FR?
`53
`
`EDITION
`
`i999
`
`
`
`PHYSICIANS’
`DESK
`PEFEPENCE
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`Ronald Ark-y,_ MD, Charles S. Davidson Professor of Medicine and Master, Francis Weld Peabody Society. Harvard Medical school
`
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`Copyright © T999 and published by Medical Economies Company, Inc. at Montvaie, N.J 0?l34-5-‘l?42. All rights reserved. None of the content of this publication
`I. may be reproduced, stored in a retrieval system, resold. redistntruised. or transmitted in any form or by any means (electronic, mechanical, photocopying, record-
`ing. or otherwise] without the prior written pennission of the publisher. PHYSICIANS‘ DESK REFERENCE”. FDR”, PDFI For Nonprescription Dmgs”, PD-H For
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`0peratioris:John Ft. Ware
`®
`MYLAN ET AL. - EXHIBIT 1005
`ISEIN: 1-55363-288-8
`
`Printed on recycled paper
`
`MYLAN ET AL. - EXHIBIT 1005
`
`

`
`
`
`F-‘HYSICIANS’ DESK REFEFIENC
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`-
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`._
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`Water for Injection, USP; buffered with I'M} mg S0d_l]_|J‘i-
`etato, USP, and 0.00715 mL Glacial Acetic Acid. USP
`dium hydroxide andlor hydrochloric acid added. as . ._
`sary, to adjust pH to 3.5-5.5.
`100 mg, 1|} mL Slngle Dose Vial-—Eac.h mL coutairia 19
`esmiolol HO! and Water for Injection, USP; bufibrsd 1..-1'1]:
`mg Sodium Acetate. USP and 0.54.6 mg Glacial Acetic -
`USP, Sodium hydroxide andfor hydrochloric acid addadu _
`necessary to adjust pH to 4.5-5.5.
`CLINICAL PHARIIIIIIICOLDGY
`BREVIBL.OC®{esrno1o1 HUI} is a bctal-selective (
`selective} adrenergic receptor blocking agent with rapid
`set, a very short duration of action, and no signilig,-.1”;
`trinsic sympatlmnumetic or membrane stabilizing : '
`at therapeutic dosages. Its elimination half—life after ..
`venous infusionis appiroximately 9 niinotes. BREW I
`inhibits the beta, receptors located chiefly in cardiac m. 5
`cle, but this preferential effect is not absolute and at -_.. ._
`doses it begins to inhibit b-etaa receptors located chiefly-.'
`the bronchial and vascular musculature.
`-
`Phsrmannltinatics and Metabolism
`BREVIBLOCIEJI (esruolol HCII is rapidly metabolized by ,,,'
`dralysis of the ester linkage, chiefly by the astersses in
`cytosol of red blood cells and not by plasma choline =.
`or red cell membrane acetylcholinesterase. Total body
`anon in man was found to be about 20 I_.J"la:g:fhr, which _
`greater than cardiac output; thus the matabolisui‘ '
`BREVIBLDCW is not limited by the rats ofblood flow to ..--I
`tsiboljaing tissues such as the liver or alfectcd by hnpa.
`renal blood flow. Bll.EVl'BL0OI® has a rapid djstrih
`half-life of about 2 minutes and an elimination half-bk
`about 9 minutes.
`.
`Using an appropriate loading dose, steady-state blood
`of BREVIELOCIB1 for dosages from 50-300 mc
`(I].(I5—Il.3 mgifisgiminl are obtained within five
`{Steadystate is reached in about 30 minutes without
`loading dose.) Steady-state blood levels of BEE II It
`increase linearly over this dosage range and elimina '
`netics are dose-independent over this range. Steady
`blood levels are maintained during infusion hut
`rapidly after termination of the infusion. Because at
`short half-life, blood levels of BREVIBLOC® can be '1'
`I
`altered by increasing or decreasing the infusion rate
`rapidly eliminated by discontinuing the infusion.
`Consistent with the high rate of blood-based metabolism
`BREVIBDCIIDIEJ, less than 2% of the drug is excreted I:
`changed in the urine. Within 2-1 hours ofthe and ofialii
`approximately 73-83% of the dosage has been accounted. ,I'
`in the urine as the acid metabolite of BR.EVIIBI.i0II}®.
`Idetaboljsm ofBREVIBLC|C® results in the formation I
`'i'.
