CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICA TION NUMBER:
`
`NDA 19-386/5-004
`NDA 19-386/S-006
`
`Trade Name:
`
`Brevibloc
`
`Generic Name:
`
`Esmolol hydrochloride in sodium chloride
`
`Sponsor:
`
`Baxter Healthcare Corporation
`
`Approval Date: August 15, 1998 .
`
`Indications:
`
`For the rapid control of ventricular rate in patients with '
`atrial fibrillation or atrial flutter in perioperative,
`postoperative, or other emergent circumstances where
`short term control of ventricular rate with a short-
`
`acting agent is desirable.
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH -
`
`APPLICA TION NUMBER:
`
`NDA 19-386/5-004
`
`NDA 19-386/8-006
`
`CONTENTS
`
`
`
` LReviews / Information Included in this NDA Reviewj
`
`
`
`
`Approval Letter
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
`
`
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`A u _I 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)
`
`
`
`
`'
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICATION NUMBER:
`
`NDA 19-386/5-004
`
`NDA 19-386/S-006
`
`APPROVAL LETTER
`
`

`

`3—00; (199/n
`S~ooz CM;32’
`.-
`‘
`'ni-iaafi
`MG 1 5 1988
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`'
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`'
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`-
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`‘
`
`non 19~386/S-004
`5:006
`
`Inc.
`DuPont Critical Care.
`Attention:
`fir. John H. Haterman
`
`1600 Maukegan Rd.
`Haukegan,
`IL 58085
`
`Dear Mr. Hatennan:
`
`1
`Flease refer to your September 17,19S7 and July 12 .1988 supplemental new
`drug applications submitted under section 505(b)(1) of the Federal Food, Drug,
`and Cosmetic Act for Brevibloc (esmolol HCl) Injection.
`
`We also acknowledge receipt of your amendments to your September 17
`supplemental application dated November 19, 1987, March 10 and
`June 17. 30,'1988.
`The latter contained final printed labeling.
`
`Your September 17 supp1emental application provides for a new dosage form of
`Brevib1oc (esmoioi H61) consisting of a 10 mL single use vial containing
`95molol HCl 10 mg/mL (total of 100 mg) suitable for direct intravenous
`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 fer Brevibloc.
`
`We have completed the review of these supplementa1_ applications and they are
`approved.
`.
`
`He remind you that you must comply with the requirements for an approved NDA
`set forth under 21 CFR 314. 80 and 314. 81
`
`_
`
`’
`
`I
`
`p
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`-
`
`.
`
`h
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`Sincerelyvyours.
`-
`cc:
`1*
`__\
`67- ¢ ‘3!” 1"
`d‘r—fl”)
`Raymond J. Lipicky. n.n.
`HFD-llO/CSO
`Director
`HFD-80/DDIR
`Division of Cardio-Renal Drug Products
`_
`.
`HFD-lOO
`,
`Office of Drug-Evaluation I
`-
`Egg—gig (mth labehng)
`_
`_
`_
`.
`__
`Center for Drug Evaluation and Researc
`HFD--llO/KBongiovanni/7/11/888/1/88
`c1b/7/ll/_88,8/3/88/0850C Kg WW883"”
`R/D:
`IDCunningham/B/l/BB
`RMolters/8/1/88 '
`CResnick/8/1/88
`SChen/B/l/BB
`CGraham/B/l/BB
`NMorgenStern/B/Z/BB
`
`'-
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`-
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`V
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`APPROVAL
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`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`NDA 19-386/5-004
`
`NDA 19-386/S-006
`
`LABELING
`
`

`

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`,‘L'!’
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`at- 1 l I‘v'?
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`r-(L '
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`AQUG i5|988
`
`BR-EVI BLOC” INJECTION
`(esmoioi hydrochloride)
`_
`liJ ltIL Ampll — 2.5]: HOT F0“ DIRECT INIHAVEN WM" I BE DillliED PRIOR TO ITS
`
`mrustou (see nosnce Alli] AleMiSTllAleli seer m.
`_
`to ml Single tiese rm — 100 mg
`AUG I 5 [988
`APPROVED
`
`DES Oil | PHI)"
`_
`BREVIBLUC° (esmoioi HCI) is a helm-selective (car ,
`i' blocking agent with a very
`short duration at action (elimination hall-tile is approximately 9 minutes). Esmoloi thl is:
`i:)—Melhyl p-[2-hydroxy-S-iisopropylamino) propoxyl hydrocinnamate hydrochloride and has the tollowing struc-
`ture:
`
`*
`
`CH.o,c0H.CH,—©>— OCH;CHOHCH,NHCH(CH,),-Hcl
`Esmoiol HCI has the empirical lormlua c|5H25N04ct and a molecular weight at 331.8. it has one asymmetric center
`and exists as an enantiorneric pair.
