Bass and Spangenberg
`v.
`Fresenius Kabi USA, LLC
`U.S. Patent No. 8,476,010
`Exhibit 1005
`
`Exh. 1005
`
`

`
`~ECEIVED
`·~SEP 0 S 1997
`(ULi\a&~
`
`PDR~
`51
`1997
`
`EDITION
`
`LDLK&M
`LIBRARY
`600 SOUTH AVE. WEST
`WESTFIELD, NJ 07090
`
`PHYSCANS'
`DESK
`REFERENCE®
`
`Medical Consultant
`Ronald Arky, MD, Charles s. Davidson Professor of Medicine and Master, Francis Weld Peabody Society, Harvard Medical School
`
`Executive VIce President, Directory Services: Paul A. Konowitch
`
`VIce President of Product Management: Stephen B. Greenberg
`Product Managers: Cy S. Caine, Mark A. Friedman
`National Sales Manager: Dikran N. Barsamian
`Senior Account Manager: Anthony Sorce
`Account Managers
`Donald V. Bruccoleri
`Lawrence C. Keary
`Jeffrey M. Keller
`Jeffrey F. Pfohl
`P. Anthony Pinsonault
`Trade Sales Manager: Robin B. Bartlett
`Trade Sales Account Executive: Bill Gaffney
`Direct Marketing Manager: Robert W. Chapman
`Marketing Communications Manager: Maryann Malorgio
`Director, Professional Support Services: Mukesh Mehta, RPh
`Drug Information Specialists: Thomas Aeming, RPh, Marion Gray, RPI1
`Editor, Special Projects: David W. Sitton
`
`Vice President of Production: David A. Pitler
`Vice President, Contract Services/ Fulfillment: Steven R. Andreazza
`Contracts and Support Services Director: Marjorie A. Duffy
`Manager, Database Administration: Lynne Handler
`Director of Production, Armuals: Carrie Williams
`Manager of Production, Annuals: Kimberly Hiller-Vivas
`Senior Production Coordinators: Amy B. Brooks, Dawn B. McCall
`Production Coordinator: Mary Ellen R. Breun
`Index/ Format Manager: Jeffrey D. Schaefer
`Senior Format Editor: Gregory J. Westley
`Assistant Index Editor: Eileen C. ldzik
`Art Associate: Joan K. Akerlind
`Electronic Publishing Coordinator: Joanne M. Pearson
`Senior Digital Imaging Coordinator: Shawn W. Cahill
`Digital Imaging Coordinator: Frank J. McElroy. Ill
`
`~ Copyright ce 1997 and published by Medical Economics Company. Inc. at Montvale. NJ 07645-1742. All rights reserved. None of the content of this pub(cid:173)
`• • lication may be reproduced. stored in a retrieval system, resold, redistributed, or transmitted in any form or by any means (electronic, mechanical. pho-
`tocopying, recording, or otherwise) without the prior written permission of the publisher. PHYSICIANS' DESK REFERENCE®. POR®. PDR For Nonprescription
`Drugs®, POR For Ophthalmolo~. Pocket POR®. and The PDR® Family Guide to Prescription Drugs® are registered trademarks used herein under license. PDR
`Guide to Drug Interactions, Side Effects. Indications, Contraindications'M, PDR® Generics '"'· PDR® Medical Dictionary'"· PDR® Nurse's Handbook'"'· PDR®
`Nurse's Dictionary"'· The PDR® Family Guide to Womero's Health and Prescription Drugs'"· The POR® Family Guide to Nutrition and Health'M, PDR® Electronic
`Library"'· and PDR® Drug REAX'" are trademarks used herein under license.
`
`Officers of Medical Economics Company: President and Chief Executive Officer: Curtis B. Allen; Vice President, Human Resources: Pamela M. Bilash: Vice
`President, Finance, and Chief Financial Officer: Thomas W. Ehardt; Executive Vice President: Richard F. Kiernan: ExecutiVe Vice President. Directory Services: Paul
`A. Konowitch; Executive Vice Pre.sldem, Magazine Publishing: Thomas F. Rice; Senior Vice President, Operations: John R. Ware: Vice President. Information
`Services. and Chief Information O.fficer: Edward J. Zecchini
`
`ISBN: 1-56363-201·2
`
`Exh. 1005
`
`

`
`PRODUCT IDENTIFICATION GUIDE/341
`
`WYUH·ItYERST LAIORATORif.S P. 2924 AX
`
`UHE'Cl PHARMAC£UTICAU
`
`P. 2934
`
`641~•
`
`642 ..
`
`,,
`
`50mg
`CasodexO!>
`(blcalutamlde}
`ZE:HECA PHARMACEUTICALS P. 2U9
`
`••
`
`317' 15mg
`
`'l'tSerax111
`(oxazepamj
`"YElH•AYf R$1 LABOROIORIES P. 2516 RX
`
`ssu
`WygesicO!>
`(I>'Oil'"')J*'oene HC1, USI'. acetilllinophoen. USI'}
`65 mg;650mg
`WHJM.AY[R$1 U 80RATOAI! $ P. 2119
`
`51' lOmg
`
`641"
`
`642'
`
`'
`
`643 ..