`corresponding free acid and ruclhe.uoL The acid in
`has been shown in animals to have about l..I"15UIlIth the
`tivity ofesmolol and in normal volunteers its blood lél-'
`not correspond to the level of beta blockade. The acid
`tsbolito has an elimination hall-life of about 3.7 helm
`is excreted in the urine with a clearance appm '
`eqtajvalent to the glornerular filtration rate. Excretion of
`acid metabolite is significantly decreased in patients
`renal disease, with the elimination half—life incre
`_ about ten-fold that ofnoinnals, and plasma levels I-I
`ably elevated.
`,
`-
`Methanol blood levels, monitored in S|.1b,i€I':I3
`BREVIBI..OC® for up to 6 hours at 300 I1‘|I:g.I'k.gi"mir1 (I13
`kgiminl and 24 hoIu.rs at 150 mcgficghuin €0.15 I'll -'3 I
`approxjrnated endogenous levels and were less than
`E
`levels usually associated with methanol toxicity.
`BREVIBLOOQ has been shown to be 55% bound to h II
`plasma protein, while the acid metabolite is only .
`hound.
`'
`Fharmacodynamios
`-.'
`Clinical pharmacology studies in normal volunteers
`confirmed the bets. blocking activity of ssrvismosi
`
`molol HC1), showing reduction in heart rate at rest and I
`ing exercise, and attenuation of isoprctereuoI-indu1>B‘l-
`creases in heart rate. Blood levels of BREVIBLCFUIU
`been shown to correlate with extent of beta blo-I:kl1Ii9I "'_
`termination of infusion, substantial recovery IWD1 "'_
`blockade is observed in 10-20 minutes.
`'-
`In human electrophysiology studies. Bftli-'VIBLDO§ '
`-
`duced effects typical of an beta blocker; a decrease ill-
`h.ea.rt rate, increase in sinus cycle length, prolODE3_
`the sinus node recovery time. prolongation of the AH '
`2 val during normal sinus rhythm and during atrial I-
`and an increase in antegradc Wcnckebach cycle Ian
`In
`patients
`undergoing
`radionuclide
`angill
`BREVIBl.JOO®, at dosages of 200 mcgfkgfmin [013
`min}, produced reductions in heart rate. systolic I11
`sum, rate p1Imsu.rc product, left and right v3nt.riCU-l-5-'_r :'
`tion fraction and cardiac index at rest, which I-II-'91‘?
`in magiitude to those produced by intravenous II ° '
`,
`I-l mg). During exercise. BREVIBLDC® |JI'UEl|-lC'3’_d
`tions in heart rate. rate pr-cssurc product and oartllfl‘ "
`which were also similar to those produced by JJITIFT '
`but produced a significantly larger fall in systoiip '
`pressure. In patients undergoing cardiac csthetefi-I‘
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`This material may be protected by copyrigm lziw (URI: 17 us. Code)
`
`624.-' BAXTE Fl H EA LTH CARE
`
`Heco mb inata-—ICo nt.
`
`tidine, 1.5 ug)'.l\.I'l'F International Unit [lUl poI,ysorbate—SD.
`Von Willebrand Factor EvW.F’] is CO-&X11l'B5BECI with the Anti-
`hemoplillic Factor {Rcoombinantl and helps to stabilize it.
`The final product contains not more than 2 ng IuWFflU
`rs]-IF which will not have any clinically relevant ail‘-act in
`patients with you Wdlebrand’$ disease. The product con-
`tains no preservative.
`Manufacturing of Recomhinatam is shared by Baxter
`Healthcare Corporation, Hyland Division and Genetics In-
`stitute, Inc. Genetics Institute produces Antihennophilic
`Factor Concentrate (Recombinant) {For Further I'II1ariufac—
`tu.ri_n.g Use]: which is then formulated and packaged at Bax-
`ter Health-:.a.rs Corporation, Hyland Division.
`Each bottle of Rewmbmateni is labeled with the AI-I.F ac-
`tivity cxprcssed in IU per bottle. Biological potency is deter
`ruined by an in uitro assay which is referenced to the World
`Health Organization {WHO} International Standard for
`Factor VIII.-C Concentrate.
`HOW SUPPLIED
`
`Antihcmophjlic Factor (Recombinant), Recombinant” is
`available in siugIe—dose bottles which contain nominally
`250, 500 and 1000 International Units per bottle. Recombi-
`natem is pacltaged with 10 mL of Sterile Water for Injec-
`tion. USE a doubIs—sudod needle, a filter needle. and a
`package insert.
`
`
`
`Baxter Pharmaceutical Products
`Inc.
`110 ALLEN ROAD, PO BOX 804
`LIBERTY CORNER. NJ M938-0804
`
`Dlrect, Inquiries ‘to:
`Professional Services Department
`(800) ANA DRUG
`I800] 262-BT34
`For Medical Information Contact
`In Emergencies.’