`'
`Bmolol 'HCl is a white to cit-white crystalline powder. it is a relatively hydrophilic compound which is very soluble
`pruprano oi.
`'
`in water and lreely soluble in alcohol. Its partition coelllcient ioctanoilwater) at pH 7.0 ls 0.42 compared to 17.0 tor
`iiitEVlBLOCo (esmoioi Hct) INJECTION is a clear, colorless to light yellow. sterile. nunpyrogenic solution tor intrave-
`nous iniusion alter dilution.
`-
`25 g. 10 mL Ampul — Each mL contains 250 mg esmoioi HCl in 25% Propylene Glycol. USP, 25% Alcohol. USP and
`Water ior Iniection._USP; buttered 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 adiust pH to 3.5—5.5.
`100 mg, 10 mL Single Dose Vial — Each mL contains 10 mg esmoioi MCI and Water tor injection, USP; bullered
`with 28 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.
`-
`'
`GliNiGAl PHARMACOLOGY
`.
`BREVlBLOC' (esmoioi MCI)
`is a helm-selective (cardioselective) adrenergic receptor blocking agent with rapid
`onset. a very short durationoi action. and no signilicant intrinsic sympathomirnetlc or membrane stabilizing activity
`at therapeutic dosages. its elimination hall-lite alter intravenous iniusion is approximately 9 minutes BREVIBLOCO
`inhibits the-betal receptors located chielly in cardiac muscle. but this prelerentiai etiect is not absolute and at
`higher doses it begins to-inhiblt beta2 receptors located chieily in the bronchial and vascular musculature.
`Phamacekloetics and Metabolism
`BREVlBLOC' (esmoioi HCl) is rapidly metabolized by hydrolysis ot the ester linkage. chletly by the esterases in the
`cytosot 01 red blood cells and not by plasma choiinesterasos or red cell membrane acetylchoilnesterase. Total body
`clearance in man was iound to be about 20 nglhr, which is greater than cardiac output; thus the metabolism of
`- BREVIBLOCI is not limited by the rate at blood tlow to metabolizing tissues such as the Ilveror attected by hepatic
`or renal blood ilow. BREl/lBLOC' has a rapid distribution hall-lite at about 2 minutes and an elimination hall—lite 01
`about 9 minutes. '
`Using an appropriate loading dose. steady-state blood levels oi BHEVlBLOC' tor dosages lrom 50-300 mcglkg/mln
`areobtained within live minutes. (Steady-state is reached in about 30 minutes without the loading dose.) Steady-
`state blood levels at BREVIBLOC' increase linearly over this dosage range and elimination kinetics are dose-
`independent over this range. Steady-state blood levels are maintained during iniusion but decrease rapidly after
`terrnlnation ol the iniusion. Because at its short hall-lite, blood levels at BREVIBLOC' can be rapidly altered by in'-
`creasing or decreasing the iniusion rate and rapidly eliminated by discontinuing the iniusion.
`Consistent with the high rate at blood-based metabolism oi BREVIbLOC', less than 2% at the drugls excreted un-
`changed in the urine Within 24 hours 0! the end oi iniusion, approximately 73-88% oi the dosage has been account—
`ed tor in the urine as the acid metabolite of BREVIBLOC'.
`Metabolism oi BREVlBLOC' results in the lormation oi the corresponding lree'acld and methanol. the acid metabo-
`me has been shown in animals to have about t/1500lh the activity at esmoioi and in normal volunteers its blood
`levels do not correspond to the level ot beta-blockade. The acid metabolite has an elimination halt-lite at about 3.7
`hours and is excreted in the urine with a' clearance approximately equivalent to the glomerular iiltration rate. Excre-
`tion at the acid metabolite is signilicantly decreased in patients with renal disease, with the elimination hail-lite in-
`creased to about ten-told that at normals, and plasma levels considerably elevated.
`Methanol blood levels. monitored in subjects receiving BREVIBLOC' tor up to 6 hours at 300 mcg/kglmin and 24
`hours at 150 mcglkg/min. approximated endogenous levels and were less than 2% of levels usually associated with
`methanol toxicity.
`'
`-
`boun .
`.
`BHEtflBLW' has been shown to be 55% bound to human plasma protein, while the acid metabolite is only 10%
`Phrmcattmnlcs
`.
`_
`».
`_
`.