`
`Prempha.se•
`(corjugated estrogens ta~lets/
`medroxyprogesterone acatate tablets. USPI
`0.625 mg I 5 .0 mg
`WYE'fH·i\YERST U.SOR,&TORIES
`
`fl. 2!0 5
`
`R:l
`
`RX
`
`Prempro""
`(corjugated estrogens tablets;
`medrOO<)'Illogeslerone acetate tablets, USP}
`0.625 mg I 2.5 mg
`AX WYUM·AYEftST UBOAATORIES P, 2111.
`
`6' 15 mg • 52' 30mg
`. .... ,
`
`4132• 25 mg
`
`.'f't Se rax111
`(oxazepaml
`WYETH·-YERST LABORATORII!S P~ 2!17
`
`Ill tiD
`
`904' 15 mg
`
`.
`
`... a
`
`4156' 100 mg
`
`RedUII'""
`(dexfenfluraminet
`WYETH·AYERST LABOFtATORifS P, 2U4 RX
`
`RIC
`
`'f'Surmontil'"
`(tnmiJ)<amine maleate}
`WY£TM·AYE.AST 1.A80RATOAICS Ill. 2!12
`
`641"
`
`642*•
`
`64JU,
`
`$SOH
`
`--.
`
`I
`
`1 gJ10 mL vial
`
`2 gj20 ml vial
`
`- )ii'
`
`-(cid:173).
`
`Clinic Pllpak®
`
`10 mg;mL per 50 ml vial
`
`Trlphasil*·28
`(28tablets containing tho following:
`6 brown tablets· 0.050 mg levonorgestrel
`+ 0.030 mg ethlnyl estradiol; 5 white
`t!tllets · O.o75 mg IO\IOnO<gestrol + 0.040 rrg
`ethlnyl estradiol: 10 llght·yellow talllet.s •
`0.125 mg levonorgestrel + 0.030 mg
`ethlnyl estradiol: 7 I' hi .green Inert tablets}
`
`Trlphasil"'·21
`(21 tablets contalning the following:
`6 b<own tablets· 0.050 mg levooorgestrel
`+ 0.030 mg ethlnyl estradiol; 5 whHe
`tablets· O.o75 rrg 18\IMOfg.Wel + 0.040 mg
`ethlnyl estradiol; 10 llght.yellow tablets .
`0.125 m~ levonorgestrel + 0.030 mg
`ethlnyl estra~lol}
`W\'ETH·AY!R$T LABORATORI ES P. 2,24 RX
`
`RX
`
`lmg
`Arlmldex•
`(anastrozole)
`UNE.C"- PHARMACEUTICALS P. 2UG RX:
`
`10 rng/mL per 20 m1 ampules • -10 mg/mL per 100 mL vial
`
`Dlprlvan"
`(propofol)
`lENECA PHAAMAC:EttTICIUS
`
`1'. 2'945
`
`'-
`
`25~
`
`l Omg
`
`50~
`
`4177' 200 1111(
`
`559' 250 mg
`
`75mg
`
`100 mg
`
`4179• 400 mg
`
`'l't Sectral•
`(acebutolol lfCI}
`
`RX
`
`WYETH
`
`560
`
`560' 500 mg
`
`t Wymolle
`(amoxlcillln}
`WY'lTH·AYERST LAIORATOIU£5
`
`2536•
`
`Trlphasll'"·28
`(28 tablets containing the fOllowing:
`6 b<own table\S · 0.050 mg levooorgestrel
`+ 0.030 mg ethinyl estradiol; 5 wllite
`tab(ets. O.Q75 mg levonorgestre! + 0.040 mg
`ethlnyl estradiol; 10 llght')'ellow tablets ·
`0.125 mg lovonorgestrel + O.Q31) mg
`ethlnyl estradiol: 7 1J~ht·~reen lnertlalllets}
`p_ 2928
`
`10 g per bulk pllarmaey package
`
`150mg
`
`Elavll"
`(amitriptyline HCI)
`ZEHE'CA PKAR.MACEUTIC ALS P. 2947
`
`OTC
`
`Tullex0 Injector anc Stenle Cartridge-Needle Unit
`with hard cannula cov~r ready for injection.
`
`Tubex0 Bluf11 Pointe'" Sterile Cartridge-Needle Unit
`for use In seleoted 'needle-less• IV port systems•
`
`Jll
`! I
`II... r:r:rMwJ.Ol1l •
`
`1 g/100 mL vial
`
`22 ml
`Sponge/Brush with nail cleaner
`
`Hlblclensll
`(chlorheJ<Idfne gluconale}
`
`( •consult product prescrlblnglnforma!lon for compat/bfliry
`lntorm~tlon In the P.roduct lnformalfon secHon of thfs PDR.J
`
`While every effort has been made
`to reproduce products faithfu lly,
`t his section is to be considered a
`quick reference identification aid.
`Tubex• Closed Injection Syste m
`In cases of suspected overdosage.