`Raul Iniuo, MD
`Director, Medical Services
`(800) ANA-DRUG
`{B00} 252-3784
`Sales and Ordurlnrg:
`‘To place an order between 'F:I'.l0AM and 8:00 PM {central}
`I300) 345-2700
`
`MTHMCUHIUH BESVLETE
`lCIIl":§»(*liJ'-I§- rim -bE—sjy.l-dial
`Injection
`
`K
`
`This drug should be used only by adequately trained indi-
`viduals familiar with its actions. characteristics, and has-
`a.rds.
`DESCRIPTION
`Atraicurium Besylate Injection is an intermedisteduratiori,
`nondepolarizing, skeletal muscle relaxant for intravenous
`administration. Atracurium in-esylate is designated as 2,2’-
`[1,5-pentanediylbis[oii.yL3-oxo-3,l-propaneI:liyllI]IhisI1-I(3,=i-
`dimetl1oxyphen;yllmeth.3'll-l.2.3.II—tetra.hydru-6,7-dlmcthnm
`y-2—met]1yl_i,soquj,nu]_ini1.I m] dibenzencsulfonate. It has amor
`lecular weight of 1243.49, and its molecular formula is
`CwH3gN301gS;. The structural foirmula is:
`
`the rats of approicimately 6% per year under refrigeration
`{fi°Cl. AI:ra.cu.Iiun:L Besylate Injection should be refrigerated
`at 2“ to 3°C (36“ to ‘l~6'Fl to preserve potency. Rate of loss in
`potency increases to apprmcimately 5% per month at 25“C
`('l’i"'F}. Upon removal from refrigeration to room I.Em]:I€1‘fi-
`irure storage conditions E25"C.i'i'7°Fl, use Atracurium Busy-
`Iate Injection within 1:1 days even ifreli-igeraled.
`' HOW SUPPLIED
`Atracurium Besylate Injection, 10 mg atracuriuozi besylate
`in each mL.
`-
`5 mL. Single Dose Vial E50 mg per visll — Packaged in 10s
`IINDC 10019-U02-D5].
`I0 rnL Muitlgule Dose V1al{10U mg per vial}. Contains bsnzyl
`alcohol (see WARNINGS in full prescribing information).
`Packaged in 105 (NDC 10019-U01-I0].
`
`,
`
`.
`
`ATRIDPIN E
`In ‘lroe—_oeei:]
`Sulfate Injection. USP
`For II'e'I. IV or 30 Use
`
`_
`
`1;!
`
`DESCEIPTIQN
`Atropine Sulfate Injection, USP‘ is a sterile solution u1‘a.I.ro-
`piinis sulfate in water for injection. Each mL contains Atm-
`piine Sulfate 0.4 mg or 1.0 mg; Sodium Chloride 9 mg; Ben-
`zarlrliloohol 9 mg: Water for injection qs; pH may be adjusted
`with H380, if necessary. pH: 3.0-6.5.
`rltropine Sulfate Injection, USP may be given intramuscu-
`larljt intraveiziously or subcutaneously.
`'
`Atropine is a white crystalline alkaloid which may be ex-
`tracted from belladonna root or may be produoecl synthetic-
`ally. It is used as atropine suliatc because this oompound
`has much greater solubility.
`Atropine sulfate is an anticholinergic drug. The empirical
`formula of atmpiilte sulfate is (C11-Hg3NCl-3),;-I'I2SO¢-H30.
`The structural formula is:
`
`‘H259-1 ‘ Hecl
`
`°i“i”‘©
`H
`o
`cH,oH
`HOW SUPPLIED
`
`,
`
`NDC Number
`1lJDl9—2liI3I—12
`10019-25-lllfl
`10019-250-EU
`
`Atropine $u|‘|‘atI-
`per ml
`0.4 u1g;‘ruL
`1 mgfmli
`0.4 mgfmL
`
`Volume
`1 mL in a 2 ml. vial
`1 mL in s 2 1ul..vial
`20 mL in a 20 ml. via]
`
`‘2 mL vials packaged 25 per shelf pack.
`20 mL multiple dose vials packaged 10 per shclfpacls.
`
`BfiEV‘IBLOC® INJECTION
`Ebrév a—biocJ
`iasmolol hydrnchlnridnl
`1|) n‘IL ArnpuI~—250D mg
`NOT FOR DIRECT INTRAVENOUS INJECTION.
`AMPUL MUST BE DILUTED PRIOR ‘I'D ITS INFUSION -
`SEE DOSAGE AND ADMINISTRATTDN.