`Clinical pharmacology slbdies'ln normal volunteers have confirmed the beta blocking activity 01 BHEVIBLOC' tes-
`moiol Hci). showing reduction in heart rate at rest and during exercise. and attenuation oi lsoproterenol-tnduced in-
`creases to heart rate. Blood levels oi BREVIBLOC' have been shown to correlate with extent oi beta blockade Alter
`termination oi iniusion. substantial recovery 1mm beta blockade is observed ln10-20 minutes.
`In human electrophysioiogystudies, BREVlBLDC' produced etlects typical oi a beta blocker: a decrease in the
`heart rate, increase In sinus cycle length, prolongation ol the sinus node recovery time. prolongation oi the All toler-
`val during normal sinus rhythm and during atrial pacing. and an increase in antegrade Wenckebach cycle length.
`in patients undergoing radionuclide angiography. BREVIBLDCO. at dosages ol 200 mcg/kg/min. produced reduc-
`
`

`

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`wound-v—m‘
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`UGi5i988
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`Labeling: .
`Ro'd._fl:td
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`RDA he :
`Reviewed by: 5 Q}; flange;
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`trons-in heart rate. systolic blood pressure, rate pressure product. lelt and right ventricular ejection traction and car-
`drac index at rest. which were similar in magnitude to those produced by intravenous propranolol (4 mg). During ex-
`ercise. BREVIBLOCO produced reductions in heart rate. rate pressure product and cardiac index which were also
`similar to those produced by propranolol, but produced a significantly larger tall in systolic blood pressure. in pa-
`tients undergorng cardiac catheteriz'ation. the maximum therapeutic dose of 300 mcglkglmin oi BHEVIBLOC' pro-
`duced similar ellects. and. in additiorl. there were small. clinically insignificant. increases in the ielt ventricular end
`diastolic pressure and pulmonary capillary 'aiedge pressure. At thirty minutes alter the discontinuation oi
`BREVIBLOCO inlusion. all-oi the hemodynamic parameters had returned to pretreatment levels
`lnlusions cl
`The relative cardioselectivity ol BREVIBLOC' was demonstrated in to mildly asthmatic patients.
`BREVlBLOC° (too. 200 and 300 mcglkglmin) produced no signiiicant increases in specitic airway resistance com-
`pared to placebo. At 800 mcglkglmin. BREViBLOC' produced slightly enhanced bronchomotor sensitivity to dry air
`stimulus These ellects were not clinically signilicant, and tiiiEVlBLoco was well tolerated by all patients. Six ol
`the patients also received intravenous propranolol, and at a dosage at l mg. two experienced slgnilicant. symp—
`tomatic bronchospasm requiring bronchodilator treatment. One other propranolol-lreated patient also experienced
`dry air-induced bronchospasm. No adverse pulmonary ellects were observed in patients with COPD 'who received
`therapeutic dosages oi BREVlBLOC" tor treatment'ol supraventricular tachycardia (51 patients) or in pedoperative -
`settings (32 patients).
`,
`Srrpravenlrlcular Tachycardia
`in two multicent'er. randomized. double-blind. controlled comparisons ol BREVlBLOC' lesmoiol HCI] with placebo
`and propranolol, maintenance doses at 50 to 300 mcglkglmin ol BHEVIBLOCO were lound to be more ellective than
`placebo and about as ellective as propranolol, 345 mg given by bolus iniections. in the treatment of supraventricular
`tachycardia. principally atrial librillalion and atrial llutter. The majority ol these patients developed their arrhyth:
`mias postoperativeiy. About 60-70% at the patients treated with BREVIBLUC° had a desired therapeutic ellect
`(either a 20% reduction in heart rate. a decrease in heart rate to less than 100 bpm. or. rarely, conversion to' N38)
`and about 95% at those who responded did so ata dosage of 200 mcglkglmin or less. The average ellective dosage
`ol BREViBLOC' was approximately too-115 mcglkglmin in the two studies. Other multicenter baseline-controlled
`studies gave essentially similar results.
`in the comparison with propranolol, about 50% of patients in both-the
`BHEViBLOC° and propranolol groups were on concomitant digoxin. Response rates were slightly higher with both
`beta-blockers in the digoxin-treated patients.
`in all studies signiticant decreases at blood pressure occurred in 20-50% ol patients, identitied either as adverse
`reaction” reports by investigators. or by observation at 5 static pressure less than 90 mmHg or diastolic pressure
`less than 50 mmHg. The hypotension was symptomatic mainly diaphoresis ordizziness) in about 12% ot patients,
`and therapy was discontinued in about l1% ol patients. about hall at whom were symptomatic. in comparison to
`propranolol, hypotension was about three times as lrequent with BREVIBLOCO. 53% vs. 17%. The hypotensiort was
`rapidly reversible with decreased inlusion rate or alter discontinuation oi therapy with BREVlBLOC". For both
`HREVIBLOCo and propranolol, hypotension was reported less'lrequentiy in patients receiving concomitant dlgoxln.