`EJ<amples of Tubex11 sterile Cattrldge-tleedle Umts. TWelill BIIMU POinte 1M Sterile Cartrtdg&-Unlt, and Tlbex<S> Injector.
`etc .. chemical analysis ofthe
`Cefota n" IMj iV
`components of the Tubex CloSed Injection System, the most comprehensive line of small-volume unit-dose J)<efilled
`product should be done.
`(sterile cefo.l etan dlsodlum)
`syringe ln)ectlbles. For complete list of product s available, consult Tube• listing in the Procuct Information Section.
`t The appearance of these tablets and capsules Is a trademarl< of Wyett>Ayerst Laboratories
`t1 The appearance of these tablet s and capsules Is a registered trademark of Wyett>Ayerst Laboratories .
`.,,.Product ldentrficatlon .. number on reverse slde
`
`2 g/100 ml vial
`
`J
`- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ,Ex!h~.1~005
`
`

`
`lntnvenoua Admlnlatration:
`The intraveno\11 route ia preferable for patients with bacter(cid:173)
`emia, bacterial aepticemia, or other aevere or life-threaten(cid:173)
`i!IC" infectiona, or for patient& who may be poor rialal because
`or lowered reslstance resultinc from aucb debilitating condi(cid:173)
`tions 111 malnutrition, trawna, ~ry. diabelel, heart fail(cid:173)
`ure, or malignancy, particularly if ahoclt is preeent or im-
`d · · •
`I t.
`t·
`pend!ni-
`·
`·
`For mterm•ttent 1ntrtveno111 a muus.n 100, a ao 11 100
`containing 1 gram or 2 grama ofCEFOTAN (cefotetan diso(cid:173)
`dhlm for injection) in Sterile Water for Injection can be in(cid:173)
`ject.ed over a period of three to five minutea. Usina an infu(cid:173)
`aiOII ayatem, the aolution may abo be given over a longer
`period of time through the tubing system by which the pa(cid:173)
`tient may be receiving other int ravenous solutions. Butter(cid:173)
`fly® or scalp vein- type need lea are preferred for this type of
`infusion. However, during infuaion of the solution contain(cid:173)
`ing CEFOTAN (cefotetan diaodium for injection), it ia advis(cid:173)
`able to dill:ontinue temporarily the administration of other
`aolutiona at the same site.
`NOTE: Solution• of CEPOTAN must not be acimjxed with
`aolutions containing amimoglycoaidea. If CEFOT AN and
`aminoglycoaidea are to be admlniatered to the same pati_ent.,
`tha.Y must be administered aeparately and not as a rruxed
`injection.
`ln1nmiiiCUiar Administration:
`A. with all intramuacular preparations, (cefotetan diaodium
`for injection) should be injected weU within the body of a
`relatively large m\IICie such u the upper outer q11adrant of
`the buttock (i.e., sluteus maximus); aspiration is nece&88ry to
`avoid inadvertent injection into a blood .--L
`CUOTETAN INJECTION
`Dl.-ctiona for U• of CEFOT AN lcefot.uon Injection) in Ga~
`axy® Plaa11c Contai...,.IPL2040l
`CEFOTAN (cefotetan injection) in Galaxy® plastic con(cid:173)
`tainer (PL 2040) ia for int u venoua administration only.
`Stonoge: Store in a freezer capable of maintaining a tempera(cid:173)
`ture of -20'C/-4'F.
`Thawing of Plaa11c ContaiMr. TM.w frozen container at
`room temperature (2S'C/77'Fl or in a refrigerator (6'C/41'Fl.
`(DO NOT FORCE THAW BY IMMERSION IN WATER
`BATHS OR BY MICROWAVE IRRADIATION.)
`Check for minute leaka by squeezing container firmly. If
`leaks are detected, discard aolution as sterility may be im-
`peirecl.
`Tbe container should be vi&ually i.Mpec:ted. Components of
`the aolution may precipitate in the frozen. sta~ and will dil!'
`aolve upon reaching room temperature With httle or no agt·
`tation. Potency is not affected. Agitate aft.er aolut.ion has
`reached room temperatuJ"Oe. If after visual iMpaction the
`aolution remaina cloudy or if an inaoluble precipitate is noted
`or If any aea1a or outlet porta are not intact, the container
`ahould be dillcarded.
`P~ratlon of lntrawn- u .. 1u .. aseptic technique~
`1. Suspend container from eyelet support.
`2. Remove protector from outlet port at bottom of container.
`3. Attach adminiatratlon aet. Refer to complete directions
`.a:ompanying aet.
`C.utlon: Do not uae plastic containers in seriea connections.
`Such use could reault in air embolism due to residual air
`being drawn from the primary container before administra(cid:173)
`tion of the fluid from the secondary container is complete.
`lnt rav-ua Administration:
`The intraven0111 route is preferable for patient& with bacter(cid:173)
`emia, bacterial ae~W.. or other severe or life threaten·
`ing infectiona. or for patienta who may be poor risu because
`of lowered reaiatance resulting from such debilitating condi(cid:173)
`tions as malnutrition, trauma, aurgery, diabetea, heart fail(cid:173)
`ure, or malignancy, particularly if shock is present or im-
`pending.