`
`Ii:
`
`ll} mL Single Dose Vial—l_.0U mg
`DESICRIP"I‘IDN
`BREVIBLO-Ci® (esruolol I-IE1] is a betarselectii-Ie [cardio-
`selectivel adrenergic receptor blocking agent with a very
`short duration of action (elimination hallllife is approxi-
`mately 9 minutes). Esmolol HUI ls:
`[_*]—l‘iIIethy1 p-[2-hydroxy—3—{isoprI0p_l.'laminol prcrpoxyl hy-
`drocinnanziate hydrochloride and has the following struc-
`turn:
`
`‘i’
`‘i
`J=l'5ei-?I'Ia0LlIliI-IsJslX.'rI3-IwCI‘l;-.
`
`“en,
`
`°““=
`
`0
`
`“
`
`Hfi II,
`
`H§fi w 67-550
`‘
`‘o
` |hUCI-Ii
`Atracurium hesylats is a complex molecule containing four
`sites at which difi"erent stereochemical oonfigiirations can
`Cl|@DCHfiHE FQGFDHCHpNHCHCFH2- I-El
`occur. The symmetry of the molecule. however, results in
`only ten, instead of sixteen, possible dilfarent isomers. The
`Esmolol I-ICI has the empirical formula C“=,H,5NCI,,Cl and a
`manufacture of atracuriurn basylato results in these iso-
`molecular weight of 33 1.8. It has one asymmetric center and
`mers being produced in unequal amounts but with 3. consis-
`exists as an cnantiomcric pair.
`tent ratio. Thosc molecules in which the methyl group at-
`Esmolol HCI is a white to ofiiwhite crystalline powder. It is
`tached to the quartcrusty nitrogen projects on the opposite
`a relatively hydrophilic compound which is very soluble in
`side to the adjacent subsI.ituled—benayl moiety predominate
`by approidmatasly 3:1.
`water and freely soluble in alcohol. its pz:.rtit.ion ooeflicierlt
`Ioclanoliiwaterl at pH 7,0 is 0.42 compared to 17.0 for pro-
`-MI'Bl3‘|J-l'i|JI|1 Besylnte Injection is a. sterile, non-pyrogcnic
`“ll-19*-‘II-IS Solution for iniravienous administration. Each mL
`pranolol.
`BREVIBLO-G® IN.l'EC'I'ION is a clear, colorless to light ye]-
`oolit-sins 10 mg atraourium besylaoe. The pH is adjusted to
`low, sterile, nonpyrogenic solution.
`'
`3.25-3.65 with bonsenesulfionic acid. The n1u1t,ip|e dose via]
`Cflfltfillls 9-995 b€I|Z].'l alcohol added as a preservative. Atro-
`2500 mg. 10 ml AmpuI—Ea::h mL contains 250 mg esmulol
`curlum B-esylate Injection slowly loses potency with time at,
`HUI in 25% Propylene Glycol, USP. 25?: Alcohol, USP and
`Information wil be superseded by supplslrnmls and subsequent editions
`
`

`
`BAXTEH PHAHMACEUTlCALI'B25
`
`The efiect of BREVTBLOOQ on the duration of succinylcho—
`line-induced neuromuscular blockade was studied in pa-
`tients undergoing surgery The onset. of neuromuscular
`blockade
`by
`succinylcholine was
`unsifected
`by
`BREV1Bl.JDC®, but the duration of neuromuscutar blockade
`was prolonged from 5 minutes to 8 minutes.
`Although the interactions observed in these studies do not
`appear to be of major clinical importance, BREVIBLCIOE
`should be titrated with caution in patients being treated
`concurrently with digoxin, morphine, succinylcholine or
`warfarin.
`While talcirlg beta blockers, patients with a history ofsevsre
`anapbylactit: reaction to a variety of allergens may be more
`reactive to repeated challenge, either accidental, diagnostic,
`or therapeutic. Such patierits may be unresponsive to the
`usual doses of epinephrine used to treat allergic reaction.
`Caution should be exercised when considering the use of
`BREVIBLDGE and verapainil in patients with depressed
`myocardial function. Fete] cardiac arrests have CH.‘.|'_'1J.'l'l'Ed in
`patients receiving both drugs. Additionally, BREVIBDDD®
`should not be used to control supraventricular tachycardia
`in the presence of agents which are vasocon_s_triI::tive and
`inotropic such as dopamine, epinephrine, and norepi.ncp_h—
`rine because of the danger of blocking cardiac oontractility
`when systemic vascular resistance is high.
`Gorclnogene-sis. Mutagenesis. Impairment of Fertility
`Because of its short term usage no carcinogenicity, rnutagun-
`icity or. reproductive performance studies have been con-
`ducted with BREVIBI..ClG® tesmolol HCl]I.