`INDICATIONS AND IISAEE
`_
`-
`-
`SI ravonlricular Tachycardia
`B EVlBLOC‘ (esmcloi MCI) is indicated tor the rapid control at ventricular rate in patients with atrial librillalion or
`atrial llutter in perioperative. postoperative. or other emergent circumstances where short term control at ventricular
`rate with ashort-acting agent is desirable. i3l-‘tEVlt3LOCo is also indicated in noncompensatory sinus tachycardia
`where. in the physician's Judgement. the rapid heart rate requires specilic intervention. i'iltEVlBLOCo Is not intended
`lor use in chronic settings where transler to another agent is anticipated.
`'
`CONTRAINDICATIDNS .
`-
`BREVIBLOC" (esmcloi HCi) is contraindicated-in patients with sinus bradycardia, heart block greater than first
`degree, cardiogenic shock or overt bean lailure (see Warnings).
`WARNINGS
`ll etculan: in clinical trials 20-50% oi patients treated with BREVIBLDC’ (eSmolot HCl) have experienced hypoten-
`s on. generally delined as systolic pressure less than 90 mmHg and/or diastolic pressure loss than 50 mmHg. About
`12% at the patients have been symptomatic (mainly diaphoresis or dizziness). Hypotension can occur at any dose
`but is dose-related so that doses beyond 200 mcglkglmin are not recommended. Patients should be closely moni-
`tored. especially il pretreatment blood pressure is low. Decrease ot dose or termination ot inlusion reverses hypoten-
`sion. usually within 30 minutes.
`.
`Girdle: Ftlllrc: Sympathetic stimulation is necessary in supporting circulatory lunction in congestive heart tallure.
`and beta blockade carries the potential hazard of further depressing myocardial contractiiily and precipitating more
`severe lailure. Continued depression ol the myocardium with beta blocking agents over a period at time can. in
`some cases, lead to cardiac lailure At the lirst sign or symptom of impending cardiac failure. the dosage should be
`reduced or tittEVltiLocn should be withdrawn. Although‘this dosage adjustment or withdrawal may be sullicient
`age.
`.
`because at the short elimination hail-tile ol BREVlBLOC‘. specilic treatment'may also be considered. (See Overdose
`lruchosptguc ltlcgam: t'ATlEttTS llTil littlchltSFtsTll: itlSEASES stintlttt.
`til min“. IllT lEcEltE lETA
`IllicltEIS. Because oi its relative beta. selectivity and titratability. BREVIBLOC'a may-be used with caution in pa-
`tients with bronchospastic diseases. However. since betaI selectivity is not absolute. BHEVIBL‘OC‘ should be care-
`. lully titrated to obtain the lowest possible ellective dose In the event at bronchospasm. the inlusion should be ter-
`minated immediately; a beta2 stimulating agent may be administered il conditions warrant but should be used with
`particular caution as patients already have rapid ventricular rates.
`litrlutu Illiiilv: and iiyplgiycanir: BREVlBLOC' should be used with caution in diabetic patients requiring a beta
`blocking agent. Beta blockers may mask tachycardia occurring with hypoglycemia. but other manllestatrons such
`as dizziness and sweating may not be significantly allected.
`PRECAUTIONS
`--
`-
`-
`.
`.
`.
`General
`inlusion concentrations ol-20 mgImL were associated with morevenous irritation and thrombophlebitis than con-
`centrations at to mgImL. Concentrations greater than to mgimL should, the'relore, be avoided.
`Because the acid metabolite oi BHEViBLOC' Is primarily excreted unchanged by the kidney, BREleLQCf_(esmotot
`' HCi) should be administered with caution to patients with impaired renal lunction. The elimination halt-lite ol the
`acid metabolite was prolonged ten-told and the plasma level was considerably elevated in patients with end-stage
`renal disease.
`'
`‘
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`-
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`._
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`llrvg interaction:
`Catecbolamine—depleting drugs. e.g., reserpine. may have an additive ellect when given with beta blocking agents.
`Patients treated concurrently with BREVIBLOC° and a catecholamine depletor should thereloreibe closely observed
`tor evidence at hypotension or marked bradycardia. which may result in vertigo. syncope. or postural hypotension.
`-
`A study at interaction between BREVlBLflC' and warlarin showed that concomitant administration at BREVIBLOC’
`and warlarin does not alter warlarin plasma levels. BREVIBLOC° concentrations were equivocally'higher when
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` Labeling: .