`. .
`.
`.
`Uaing an infualon syatem, CEFOTAN (cefotetan •nJectlon) 10
`Galaxy® plaatic container (PL 2040) should be given over~
`to eo minutea through the tubing aystem by which the pa(cid:173)
`tient may be receiving other intravenous solutions. Butter(cid:173)
`fly® or scalp vein-type need lea are preferred for this type_ of
`infusion. However, during infusion of the solution contain·
`lng CEFOTAN (cefotetan in jection) in Galaxy® plastic con(cid:173)
`tainer (PL 2040). it is adviaable to disoontinue temporarily
`the administration of other aolutlons at the same site.
`Com.,.tibillty and Stability of CEFOTAN Products:
`Frozen aamplea should be thawed at room temperature be(cid:173)
`fore uae. After the period• mentioned below, allY unused
`aolutions or frcn.en materia l ahould be diacarded. DO NOT
`REFREEZE.
`NOTE: Solutionl of CEFOTAN must not be ad.mixed-with
`aolutlona coatainin& aminOJI)'COiidea. If CEFOI'AN and
`anrinoglycoaidea are to be adminiltered to the same patient.
`they muat be adminlaterecl aaparataly and not aa a mixed
`injection. DO NOT ADD SUPPLEMENTARY MEDICATION.
`CEFOTETAN OISOOIUM FOR INJECTION
`CEFOT AN (cefotetan di.lod.ium for injection) reconatituted
`11 described above <PREPARATION OF SOLUTION! main(cid:173)
`tains aa~ac:tory poteDC)' for 24 houra at room temperature
`12S"C/7TF), for 96 houra under refrigeration (6'C/fl'Fl, and
`for at least 1 week in the frozen state (-20'C/-4'F). After re-
`
`conatitution and subaequent storage in d.iaposable glaaa or
`plutic syringea. CEFOI'AN lcefotetan disodium for injec·
`tion) ia stable for 24 hours at room temperature and 96 hours
`under refrigeration.
`ADO.Vanuge Vialt:
`Ordinarily, ADO. Vantage Vialuhould be reconstituted only
`when it is certain that the patie.nt ia ready to receive the
`drug. However, ADO. Vantage Vials of CEFOTAN reconsti(cid:173)
`tuted as deteribed in Preparation of Solution, for ADO.
`Vantage Vials, maintains satisfactory potency for 24 hours
`at room temperature (2S'C/77'Fl.
`(00 N<Yl' REFRIGERATE OR fREEZE CEFOO'AN IN ADD(cid:173)
`VANTAGE VIALS.)
`CEFOTETAN INJECTION
`The thawed solution in Galaxy® plastic container (PL 2040)
`remains chemically atable for 48 hours at room temperature
`(25'C/7TFJ or for 21 days under refrigeration (5'C/41'FI.
`NOTE: Parenteral drug product& should be inspected visu(cid:173)
`ally for particulate mal~r and dill:olo~tion prio~ to admin(cid:173)
`istration whenever aolut1on and contatner pe.nml
`
`HOW SUPPLIED
`CEFOTAN tcefotetan disodiwn for injection) is a dry, white
`to pale yellow powder supplied in viala containi~ _cef~
`diaod.ium equivalent to 1 g and 2 g ~fo:tet&n. actiVIty for. on·
`travenous and inlramu.cular admtniatrabon. The VJals
`ahould not be atored at temperaturea above 22' C (72' Fl and
`should be protected from light.
`1 g ADO. Vantage Vial <NDC 031G-037S.31l
`2 1 ADD-Vantage Vial <NDC 03\G-0377-32)
`1 J Vial (Nl)C 0310-0376-10)
`2 1 Vial (Nl)C 031G-0377-~)
`I g Pigsybaclt Vi&llNDC 0310-0376-11)
`2 g Piggyback Vial tNDC OSIG-0377-211
`CEFCYI'AN ia also available as a 10 g pharmacy bulk pack(cid:173)
`age.
`.
`lOg in 100 mL ViallNDC 0310-0375-101
`CEFCYI'AN (cefotete.n injection) ia &upplied as a frozen, 1»
`OIDIOlic, premixed aolulion in lingle dOR Galaxy® plastic
`containers tPL 2040) u follows:
`1 g in 50 mL plastic container tNDC 0310-0378-Sll
`2 g in 50 mL plastic container tNDC 0310-0379-511
`Store containers at or below -20'C/-4'F. [See DIRECTIONS
`FOR USE OF CEFOTAN (cefotttan Infection) IN GALAXY®
`P'LAt TIC CO~TAIN£11 U'L ZQ40l),
`
`REFERENCES
`1. NatiO<nal Committee for Cliniclll Laboratory Standards.
`Methods for Dilution Antimicrobial SIIICOptibility Testa for
`Bacteria that Grow Aerobically- Third Edition. Approved
`Standard NCCLS Document M7-A3, Vol. 13, No. 25, NCCLS,
`Villanova. PA. December, 1993.
`2. National Committee for Clinical Laboratory Standards.