`Pregnancy Category C
`_
`Te1'atogeniciI:y studies in rats at intravenous dosages of
`BREVIBLGOE {molol HCll. up to 3000 mcgilrgfrnin (3 m.g.I'
`lrgimiul (ten times the maximum human maintenance dos-
`age} for 30 minutes daily produced no evidence of maternal
`toxicity. embryctoxicity or teratogunicity. while a dosage of
`10,000 me:-g;"l:,g"1nin [10 mgfkgjlmin} produced maternal tox-
`icity and lethality. In rabbits, intravenous dosages up to
`1000 mcgllrghnin (1 mylrglminl for 30 minutes daily pro-
`duced no evidence of maternal toxicity, embryotoxicity or
`terstogenicity, while 2500 mcgllsglmin (2.5 mgflsgiminl pro-
`duced minimal maternal toxicity and increased fetal re-corp
`tions.
`Although there are no adequate and well-controlled studies
`in pregnant women, use of esmolol in the last trimester of
`pregnancy or during labor or delivery has been reported to
`cause fetal bradycardia, which continued afisr termination
`of drug infusion. BREV"IELUC® should be used during
`pregnancy only ifthe potential benefitjuutifies the potential
`risk to the fetus.
`Nursing Mothers
`It is not known whether B'R.E'_i"IBLOG® fesmolol H01) is ex-
`creted. in human milk; however, _caution should be exercised
`when BREVIBLOG®is administered to a nursing woman.
`Pediatric Use
`The safety and efi"ec1.iveness'ofBREVIBLOO® (eamclol HUD
`in children have not been established.
`'
`'
`
`anvm" Reactions"
`The following adverse resction-rstes are "based on use of
`BREVLBLUCEF lesmolol HClJ in clinical trials involving 369
`patients with supraventricnlar tachycardia and over 600 in-
`traopcrative and postoperative patients enrolled in clinical
`trials. l|-lost adverse eil'ect.s observed in controlled clinical
`trial settings have been mild and transient. The most im-
`poi-tent adverse eifect has been hypotension (see WARN-
`INGS]. Deaths have been reported in post-msrlscting expe-
`rience occurring during complex clinical states where
`EREVIBI.-(JOE was presumably being used simply to con-
`trol ventricular rate {see WARNING»S:"Cardiac Failure).
`GordIovascular—SymptoInatic hypotension tdiaphoresis.
`dizziness} occurred in 12% ofpatients, and therapy was dis-
`continued in about 11%, about halfofwboro were symptom-
`atic. Asymptomatic hypotension ocoLu'rsd in about 25% of
`patients. Hypotensio-n resolved during BREVIELUCQ Les-
`molol I-ICU infusionin 63% of these patients and withirl 3-0
`minutes afier discontinuation of infusion in 80% of the re-
`maining patients. Diaphoresis accompanied hypotension in
`10% of patients. Peripheral ischernia occurred in approxi-
`mately 1% of patients. Pallor, flushing, bradycardia (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 so-
`praventricular tachycardia but with serious coronary artery
`disease (post inferior myocardial infarction or unstable an-
`gina}, severe bradycardiaisiuus pause-Jasystole has deve -
`oped, reversible in both cases with discontinuation of treat-
`mETlt-
`.
`Carmel Nervous Systen1—Dizzinsss has occurred in 3% of
`patients; somnolcnce in 3%; confusion, headache, and agita-
`tion in about 2%; and fatigue in about 1% ofpatients. Par-
`esthesia, asthenia, depression, abnormal thinlsing, anxiety.
`anorexia, and lighthcadedness were reported in less than
`1% of patients. Seizures were also reported in less than 1%
`of patients, with one death.
`
`Consult 1 999 FDR” suppIsI11sI1ts and future edllons for revisions
`
`Continued on next page
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`1
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`il
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`'1
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`dose-related so tha_t-doses beyond 200 mcylrgimhi (0.2 mg!’
`lrglmin} are not recommended. Patients should be closely
`monitored, especially if pretreatment blood pressime is low.
`Decrease of dose or termination ofinfusion reverses hypo-
`tension, usually within 30 minutes.
