%b~
`
`BREVIBLOC’E’)
`lesmnlal hpdrochlmidel
`lnjectiun [IOU mg/le
`lgm
`'
`
`IOrnLAMPUL
`
`USP.‘ wad-Ha A-qacqm'usa Bull-Id
`.
`W
`mmwwmuw i
`Wield-dam h ndjuu pH.
`not M Dunn lV. ruler-on
`nun ll mun“ upon us:
`.
`cwnou: Foo-u mew u. mm. m.- __
`mummmm.
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`
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`
`

`

`NDA 19—386
`
`BREVIBLOC'
`
`INJECTION
`
`(ESMOLOL HYDROCHLORIDE)
`.
`1 GRAN AMPUL SHELF TRAY - AS7049 I
`
`RRRRWER
`
`BREVIBLOC“ .
`(osmolm HCI)
`..
`
`.
`
`DU PONT PHARMACEUTICALS
`@BREVIBLOC”
`
`%
`
`Iginjection
`l100mg/mL)
`
`_
`
`;
`
`Jill M"!
`
`O
`
`20-lfllflllls
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`19-386/8007
`
`CHEMISTRY REVIEW! S!
`
`

`

`so.l
`
`APR l 8 1989
`
`l I
`
`!
`I
`
`,
`
`,
`
`I
`!2. NBA Number
`.'l. Organization
`'
`!
`l9-386
`!
`HFD — llo
`I
`!4. AF Number
`I3. Name and Address of Applicant (City & State)
`.1
`!
`!
`DuPont Critical Care
`I
`Supplementgsl
`!5.
`!
`l600 Naukegan Road
`!
`! Numbergsz I Dategsz
`!
`Naukegan,
`IL 59985
`'
`!
`I
`-
`.
`!7. Nonproprietary Name
`!6. Name of Drug
`.
`'
`!
`Esmolol Hydrochloride 9 5-007
`V! 4/6/89
`!
`Brevibloc
`'
`!
`!
`(LF)
`5
`!
`.
`'I
`.
`!8. Supplement(s) Provides For:
`!
`I
`!
`.9.
`Amendments and Other!
`(Reports, etc.) Dates!I
`.
`l
`
`CHEMIST'S REVIEW
`
`Labels and labeling for l g ampul,
`response to approvable letter of
`December 3l,
`l986.
`
`1
`
`V
`
`ll. How Dispensedllz; Related IND/NDA/DMF(s)
`!
`.10. Pharmaco_logical Category
`__
`!
`!
`Anti—adrenergic (B—receptor)‘
`X / / 0
`!
`9
`!
`IX
`!l3. Dosage Form(s)
`!
`l4. .Potency(ies)
`!
`!
`5
`Injection
`!
`lOO mg/mL, 250 mg/mL
`!
`I
`!
`IQ mg/mL
`:
`!
`. Re ords & Re ort’
`!lS. Chemical Name and Structure
`!
`E
`I
`!Current
`.
`.5
`'
`!
`!
`!
`L
`!
`!
`!Reviewed
`'
`No
`_
`l
`I
`Yes
`'
`
`l I
`I
`l
`:l7. Commentsr
`I
`I
`
`'
`
`'
`
`1
`
`,
`
`.
`
`.
`
`-
`
`No
`
`Yes
`
`Labeling included is for the dosage of lOO mg/mL in lO'mL ampul or
`l g esmolol hydrochloride/ampul. Ampul
`label and tray label do not
`have expiration date or lot number. Expiration date and lot no. are
`stamped on at the time of the manufacture (CSO called for the infor-
`mation).
`Package insert — A43ll3. Rev. March 1989 — satisfactory for
`DESCRIPTION and HON SUPPLIED sections.
`V
`
`'
`
`'
`'
`'
`'
`I
`I
`:
`1
`I
`
`I I
`
`I I
`
`§_!l8. Conclusions and Recommendations
`‘i
`5
`'
`Insert is satisfactory for DESCRIPTION and HON SUPPLIED sections.
`!
`I
`Ampul and shell
`tray labels — satisfactory. Expiration date and lot
`%
`5
`number is stamped on at the time of the manufacture.
`l
`311.
`.
`'
`REVI NER
`-
`v
`1
`E
`'
`!Name
`‘ nature
`I Date Completed
`!Da
`“éb~ dzutvu/
`'
`.
`fig?
`'
`
`
`
`
`L_/Reviewer
`1_/Div. File
`~lDistribution
`Original Jacket
`
`
`Nang 0288c
`I
`g
`‘
`1_/ cs0 (McDOnald)
`
`I I
`
`'
`'
`'
`!
`!
`'
`'
`
`I 1
`
`I
`l
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICATION NUMBER:
`
` _ 19-386/8007
`
`ADMINISTRATIVE and CORRESPONDENCE
`DOCUMENTS
`
`

`

`CSO Review of Final Printed Labeling
`NDA 19-386/3—007
`
`MAY 5
`
`l
`
`|939
`
`Date of submission:
`
`April 6, 1989
`
`Date of Review:
`
`April 22, 1989
`
`Applicant Name:
`
`_
`
`Dupont Critical Care,
`
`Inc.
`
`Product Name:
`
`‘Brevibloc (esmolol HCL)
`
`Injection
`
`Evaluation:
`
`This, supplement provides for the addition of the 1 gram strength to the
`Ampul, Shelf, Tray and Package Insert labels. The original NDA provided for
`this strength in theManufacturing and Controls section (Vol. 2.1)
`submitted on November 30, 1984. Dupont has not wished to market this
`strength until now.
`-
`
`There were no other changes from the last approved package insert.
`
`Ms. Cunningham‘s review found the DESCRIPTION and HOW SUPPLIED
`sections
`satisfactory.
`'
`
`Recommendation