`Performance Standards for antimicrobial Disk Suaceptibil·
`ity Tes~Fil\h Edition. Approved Standard NCCLS Docu(cid:173)
`ment M2-A5, Vol. IS, No. 24, NCCLS, Villanova, PA, Decem·
`ber 1993.
`3 National Committee for Clinical Laboratory St.ndarcls.
`Methods for Antimicrobial Suaceptibility Testing of Anaero(cid:173)
`bic Bacteria-Third Edition. Approved Standard NeeLS
`DocumenL Mll-A3, Vol 13, No. 26, NCCLS, Villanova, PA,
`December 1993.
`•Galaxy® ia a regiltered trademark of Baxter Hcalthcare
`Corporation.
`tADO.Van~e is a reJiatered trademark ol Abbott Labora(cid:173)
`tories lne.
`~ Clinitest® ia a registered trademark of Amea Division,
`Milet Laboratories. Inc.
`CErofAN® (cefoteton injection) in Galaxy® plastic con(cid:173)
`tainer (PL 2040) is manufactured by Baxter Healthcare Cor(cid:173)
`poration, Deerfield, lllinois 60016 USA for Zeoeca Phanna(cid:173)
`ceuticala.
`CEFOTAN® (cefotetan diaodium for injection) ia manufac(cid:173)
`t ured by SmitbKiine Beecha.m Corporation for:
`Zeneca Pharmaceuticals
`A Business Unit of Zeneca Inc.
`Wilmington, Delaware 1985().5437
`SIC 6406&{)1
`Rev E 1/96
`Shown in Producl l lknti{ICOIIOII Guide, J101t 341
`
`DIPRIVAN® 1%
`INJECTABLE EMULSION
`10 mg/ml propofol
`FOR I.V. ADMINISTRATION
`Form«ty DIPRIVAN@ (propofol} ln}«;tion
`PROFESSIONAL INFORMATION BROCHURE
`
`ft.
`
`DESCRIPl'ION
`DIPRJV AN® Injectable Emulaion it a aterile, noop)'I'Oienic
`emulsion containiDJ 10 mg/ mL ofpropofol suitable for intra(cid:173)
`venous administration. Propofol ia chemically described as
`
`PRODUCT INFOAMATION/2939
`
`2,6-<IU.Opropylpbenol and haa a molecular weight of 178.27.
`The structural and molecula r formulas are:
`
`C,2H ,s0
`P ropofol is very slightly soluble in water end, thus, is formu(cid:173)
`lated in a white, oil-in-water emulsion. The pKa is il. The
`octanollwater partition coefficient for propofol 6761:1 at a
`pH of 6-8.5. In addition to the active component. propofol, the
`formulation also contains aoybean oil (100 mg/ mLl, glycerol
`(22.5 mg/ mLI, egg lecithin (12 mg/ mLI, and diaodium edetate
`(0.005%1; with sodium hydro><ide
`to odjuet pH. Tho
`DIPRIV AN Injectable Emulsion is isotonic and has a pH of
`7-8.5.
`STRICT ASEPTIC TECHNIQUE MUST ALWAYS BE MAIN(cid:173)
`TAINED DURING HANDLING. DIPRIVAN INJECTABLE
`EMULSION IS A SINGLE-USE PARENTERAL PRODUCT
`WHICH CONTAINS 0.006% DISODIUM EDETATE TORE·
`TARO THE RATE OF GROWTH OF MICROORGANISMS IN
`THE EVENT OF ACCIDENTAL EXTRINSIC CONTAMINA(cid:173)
`TION. HOWEVER, DIPRIVAN INJ ECTABLE EMULSION
`CAN STILL SUPPORT THE GROWTH OF MICROORGAN(cid:173)
`ISMS AS IT IS NOT AN ANTIMICROBIALL Y PRESERVED
`PRODUCT UNDER USP STANDARDS. ACCORDINGLY,
`STRICT ASEPTIC TECHNIQUE MUST STILL BE ADHERED
`TO. DO NOT USE IF CONTAMINATION IS SUSPECTED.
`DISCARD UNUSED PORTIONS AS DIRECTED WITHIN
`THE REQUIREO TIME UMITS (SEE DOSAGE AND ADMIN(cid:173)
`ISTRATION, HANDLING PROCEDURES~ THERE HAVE
`BEENI REPORTS IN WHICH FAILURE TO USE ASEPTIC
`TECHNIQUE WHEN HANDLING DIPRIVAN INJECTABLE
`EMULSION WAS ASSOCIATED WITH MICROBIAL CON(cid:173)
`TAMINATION OF THE PRODUCT AND WITH FEVER, IN·
`FECTION/SEPSIS. OTHER UFE-THREATENING ILLNESS.
`AND/ OR DEATH.
`CLINICAL PHARMACOLOGY
`General
`DIPRIV AN Injectable Emulsion is on intravenous sedative(cid:173)
`hypnotic agent for use in the lnducUon and maintenance of
`anesthesia or sedation. lnlnwl!nOUS injolct.ion of a lhl!nlpo!U·
`tic dose or propofol produces hypnosis rapidly with minimal
`excitation, usually within 40 seconds from the start of an
`injection (the time for one arm-brain circulation). As with
`other rapidly acting intravenous anesthclic ogen\i, the half(cid:173)
`time oflhe blood-brain equili bration is approximatel.Y 1 to 3
`minutes. and this account& for the rapid induction of anea..