`Gordian Failure:
`Sympathetic stimulation is necessary in
`supporting circulatory function in congestive heart failure,
`and beta blockade carries the potential hazard offlirthor da-
`pressing myocardial contractility and precipitating more se-
`vere failure. Continued depression of the myocerdiuin with
`beta blocking agents over-s period of time can, in some
`cases, lead to cardiac failure. At. the first sign or symptom of
`impending cardiac failure, BREVIBLOOG (eemolol HOD
`should be withdrawn. Although withdrawal may be sulfi-
`cient because of
`the short
`eli_m_inatiIJn half-life of
`BREV'IBLOO®, specific trsnt'n:Ier1t may also be considered
`(see OVERDDSAG-E}. The use of BREVIBIJDOE for control
`of ventricular response in patients with supraventricular
`nrrhythmias should be undertaken with caution when the
`patient is compromised hemodynamically or is taking other
`drugs that decrease any or all of the following: peripheral
`resistance, myocardial filling, myocardial contraclxility, or
`electrical impulse propagation in the myocardium. Despite
`the rapid onset and offset of the efiects of BREW-’lBLOG®,
`several cases of death have been reported in complex clini-
`cal states where BREVIBLOGQ was presumably being used
`to control ventricular rate.
`.
`lntraopelative and Pnstnp-sralivo Tachycardia andfor Hy-
`pertension:
`BREVIBLDCQ lesmolol HUI) should not be
`used as the treatment for hypertension in patients in whom
`the increased blood prressime is primarily due to the vaso-
`constriction associated with hypothermia.
`Bronchospastic Diseases:
`FA11EN'I'S WITH BFI0l\IGHO-
`SFNSTIC |.'.l|'5E-IISES SHOULD. III GENERAL, NUT RECEIVE
`BETA BLDCIEERS. Because of its relative betel selectivity
`and titratnbility, BREVIBLOO3{es1:nolol HUI} may be used
`with caution in patients with bronchospastlc diseases. How-
`ever, since betai selectivity is not absolute, BREVEBLUUU
`should be carefully titrated to obtain the lowest possible ef-
`fective dose. In the event of bronchospasm, the infusion
`should be terminated immediately; a beta; stimulating
`agent may be administered if conditions warrant-but should
`be used with particular caution as patients already have
`rapid ventricular rates.
`Diabetics Mullitus and Hypoglycemia: BREVIBLOCW (es-
`molol I-{Cl} should be used with caution in diabetic patients
`requiring a beta blocking agent. Beta blockers may mask
`tachycardia occurring with hyp-oglycelnia. but other mani-
`festations such as dissinsss and sweating may not he signif-
`icantly affected.
`-
`PRECAUTIONS
`General
`Infusion concentrations of 20 mgfmL were associated with
`more serious venous irritation, including Ihrdinbophlebitis,
`than concentrations of 10 mgfmb. Extravasation of 20
`mg;'n1L'may lead to a serious local reaction and possible
`skin necrosis. Concentrations greater than 10 mgfmL or in-
`fusion into small veins or through a butterfly catheter
`should be avoided.
`-
`
`excreted unchanged by the kidney, Bl"-tEVIBLOU® (esrnolol
`HCD should be administered with caution to patients with
`impaired renal function. The elimination half-life of the acid
`metabolite was prolonged ten-fold and the plasma level was
`considerably elevated in patients with end-stage renal dis-
`I!9SQ_
`'
`'
`Care should be talren iii the intravenous administration of
`BREVIBLOOG as sloughing of the skin and necrosis have
`been reported in association with infiltration and extrava-
`sation ofintravenous infusions.
`Drug Interactions
`Catocholamine-depletiirg drugs, e.g., reserpirie, may have
`an additive efilecl; when given with beta blocking agents. Pa-
`tients treated concurrently with BHEVIBLOGE‘ (esmolol
`HCl) and a catecholarnine depletor should therefore be
`closely observed for evidence of hypotenaion or marked
`bradycardia, which may result in vertigo, syncope, or pos-
`tural nypotension.
`A study of interaction between BREVl_Bl..C'Cr® and warfarin
`showed that. concomitant admiiiistration of BREVIBLUUQ
`and vvarfarin does not alter warfarin plasma levels.
`BREVIBLOCI3: concentrations were equivocnlly higher
`when given with warfarin, but this is not likely to be clim-
`cally important.
`When digoxin and EREVIBLUOE were concomitantly ad-
`ministered intravenously to normal volunteers. there was a
`10-20% increase in digoicin blood levels at some time points.
`Digoxin did not alfecl. BREVIBLDOCE pbarmacokine-tics.
`When intravenous morphine and EREVIBLOOQ were con-
`comitantly administered in normal subjects, no cflcct on
`morphine blood levels was seen, but BREVIBIJUCOD steady-
`state blood levels were iricceas-ed by 4-6% in the presence of
`morphine. No other pharmacokinetic parameters were
`chmsri
`
`BecausetheacidmetaboliteofBll.E\’IBl..O03'isprimarily
`
` _r3-UCT INFORMATION
`
`.