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`not so: [$325 ao-a. Hui
`“"1““ by‘ Wes:—
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`given with warfarin. butti'iis isnot likely to be clinically important.
`When digoxln_'and' BR EVIBLUCF iesmotol HCI) were concomitantly administered intravenously to normal volunteers.
`there was a 10-20% increase‘in digdxin blood levels at some time points. Digoxin did not affect ITIiEVlIiLOC‘t phar-
`macokinetics. When intravenous morphine and BREVIBLOC' were concomitantly administered in normal subjects.
`no effect on morphine blood levels was seen. but'BltEVlBLlJCo steady-slate blood levels were increased by 46% in
`the presence of morphine. No other pharma'coklnetic parameters were changed.
`The effect of BITEVIBLOC' on he'
`‘
`' -induced neurornuscular blockade was studied In pa-
`tients undergoing surgery.
`he onset of neuromusc‘u r blockade by subcinylcholine was unaffected by
`Eli EVIBLOCEbut' the ddiatrq
`Ineurotfigchjafiqo‘gifide w prolonged irorn 5 minutes to B minutes.
`
`Although the interactions ob
`ed in these studies do not
`pear to be of maior‘clinical importance. HREVIBLOC‘
`
`war arm.
`
`should be titrated with muti
`. currently with digoxin. morphine. succinylcholihe or
`Carcinogenesis. Muta elects. impairment of Fertility
`Because of its short erm usage no carcinogenicity. mutagenicity or reproductive performance studies have been-
`conducted with BREVIELOC".
`_
`Pregnancy category c-
`.
`Teratogenicity studies in rats at intravenous dosages of BREVIBLOC' up to 3000 moglkglmin (ten times the maxi-
`mum human maintenance dosage) ior 30 minutes daily produced no evidence of maternal toxicity. embryotoxicity
`or teratogenicity. while a dosage of 10.000 mcglkglmin produced maternal toxicity and lethality. lo rabbits. intrave-
`nous dosages up to 1000 mcgfkglmin for 30 minutes daily produced no evidence of maternal toxicity. embryotoxici-
`ty or teratogenicity. while 2500 mcgllrg/mln produced minimal maternal toxicity and Increased fetal resorptions.
`There are no adequate and well controlled studies in pregnant women. BHEVIBLOC'--shoufd be used during
`pregnancy only if the potential benefit Iustifies the potential risk to the fetus.
`Hurting Mother:
`.
`It is not known whether BREVIHLOG' ls excreted in human milk. however. caution should be exercised when
`BREVIBLOC° Is administered toa nursing woman.
`.
`Pediatric Ilse
`The safetyand effectiveness of BREVIBLOC‘ in children have not been establlshed.
`ADVERSE REAGT‘IIIIIS
`_.._
`.
`.
`Serum-tricolor Tachycardia
`The following adverse reaction rates are based on use of BREVIBLOC' (esmoloi Hcll In almost 400 clinical trial pa-
`tients with supraventricuiar tachycardia.
`In addition. over 600 patients have been exposed in clinical studies of
`other conditions The most important adverse effect has been hypotension (see Warnings). Most adverse effects
`have been mild and transient.
`-
`carllciucxlar — Symptomatic hypotenslon idiaphoresis. dizziness) oocu'riEd In 12% of patients and therapy was
`discontinued in about 11%. about half of whom were symptomatic. Asymptomatic hypotenston occurred In about
`25% of patients. Hypotensronr'esolved during BREVIBLOC' infusion in 63% of these patients and within 30 minutes
`after discontinuation of Infusion in 80% of the remaining patients. Uiaphoresis amompanied hypotension In 10% of
`patients. Peripheral ischemia occurred in approximately 1% of patients Pallor. flushing. bradyardla (heart rate
`less than 50 beats per minute), chest pain. syncope. pulmonary edema and heart block have each been reported In
`less than 1% of patients. In two patients without supraventricuiar tachycardia but with serious coronary artery dis-
`ease (post inferior myocardial infarction or unstable angina). severe bradyaardia/sinus pause/asystole has devel-
`. oped. reversible In both cases with discontinuation of treatment.
`Central llama; 3 tall -- Dizziness hasoccurred in 3% of patients; somnoience in 3%,confusion. headache. and agi-
`tation in about
`. and fatigue In about fit of patients. Paresthesia. asthonla. depression. abnormal thinking. anxi-
`ety. anorexia. and lightheadedness were reported in less than 1% of patients One brief (30 second) eplsodeof grand
`mat-seizure has been reported.
`'-
`‘
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`Ilsplntery i Bronchospasm. wheezing. dyspnea. nasal congestion. rhonchi. and rates have each been repdited In
`less than't Scot patients.