`thceio.
`Pharmacodynamica
`Pha.rmacodynamic properties of propofol are dependent
`upon the therapeutic blood propofol concentrations. Stead,y
`stele propofol blood concentrations are generally propor(cid:173)
`tional to infusion rates. especially within an individual pa(cid:173)
`tient. Undesirable aide effects such u cardiorespiratory de(cid:173)
`pression are likely to occur at higher blood concent.rationa
`which result from bolua doa•ng or rapid increase in infusion
`rate. An adequate interval (l to 5 minutea) must be allowed
`between clinical dosage adjustmenta in order to aaseaa drug
`efTecta.
`The hemodynamic effects of DIPRJV AN Injectable Emul(cid:173)
`sion during induction of anestheaia vary. If spontaneous
`ventilation is maintained, the major cardiovasc:ular effecta
`are arterial hypotenaion (aometimea sreater than • ~
`decreaae) with little or no change in heart rate and no appre(cid:173)
`ciable decrease in cardiac output. lf ventilation ia 818iated or
`controlled (positive pressure ventilation), the degree and
`incidence of decrease in cardiac output are accentuated. Ad(cid:173)
`dition of a potent opioid (e.g .• fentanyl) when used aa a pre(cid:173)
`medicant further decreaaea cardiac output and respiratory
`drive.
`If anesthe5ia is continued by infusion of DlPRJV AN lnject.(cid:173)
`able Emulsion, the stimulat<on of endotracheal intubation
`and surgery may return arterial preaaure towards normal.
`However card.iac output may remain depreaaed. Compara(cid:173)
`tive clini~ stu.diea have shown that the hemodynamic ef(cid:173)
`fects of DIPRJV AN Injectable Emulsion during induction of
`aneatheaia are generally more pronounced th_an with other
`rv mduction agent.a traditionally used for this purpoee.
`Clinical and preclinical studies suggest that DIPRIVAN
`Injectable Emulsion is rarely asaociated with elevation of
`plasma histamine levela.
`Induction of anesthesia with DIPRIV AN Injectable Emul(cid:173)
`sion ia frequently aaaociated with apnea in both adulta and
`children. ln 1573 adult patients who received DIPRIV AN
`Injectable Emulsion (2 to 2.5 mg/ kg); apnea luted leas than
`30 seconds in 7% of patlenta, 3Q.60 seconds in 249'0 of pa(cid:173)
`tien~ and more than 60 seconds in 12% of patient&. ln the
`213 pediatric patient& between the aget of 3 and 12 yeera
`..-able for apnea who received DlPRJV AN Injectable
`Emu~on (1 to 3.6 mg/kgl, apnea lasted 1- than 30 eeconda
`Continu«< on next pii(Je
`
`COIIIUit 1997 ouppl• menta and Mutt adltiOM lot r41'tlliona
`
`Exh. 1005
`
`

`
`2940/PHYSICIANS' DESK REFERENCE®
`
`Zeneca Pharmaceuticals-Cont.
`
`in 12% of patients, 30-60 seconds in 10% of patients, and
`more than 60 seconds in 5% of patients.
`During maintenance, DIPRIV AN
`lnjectable Emulsion
`ca~ a decrease in ventilation usually associated with an
`increase in carbon dioxide tension which may be marked
`depending upon the rat<> of administration and other concur·
`rent medications (e.g., opiGids, sedatives, etc.).
`During monitored anesthesia care (MAC) sedation, attention
`mUBt be given to t he cardiorespiratory effects of DIPRIV AN
`Injectable Emulsion. Hypotension, oxyhemoglobin desatura·
`tion, apnea, airway obstructio.n, an.dlor oxygen desaturation
`can occur, especially following a rapid bolus of DIPRIV AN
`lnjectable Emulsion. During initiation or MAC sedation,
`slow infusion or slow injection techniques are preferable
`over rapid bolus administration, and during maintenance of
`MAC sedation, a variable rate infusion is preferable over
`intermittent bolus administration in order to minimize UD·
`desirable cardiorespiratory effects. ln the elderly, debili·
`tated, or ASA Ill/ IV patients, rapid (single or repeated) ~Ius
`dose administration should not be used for MAC sedation.
`(See WARNINGS.) DIPRIV AN Injectable Emulsion is not
`recommended for MAC Sedation in children because aafety
`and effectiveness have not been established.
`Clinical studies in humans and studies in animals show that
`DIPRIV AN Injectable Emulsion does not suppress the adre(cid:173)
`nal response to ACTH. Preliminary findings in patients with
`normal intraocular pressure indi.cate that DIPRIV AN ln·
`jectable Emulsion anesthesia prod~ces a d~rease in int~aoc·
`ula.r pressure which may be assoCiated with a concomitant
`decrease in systemic vascular resistance.