`
`,
`
`.
`,
`
`flflmum therapeutic dose of 300 mcgflrghniri (0.3 mg!
`l
`] p1'ERE‘\-"IBLUC® produced similar eflects and, in
`. , there were small, clinically insignificant increases
`lafi ventricular end diastolic presume and pulmonary
`wedge pressure. At thirty minutes after the dis-
`'u,g:|:iI.'In of BREVIBLO-O3 infusion, all of t.h.e.heInody—
`Parameters had returned to pretreatment levels. '
`fimtjve cardioselectivity of BREVTBLDCE was demon-
`-in i0 mildly asthmatic patients. Infusions of
`"
`'
`LUCA‘? L100, Eiflflund 300 mlxgfkgfmiii (0.1, 0.2 and
`3;‘:-ninll produced no significant increases in specific
`1-esistance compared to placebo. At. 3_ll0
`in
` m, BEE-VIBLCIC® produced slightly enhanced
`tor ssitivily to dry air stimulus. These elfects
`clinically significant, and BREVlBLOO3l was well
`by all patients. Six of the patients also received
`u'u_a_ propranolol, and ate dosage of 1 mg, two expe-
`. significant, symptomatic bronchoepasm requiring
`‘lctor treatment. One other propranolol-treated
`, -also experienced dry air-induced bronchospasm. No
`. Pulmonary efiects were observed in -patients with
`-
`who received therapeutic dosages of BREVIBLDCI3
`.. nt, of snpraventricular ,tachy'ca.rd.is (51 patients)
`..pg.1-ioperutive settings [32 patients}.
`.vuntricuIar Tachycardia
`- g multicenter, randomized, double—blind..contiolled
`. .. of Bli.EVIBL00® tesmolol H01) with placebo
`pmpfanfllfll, maintenance doses of_E-Ill to 300 rncgfkgf
`05 to 0.3 mgfkgtminl of BREVIBLO-O® were found to
`..
`- efioctive than placebo and about as effective as pro-
`.
`I
`, 3-6 mg giveohy bolus injections, in the treatment
`. entricular tachycardia, principally atrial fibrilla-
`gnd atrial flutter. The majority of these patients devel-
`tllcir arrhytlimias post-o|:IeIatively. About -50-70% of
`patients treated with BREV'[BLDC® had a desired their
`eflbct {either a 20% reduction in-heart rate. a de-
`in heart rate to less than 100 bpm, or, rarely, conver-
`NSRI and about 95% of those who responded did so
`offltlll rI1cg2'kg.I’Inin (0.2 mgikglminl or less. The
`afigctive dosage of BRE'\"IBL0l3® was approxi-
`100—l1En mcgzflsgfmin (0.1-0.115 mgflrglminll in the
`studies, Other multicenter baseline-controlled studies
`‘essentially similar results. In the comparison with pro-
`.. .
`, about 50% of patients in both the BREVIBLOOUB
`-- ariolol groups were on conconiitantdigoxin. Re-
`riites were slightly higher with both beta blockers in
`' -treated patients.
`_
`dies significant decreases of blood pressure oc-
`-‘ih 20-50% of patients‘, identified either as adverse
`< n reports by investigators, or by observation of sys-
`‘ ssure less than 90 mmHg or diastolic pressure less
`> | mmllg. The hypotension was symptomatic (mainly
`s or dizziness} in about 12% ofpatiente. and ther-
`discnntinued in about 11% ofpatients. about halfof
`- symptomatic. In comparison to propranolol, hy-
`was about
`three times as frequent with
`DEE}, 53% vs. 17%. The hypotension was rapidly
`with decreased infusion rate or after discontinu-
`therapy with BREV'l.BLOC®. For
`both
`(E and propranolol, hype-tension was reported
`ntly in patients receiving concomitant digoxin.