`Glalraiaiaatlaal — Nausea was reported In 7% of_ patients. Vomiting has occurred in abouttlibf patients. Dyspepsia.
`constipation, dryrnouth. and abdominal discomfort have each occurred in less than 1% of patients. Taste perversion
`has also bwn reported.
`‘
`'
`Side Ilafualon site] -— Infusion site reactions including inflammation and lnduratlon were reported In about 8% ofpa-
`tlents. Edema. erythema. skin discoloration. and burning at the infusion site have each occurred in less than 1% of
`patients
`‘
`_
`.
`._
`lilacellaaeaaa — Each of the following has been reported in-tess than 1% of patients: Urinary retention. speech disor-
`der.‘ abnormal vision. midscapular pain. rigors. and fever.
`.
`flVElIIIIJSAEE
`..
`_
`-
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`Acute Toxicity
`A few cases of massive accidental overdosage of BREVIBLOC' (esmolol HCI) have occurred due to errors In dilution;
`These intravenous bolus doses of BREVIBLOC" of 5000-5250 mcglkg over 1-2 minutes have produwd hypotension;
`bradycardia. drowsiness and loss of consciousness. The effects have resolved within 10 minutes. in some cases
`with administra'tion‘of a pressor agent.
`.
`'
`‘
`Because of its approximately 9-minute elimination half-life. the first step In the management of toxicity should be
`to discontinue the BHEVIBLOC‘ infusion. Then, based on the observed clinical effeds. the-following general mea-
`sures should also beconsidered;
`‘
`'
`'
`'
`' "
`.
`I
`lra'dyi‘arliafini'ravenous administration of atropine or another antichoiinergic drug.
`E
`Ircochcpaan: Intravenous administration of a beta, stimulating agent and/or a theophylllne derivative.
`Cardiac Fall-re: intravenous administrationoi a diuretic and/or digitalis giycosichn shock resulting from inade-
`quate cardiac contractility. intravenous administration of dopamine, dobutamine. isoproterenol;or amrinone may be
`mnsidered.
`'
`Symptomatic Ifypotemlon: Intravenous administration of fluids and/or pressor agents
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`not No: 19—3225 ne'e._fl:u.Ir
`“Mend Mr:W
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`DOSAOPE AND ADMINISTRATION
`2.5 I AM Ill
`THE 2.5 g AMPUL IS NOT FOR DIRECT INTRAVENOUS INJECTION. THIS DOSAGE FORM IS A CONCENTRATED.
`POTENT DRUG WHICH MUST BE OILUTEO PRIOR TO [TS INFUSION. BREVIBLDC‘ SHOULD NOT BE ADMIXEO
`WITH SODIUM BICARBONATE. BREVIBLOCo SHOULD NOT BE MIXEO WITH OTHER DRUGS PRIOR TO OILUTION IN
`A SUITABLE INTRAVENOUS FLUID. (See Compatibility Section below.)
`'
`ltlluliu: Aseptically prepare a to mglmL inlusion. by adding twp 2.5 g ampuis lo a 500 mL container. or one 2.5 g
`amput to a 250 mL container. at a compatible intravenous solution listed below. (Remove overage prior to dilution as
`appropriate). This yields a' linal concentration at to mgImL. The diluted solution is. stable for at least 24 horns at
`room temperature. Note: Concentrations ol BREVIBLOCo greater than 10 mglmL are likely to produce irritation on
`continued II'IIIJSIDI'I (see Precautions). BREVIBLOCO has. however, been well tolerated when administered via a cen-
`tral vein.
`'
`.
`.
`Itili ng-illM.
`This dosage (arm is prediluted to provide a ready-to—use lo mglmL concentrationrecommended lor Brevibioc' in-
`travenous administration.
`it may be used to administer the appropriate Brevibloc° loading dosage inlusions by
`hand-held syringe while the maintenance infusion is being prepared.
`_
`Supnvratricular Tachycardia
`In_ the treatment of supraventricular tachycardia. responseslto BHEVIBLOC' usually (over 95%) occur within the
`range or 50 to 200 mcglkglmin. The average ellective dosage is approximately 100 mcglkglmin although dosages
`as low as 25 mcglkglmin have been adequate in some patients Dosages as high as 300 mcglkglmin have been
`used. but these provide little added ellect and an increased rate at adverse ellects. and are not recommended.
`Dosage ol DREVIBLOC“ in supraventricular tachycardia must be individualized by titration in which each step con-
`sists of a loading dosage followed by a maintenance dosage".
`.