`Animal studies and limited experience in susceptible pa·
`tients have not indicated any propensity of DIPRIV AN
`Injectable Emulsion to ind.uce malignant hyperthermia.
`Studies to date indicate that DIPRIV AN lnjectable Emul(cid:173)
`sion when used in combination with hypocarbia increases
`cerebrovascular resistance and decreases cerebral blood
`flow, cerebral metabolic oxygen cOnsumption, and intracra·
`nial pressure. DIPRIV AN Injectable Emulsion does not af·
`feet cerebrovascular reactivity to changes in arterial carbon
`dioxide tension. (see Clinical Trials-Neuroanesthesia).
`Hemosiderin deposits have been observed in the livers of
`dogs receiving DIPRIV AN Injectable Emulsion containing
`0.005% disodium edetate over a four week penod; the cltru·
`~I significance is unknown.
`
`Pharmacokinetics
`The proper use of DIPRIV AN Injecwble Emulsion requires ~n
`underswnding of the di8position and eliminatwn characterrs·
`tks of propofoL
`The pharmacokinetics of propofol are well described by a
`three compartment linear model with compartments repre(cid:173)
`senting the plasma, rapidly equilibrat ing tissues, and slowly
`equilibrating tissues.
`Following an IV bolus dose, there is rapid equilibration '?&
`tween the plasma and the highly perfused tissue of the bram,
`thus accounting for the rapid onset of anesthesia .. Pl~ma
`levels initially decline rapidly as a result of both rapid distri·
`but:ion and high metabolic clearance. Distribution accounts
`for about half of this decline following a bolus of propofol.
`However, distribution is not constant over time, but de(cid:173)
`creases as body tissues equilibrate with plasma and become
`saturated. The rate at which equilibration occurs :is a func·
`tion of the rate and duration of the infusion. When equilibra·
`tion occurs there is no longer a net transfer of propofol be(cid:173)
`tween tissues and plasma.
`Discontinuation of the recommended doses of DIPRIV AN
`Injectable Emulsion after the maintenance of anesthesia for
`approximately one-hour, or for sedation in the ICU for one(cid:173)
`day results in a prompt decrease in blood propofol concen·
`traitons and rapid awakening. Longer infusions (10 days of
`ICU sedation) result in accumulation of significant tissue
`stores of propofol, such tbat the reduction in circulating
`propofol is slowed and the time to awakening is increased.
`By daily titration of DIPRIV AN lnjectable Emulsion dosage
`to achieve only the minimum effective therapeutic concen·
`tration, rapid awakening within 10 to 15 minutes will occur
`eve:n after long term administration. If, however, higher
`than necessary infusion levels have been maintained for a
`lohg time, propofol will be redistributed from fat and .muscle
`to the plasma, and this return of propofol from penpheral
`tissues will slow recovery.
`
`The figure below illustrates t be fall of plasma propofollevels
`following rcu sedation infusions of various durations.
`
`1.00
`
`5
`~
`~ 0.75
`s-o i 0.50
`}1
`:s.
`0.25 J 0.00
`
`0
`
`60
`20
`Minutes after end of intuslon
`
`80
`
`The large contribution of distribution (about 50%) to the fall
`of propofol plasma levels following brief infusions means
`that after very long infusions (atsteady state), about halfthe
`initial rate will maintain the same plasma levels. Failure to
`reduce the infusion rate in patients receiving DIPRIV AN
`lnjectable Emulsion for extended periods may result in ex·
`cessively high blood concentrations of the drug. Thus, titra·
`tion to clinical response. and daily evaluation of sedation
`levels are important during use of DIPRIV AN lnjectable
`Emulsion infusion for JCU sedation, especially of long dura·
`tion.
`Adults: Propofol clearance ranges from 23-50 mL/ kg/min
`(1.6 to 3.4 L/ mi.n in 70 kg adults). It is chiefly eliminated by
`hepatic conjugation to inactive metabolites which are ex·
`creted by t·he kidney. A glucuronide conjugate accounts for
`about 50% of the administered dose. PropofoE has a steady
`state volume of distribution (lG-day infusion) approaching 60
`L!kg in healthy adults. A difference in pharmacokinetics
`due to gender has not been observed. The terminal half· life of
`propofol after a 1!klay infusion is 1. to 3 days.
`Geriatrics: Witb increasing patient age, the dose of propofol
`needed to achieve a d.efmed anesthetic endpoint (dose(cid:173)
`requirement) decreases. This does not appear to be an age(cid:173)
`related change of pharmacodynamics or brain sensitivity, as
`measured by EEG burst suppression. With increasing. pa·
`tient age pharmacokinetic changes are such that_for a given
`IV bolus dose, higher peak plasma concen.t..atJons occur,
`which can explain the decreased dose requu>emenl Th~
`higher pea.k plasma concentrations in the elderly can predt&(cid:173)
`pose patients to cardiorespiratory effects including hypo~·
`si.on, apnea, airway obstruction and/or oxygen desaturatJon.
`The higher plasma levels reflect an age-related decrease 10
`volume of distribution and reduced intercompart.mental
`clearance. Lower dooos are thus recommended for initiation
`and maintenance or sedation/anesthesia in elderly patients.