`oNs AND USAGE
`'
`iculsr Tachycardia
`1 U013 {esmoiol HUI} is indicated for the rapid con-
`.éntri'cular rate in patients with atrial fibfillation or
`-i H‘.-or in Derioperative. postoperative. or other emer-
`H = noes where short term control ofventricular
`H‘ Ellflrtwacling agent is desirable. BREVIBLDCIZJ
`_
`' Indicated in noncompensetory sinus tachycardia
`' H19 P1'lIr'Slt‘ia.n's judgment, the rapid heart rate re-
`I
`tervention. BREVIETJDDE is not intended
`mchroni
`'2 settings where izunsfer to another agent
`
`-
`
`of‘
`
`
`
`us and Postoperative Tachycardia andior Hy-
`
`_lB.-$mu|olHC1l is indicated for the treatment
`!_i and hypertension that. occur during induction
`.IJ:_Il:,ubali.on, during surgery, on emergence from
`_Ii in the postoperative period, when in the
`‘_'.I;»1t1g_'IJient such specific intervention is consid-
`L0O® to prevent such events is not recom-
`
`IcA'1'1oNs'
`'
`' "3'lE$mo1ol HCl} is contreirtdicated in patients
`h'5i?}‘¢!ardis, heart bloclr greater than first de-
`Ehulc shock or overt heart failure [see WARN-
`
`I
`
`In clinical trials 20-50% ofpationts treated
`“"5
`L005’ {csrnolol HCll have experienced hypo-
`at"e1'3l-lli defined as systolic pressure less than 90
`'
`'
`fl-lflfitolic pressure less then 50 mmHg. About
`‘he'll-S have been symptomatic (mainly diapho—
`- 93- Hfmotcnsion can occur at any dose but is
`
`U:
`
`I
`
`

`
`
`
`PHYSICIANS‘ DESK FIEFEREN
`
`_
`
`:.._
`
`sion, ifneceseery. Adjust the infusion rate as req '
`to 300 mcgflaglmjn to maintain desired heart ram _
`blood pressure.
`2. Gradual Control
`Ffifpostoperative tachycardia and l'l_‘.-"pBI‘i.Ens.lm]’ um .
`ing schedule is the some as that used in supraveu
`tachycardia. "lb initiate treatment, administer a
`dosage infusion of 500 mcgl'kga‘nu'n of BREVIBL
`one minute followed by s four-minute maintnnm-M
`sion offifl mcglkgulmin. Ifau adequate l.'.l1B'I'apE;}_|fi¢ '
`not observed within five minutes, repeat the some
`i_11g'dosage and follow with a Inaintanoe 1'.
`creased to 100 mcgflcgfmin (see above Supra».-
`'1‘achycardi:-1}.
`Note: Higher dosages (250—3[)0 mi::g."l:g;'min}I may
`quired for adequate control of blood pressure than
`required for the treatment of atrial fibrilletimi’ ;,
`and sinus tachycardia. One third ofthe postoperative
`pertensivc patients required these higher doses.
`comps-iibilmr with Commonly Use Intravenous an .
`BREVIBLOCIE INJECTION was tested for compat;
`with ten commonly used intravenous fluids at a fins] _
`oentration of ll) mg esmolol HUI per mL. BREVIBLO |-
`u'_'
`JECTION was found to be compatible with the followiif
`"
`lutions and was stable for at least 24 hours at can
`
`room temperature or under refrigeration:
`-
`Dextrose (5%) Injection, USP
`Dextrose (5%) in Lactated Ringer’sl11_ie-ction
`Dextrose (5%) in Ringer's Injection
`Dextrose (5%) and Sodium Chloride (0.45%) In‘
`-
`USP
`Dextrose (5%) and Sodium Chloride 110.9%) In;
`USP
`.
`.
`.
`-
`Lnctoted Ringer’s Injection, USP
`Potassium Chloride (40 mEq.n'liter) in Dextrose (5%
`jection, USP
`.-.'
`Sodiuin Chloride (0.45%) Injection, USP
`'
`Sodium Chloride (0.9%) Injection, USP
`.-'
`DRE-\«'IBLOC® INJECITON was NOT compatible wi‘ll1;_
`dium Bicarbonate (5%) Injection, USP.
`Ho-to: Parenteral drug products should be inspected
`ally for particulate matter and discoloration prior to :
`istration, whenever solution and container permit.
`
`
`
`.
`
`'
`
`
`
`HOW SUPPLIIILD
`NDC 10019-015-T1, 100 mg—1() mL vial, Box of20 . .'
`ND-C 10019-02518, 2500 mg—10 mL ampul. Box M10-"
`STORE AT CONTROLLED ROOM TEMPERATUREI
`36° F, 15°—3D° Cl. Freezing does not adversely anon.
`product. but exposure to elevated temperatures aha -f
`avoided.
`--
`OHMEDA
`__‘
`-
`THE BUG GROUP
`Mfd. for: Dhrueda Pharmaceutical Products Division I
`.-
`110 Allen Road PO Box 301 Liberty Corner NJ (37933 '3,-!-_
`ran. by: Fauldiug Puerto Rico, Inc. R0. Box H1 -: =-!-'
`PR 00604
`-
`For Product Inquiry 1 300 ANA DRUG
`1'
`400-2’i"i‘—02
`
`BUHEITINIDE Inlectlrm, USP
`[bum-§—ra.n Ede]
`
`WA.llN'lNG=. Burnstanido is a potent