`'
`To initiate treatment at a patient with supraventricular tachycardia. administer a loading dosage Infusion of 500
`mcglkglmin oi BREVIBLOC° lor one minute tollowed by a 4 min maintenance inlusion 'ol 50 mcglkglmin. it an ade-
`quate therapeutic effect is not observed within live minutes. repeat the same loading dosage and follow with a main-
`tenance inlusion increased to too mcglkglmin.
`Continue titration procedure as above, repeating loading inlusion (500 mcglkglmin tort mtnute).'increasing main-
`tenance inlusion by Increments at 50 meg/kg! min (tor 4 minutes). As the desired heart rate or a salety end-point
`(eg.. lowered blood pressure) is appmached. omit the loading inlusion and reduce incremental dose in maintenance
`Inlusioo from 50 mcglkglmin to 25 mcglkglmin or lower. Also. it desired. increase interval between titration steps
`lr_om 6 to in minutes.
`this specific dosage regimen has‘ not been studied intrauperatively and. because ol the time required lor titration.
`may not be optimal lor intraoperative use.
`Maintenance dosages-above 200 mcglkglmin have not been shown to have significantly increased benefits. and the
`safety of dosages above 300 mcglkglmin has not been studied.
`in the event of an adverse reaction. the dosage ol BREVIBLDC'may be reduced or discontinued if a local Infusion
`site reaction develops. an alternative inlusion site should be used. 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
`oocurwith abrupt withdrawal ol beta blockers lollowing chronic use in coronary artery disease (CAD)'natients How-
`ever. caution should still be used in abruptly discontinuing inlusions ul BREVIBLOC' in CAD patients
`Alter achieving an adequate control of the heart rate and a stable clinical status in patients with supraventricular
`tachycardia. transition to alternative antiarrhythmic agents such as propranolol. dignxin. or verapamll. may be ac-
`complished. A recommended guideline lor such a transition is given below but the physician should carefully con-
`sider the labeling instnrctions lor the alternative agent selected:
`-
`Alternative
`all
`lineage
`-
`Propranolol ydrochloride
`lit-20 mg q Hit]
`Digoxln,
`0.1 25-115 mg q 6 n (no or iv.)
`Verapamil
`80 mg q 6 h
`The dosage of DR EVIBLOC;c should be reduced as Ioiiowszv
`.
`l. WI? gan’i‘nutes following the first dose at the alternative agent. reduce the infusion rate of t‘iliiEillBLOCo by one-
`ha
`.
`'
`‘
`'
`-
`Z Following the second dose at the alternative agent. monitor the patient's response and ii satislactory control is
`maintained (or the iirst hour. discontinue BREVIBLOC.o
`'
`The use at tnlusions oi BREVIBLOC° up to 24 hours has been well documented: in addition. limited data lrom 24-48
`hrs (N=48) Indicate that BREVIBLOCm is well tolerated up' to 48 hours.
`_
`lion Itiilility with Comment
`tired Intravenous Fluids
`g
`BR
`iBL'DC' (esmolol'HCl
`INJECTION was tested for compatibility with ten commonly used intravenous lluids at
`a lihal concentration at 1Q. mg esmolol HCI per mL. BREVIDLOC‘ INJECTIDN was lound to be compatible with the
`(allowing solutions and was stable tor at least 24 hours at controlled room temperature or unde'r'reIrigeratlon: '
`Dextrose (5%) lnieCtion. USP
`,
`_
`.
`__
`Dextrose (5%) in lat-Stated Ringer's Inlection
`.Dextr'ose (5%) In Ringer's lnlection
`_
`Dextrose (5%) and Sodium Chloride (0.45%) ln]ectipn.USP
`Dextrose (5%) and Sodium Chloride (0.9%) injection. USP
`Lactated Ringer'sln eclion. USP
`'
`.
`'
`Potassium Chloride 40 mquliter) in Dextrose (5%) l
`niecticn. USP
`Sodium Chloride (0.45%) injection. USP
`Sodium Chloride (0.9%) Injection. USP
`--
`.
`BREVIBLDC' INJECTION was NOT compatible with Sodium Bicarbonate (5%) Injection. USP. .
`lute: Parenteral d’rugiprdducts should be inspected visually lor particulate matter and discoloration prior'to admin- '
`istration. whenever solution and container permit. '
`'
`.
`'
`.'
`HOW SUEI’IJEDf-f
`-
`.
`.
`rtDc boot-got 5:71, too mg -— to mL vial. Box at go
`NDC moieties-1 e. 2.5 g — to mL ampui. Box 'or 10
`STORE AT CONTROLLED ROOM TEMPERATURE l59'-86'F. 15'—30‘C). Freezing does not adversely affect theprod-
`not. but exposurelto elevated temperatures should be avoided.