`(See CUNICAL PHARMACOLOGY- lndividualization of
`Dosage.)
`Pediatrics: The pharmacokinetics of propofol were studied in
`53 children between the ages of 3 and 12 years who received
`DIPRIV AN Injectable Emulsion for periods of approxi·
`mately 1- 2 hours. The observed distribution and clearance of
`propofol im these children was .similar to aduJits.
`Organ Failure: The pharrnaco~etJcs of proporol do_not a!'"
`pear to be different in people with chrome hepatic c~rrhOSIS
`or chronic renal impairment compared to adults W1th nor·
`mal hepatic and renal function. The effects of acute hepatic
`or renal failure on the pharmacokinetics ofpro;pofol have not
`been studied.
`Clinical Trials
`Anesthnla and MonhoJed Anesthesia Care lMACI Sedation
`DIPRIV AN Injectable Emulsion was compared to intrave(cid:173)
`nous and inhalational anesthetic or sedative agents in 91
`trials involving a total of 5,135 patients. Of these 3,354 re(cid:173)
`ceived DIPRIV AN lnjectable Emulsion and comprised the
`overall safety database for anesthesia and MAC sedation.
`Fift.y.five of these trials, 20 for anesthesia induction and 35
`for induction and maintenance of anesthesia or MAC seda·
`tion, were carried out in the US or Canada and provided the
`basis for dosage recommendations and the adverse event
`profile during anesthesia or MAC sedation.
`Pediatric Anesthnia
`DIPRIV AN lnjectable Emulsion was compared to standard
`anesthetic agents in 12 clinical trials involving 534 patients
`receiving DIPRIV AN lnjectable Emulsion. Of these, 349
`were from US/Canadian clinical trials and comprised the
`overall safety database for Pediatric Anesthet~ia.
`
`TABLE 2. NEUROANESTHESIA CLINICAL TRIALS
`Patients Receiving DIPRIV AN lnjectable Emulsion Median and (Range)
`
`Patient Type
`
`Craniotomy patients
`
`No. of
`Patients
`
`50
`
`lnduction Bolus
`Dosages (mg/kg)
`
`1.36
`(0.9~.9)
`
`lnl.,..malion will be 5UP"f$eded by •upplements and subsequent editi0<1s
`
`Maintenance
`Dosage
`(Wl/ kg/ minl
`
`146
`(68-425)
`
`Maintenance
`Duration
`ill!i!U
`285
`(48-022)
`
`TABLE 1. PEDIATRIC ANESTHESIA CLINICAL TRIALS
`Patients Receiving DIPRIV AN lnjectable Emulsion
`Median and (Range)
`Induction
`Q!!!y
`243
`2.5 mg/kg
`(1-3.5)
`20sec
`(6-45)
`
`lnduction and
`Maintenance
`105
`3 mg/kg
`(2-3.6)
`
`Number of Patients'
`Induction Bolus Dosages
`
`Injection Duration
`
`Maintenance Dosage
`
`Maintenance Duration
`
`181 j.Lg/kg/ min
`(107-418)
`78 min
`(29-268)
`
`'Body weight not recorded for one patient.
`Neuro.anesthesla
`DIPRIV AN Injectable Emulsion was studied in 50 patients
`undergoing craniotomy for supratentorial tumors in two
`clinical trials. The mean lesion size (anterior/ posterior and
`lateral) was 31 mm and 32 mm in one trial and 55 mm and
`42 mm in the other trial respectively. [See Table 2 below.J
`ln ten of these patients, DIPRIV AN lnjectable Emulsion was
`administered by infusion in a controlled clinical trial to eva].
`uate the effect of DIPRIV AN lnjectable Emulsion on cere(cid:173)
`brospinal fluid pressure (CSFP). The mean arterial pressure
`was maintained relatively constant over 25 minutes with a
`change from baseline of -4% ± 17% (mean ± SO), whereas
`the percent change in cerebr-ospinal fluid pressure CCSFP)
`was -4{;% ± 14%. As CSFP ia an indirect measure of intra(cid:173)
`cranial pressure (ICP), when given by infusion or slow bolus,
`DIPRJV AN Injectable Emulsion, in combination with hypo.
`carbia, is capable of decreasing ICP independent of changes
`in arterial pressure.
`Intensive Care Unit (I CUI Sedation
`DIPRIV AN lnjectable Emulsion was compared to ben·
`wdiaz.epines and/or opioids in 14 clinical trials involving a
`total of 550 ICU patients. Of these, 302 received DlPRIV AN
`lnject.able Emulsion and comprise the overall safety data.
`base for ICU sedation. Six of these studies were carried out in
`the US or Canada and provide the basis for dosage recom·
`mendations and the adverse event proflle.
`Information from 193 literat ure reports of DIPRIV AN In·
`jectable Emulsion used for ICl! s_edatio!l in over 950 pati~ots
`and information from the clintcal trials are summarized
`below: [See Table 3 at top of next page.)
`Cardiac Anesthesia
`DIPRIV AN ln