`_
`_
`_
`'
`'
`-. Dtr'Pont-Pharmaoeuticals
`E. I. duPopt de Nemours and Company
`Wilmington. Delaware 19898
`--'----_=
`Date: May. 1988
`
`A43049
`
`.
`
`-
`
`-
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`. APPLICATION NUMBER:
`
`I
`
`NDA 19-386/5-004
`
`CHEMISTRY REVIEW! S!
`
`

`

`.
`
`CHEMIST'S REVIEW
`
`9.904
`
`MAR 15 l988
`
`
`
`' 1. Organization
` 2. NDA Number
`
`urn-110
`l9-386
`4. AF Number
`
`
`
`5
`Su . figment 5-,
`
`_I_-
`5-005‘
`9/]7/87
`
`3. Name and Address of Applicant City & State
`DuPont Critical Care,
`Inc.
`
`1600 Waukegan Road
`
`Waukean.
`IL 60085
`. Name of Drug
`BREVIBLOC
`
`.Nonproprietary Name
`Esmolol Hydrochloride
`
`
`
`9.
`
`
`
`8. Supplement 5) Provides or:
`A new dosage form, comprising a new formulation
`Amendments and Other
`
`
`
`
`and a new container/closure system. Also provide~
`(Reports, etc.) Dates
`
`for additional clinical
`indication for BREVIBLOC.
`ll/l9/87
`
`
`
`
`
`ll. How DiSpensed l2. Related IND/NDA/DMF s
`
`
`0. Pharmaco ogical Category
`'Anti-adrenergic (B—receptor)
`
`‘
`Ix—7 RX/—7 01c
`
`
`
`3. Dosage Form 5
`l4.
`'otency ies
`Injection
`l0 mg/mL or 100 mg/lO m
`
`l5. Chemical Name and Structure
`
`‘
`
`'
`
`.
`
`
`
`
` Reviewed
`
`Yes
`
`
` l7. Comments
`See attached pages.
`
`
`Included in the draft labeling is the recommendation for administering an
`
`
`80 mg_ loading dose of BREVIBLOC over 30 seconds,
`to initiate immediate
`
`
`control of intraoperative tachycardia or hypertension.
`The loading dose is
`
`
`to be followed by a constant
`infusion.
`The 100 mg single use vial re-
`presents a safe, convenient means of initiating therapy by slow intravenous
`
`
`injection while the infusion dilution is being prepared.
`.
`
`18. Conclusions and Recommendations
`AE pending submissio-n of additional sta-
`
`
`
`bility data. With the exception of expiration dating, manufacturing and
`
`
`
`controls information are satisfactory. Need additional stability data_
`
`before the requested 24 month expiration date could be approved.
`
`
`r-
`Deficiencies in labels and package insert:
`A————7——————-————-—--—---1
`.
`
`
`
`
`DESCRIPTION section for the l0 mg/mL product should include
`quantities of the other ingredients present in the injection.
`If one
`patkage insert will be used for both strengths. the header (p. 93)
`infor-
`' mation should be added to-the current insert information.
`HON SUPPLIED -
`satisfactory as proposed.
`Company agreed to revise the labeling as
`
`[_/Div. File
`
`Date Completed
`March l5,
`l988
`
`

`

`CHEMIST'S REVIEW
`
`1.
`
`Organization
`HFD — llO
`
`
`
`
`
`. Name and Address of Applicant (City & State)
`DuPont Critical Care,
`Inc.
`1600 Naukegan Road
`'
`
`JUN 411988
`
`
`2. NBA NUmber
`19—386
`
`
`
`
`
`
`
`
`
` Suglement
` sNher5 Date 5
`
`
`6. Name of Drug
`'7. Nonproprietary Name
`
`6/30/88
`Brevibloc
`S—004
`Esmolol Hydrochloride
`
`
` '. Supplement(s) Provides For:
`
`Amendments and Other
`
`
`(Reports, etc.) Dates
`. 9/17/87, 3/l0/88 ,
`6/8/88
`
`Final printed labeling
`
`
`l0. Pharmacological Category
`Anti —adrenergic (8 receptor)
`
`.How Dispensed l2.
`
`
`
`
`
`
`
` Reviewed
`-Yes
`
`
` l7. Comments
`Carton and vial
`labels are included. Lot No. and expiration date are not
`
`
`
`included on the label.
`Package inSert (A43094,May,1l988) - DESCRIPTION section — satisfactory,
`HON SUPPLIED section - satisfactory.
`
`
`
`‘ l3. Dosage Form(s)
`Injection
`
`/X/ RX /
`I OTC
`l4. Potency(ies)
`10 mg/mL