`
`Apotex v. Abraxis -IPR20IS-00151 , Ex. 1027, p.OI of 15
`Apotex V. Abraxis - IPRZOIS-OOIS 1, Ex. 1027, p.01 0f15
`
`

`

`Entered according to Act of Congress, in the yMr 1885 by Joseph P Remington,
`in the OffiCf! of the Libra ri an of Congress, at Washington DC
`
`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P Remington
`
`Copyright 1926, 1936, by JOIieph P Remington Estate
`
`Copyright 1948, 1951, by The Philadelphia Colleg~ of Pharma~'Y and Scien~
`Copyright e 1956. 1960, 1965, 1970, 1975, 1980, 1985,1990, by The Philatlelphia COllege of
`P har!I1llCY a!H] Scien~'Il
`.
`
`All Rights Re~eroed
`
`Library of Congre6S Catalog Card No. 60·53334
`
`ISBN 0·912734-04-3
`
`';:.J ~~ ~\\ iC1! ,,: ~ i
`,
`The!lSe of &trlJ.ctu.ralifofQ~ti'il,.;;;,,~fSAN.an~ the lJSP Dictionary of Drug Nome8 i8 hy
`permU8ion of The USP Conuention. The Convention i3 not rl'spOn8ible f"ra"y inaccuracy
`COllt .. i""tlhl'l'ein~ rn\ ,': I
`~l+:'
`
`NOTICE-Thi, le.J: ~ is no~jnte'fded (o[~pr~$f;nt. nor sholl it be interpreted to be, the equivalent
`of or a 3ubsi'itMe , gNhefifh'c'i'a(U'ii/(ea States Pharmacopeia (USp) and/or 1M National
`Formulary (NF). In the event of any difference or di$creparn:y between the current official
`USP or NF $tandarrh of strength. qUQ,lity, pwity, packaging and labeling for drugs and
`repre$entations of them herein, Ihe conle%1 and effect of the official compendia shall
`prevail,
`
`Printed in the United States vf America by the Mack Prilltillg Comp<lny, Ea.<tofl., Pe"nsyloo,,;a
`
`Apotex v. Abraxis - IPR201 8-00 151 , Ex. 1027, p.02 of 15
`
`

`

`Table of Contents
`
`44
`
`46
`
`"
`" " 49
`
`50
`
`" " '" " " " " " '9
`
`60
`
`" 62
`'" 64
`" 66
`" 69
`
`67
`
`70
`
`609
`
`Cholinomimetic Drugs • . ... . • • • . .. . .. . .. .. . . •
`Adnene r<;llc ood Adre nergic Neuron Blocking
`Drugs
`. . . . . ..• .••.•..•••••.••• • .••..
`6%
`907
`Antlmu,carinic and Anrhposm<><11c Drugs
`916
`Skll!'ll1!'tol Muscle Relaxonts ••.•••••••••.••.•••
`929
`Dlurerlc Drug. • •••• .•• •. .•..• .• . .• . •• • •. . .•
`943
`Ute rIne and Antlm lgrolne Drugs .••.••••••...•
`948
`Hormones. . .. . .. . .
`. . . . . . .. . .. . . • . .
`1002
`Vitamlill and Other Nutrients. • . . •• . • • . •• . •• .
`lr05
`Enzymes .•••..••..••••••.••.••.••.•.•••.•
`l rog
`General Anesthetics ••.•••••••.••.• • .•••••.•
`1046
`Local Anesthetics..... ..••.•••.••.••.•. .• • ..
`1057
`Sedatlye s ond Hypnotlo . •• . • . • . •• . •• . •• . ••• .
`• .•.•••• . ••.••.••••••.••.••.. 1072
`Antieplleptics
`Psyd-oopharmaCQloglc Agen ts ... . ..
`1062
`Analgesics and Antipyrll!'tics .••.••••.•.••
`1097
`Histamine and AntihistamInes . . ........ .
`112.:1
`CenlJal Neryous System Stlmulonts .••.• ..
`1132
`" ntlneoplostk and Immu~uppress lye Drugs...
`1136
`Antimlctobial Drugs.. . ...................... 116.:1
`Poraslticldll!'s •.... • . . . •..•.•.•• • .. • ••.••...• 1242
`1249
`PII!'Uickles •••... . . .. •••••..••.••.•. . ••••• . •
`Diagnostic Drugs . .... ..... . ... ... . . . .. ..... 1272
`Pharmacevllool NeceSSIt ies
`. •••.• •• ••.•. • • • . •
`1266
`AdYerse Drug Reoctlons . . ...... . . . .. ...
`1.:1.:10
`Pharmocogene tlcs •.• . ...•...•. . .• . .. . •... . •.. 1.:144
`PharmocologJcoI Aspeers of Drug Abuse .•• . •• .
`1.:149
`IntlOduction of New Drugs •.•••.•••••.••.••••
`1.:165
`
`'art 7
`
`71
`72
`
`" 74
`
`Prln<lples of Immunology, ••• , •••••••• " ." ••
`Immunizing Agent~ ond Diagnostic Skin
`Anl igens ....... .. ....................... . .
`AIIII!'r<;Ienl~ EXlracts ••••••••••••..•.••.•••••.•
`Biotechnology ond Drugs .•.•••••.•••.••••••.
`
`1.:179
`
`'309
`1405
`14 16
`
`Put.
`
`Ph_maceutkGI P'l'po.rotlons Gnd Thl'l,
`Manu'auwl'
`
`" 76
`
`77
`76
`79
`00
`
`" " OJ
`" " 06
`07 .. .9
`
`90
`9 '
`92
`
`Pref orm ulot lon •..•••.•.••.•••••.•••••••••.•
`Blooyoilabllityand Oioequlyolency Testing •...•
`Separation • • . ... . ..•••••..••.••.••.•••••. •
`SllI!'rllirolion •.••. . •.•••••••••.••.••••••••.•
`Tonldty. Osmoticll y, Osmolality ond Osmolarity •
`Plastic Pockoglng Morertals .•••••.. . ••••
`StabililY of Phormoceutlcal Products
`. _ ....
`Qual ity Assurance ond Control .....•..••
`Solutions. Em ulsions, Suspensions and
`Extracllyes ••• • .•• , ••• . •••• , •• . •• . •• • , •• • ••
`Parenteral Preparollons ••. .. . . ••.••.•••••.••
`Intrayenous Adm ixture s •..•.•.••.••.•.•••.••
`Ophlholmlc Prepalotions . .. . . . .. . •• ••. ..... .
`Medlcatll!'d Applicotlons .•.• _ .. . ....... . ....•
`Powders .•.•••••••. .. •• . •.•..•..••••.•••..
`Ora l Solid Dosage Forms ••....•..•••. . •.••••.
`Cooring of Pharmaceutical Dosoge Forms .•••.••
`Susl ained.Release Drug o..liyery Systems
`"erasols .. . .
`
`'arl'
`
`'harma'l'",tl," Proctl,1'
`
`'"''
`
`1451
`" 59
`1470
`1481
`1499
`' 504
`1513
`
`1~ 1 9
`
`""
`
`1570
`
`"" " ..
`
`1615
`
`,6:"
`
`'666
`1676
`169"
`
`Pert f
`
`. ................ .
`Sco~ ..
`2 EvolUTion 01 Pharmacy ...•..• . .• . ••• . . .. .•.•
`:) Elhles •.• • ••••.•••.•••••.•••. . .•••.... . •.•
`.. Th" PracTicE' ofCommunHy Pharmacy
`5 Opporrunlrl (' ~ for PhQrrnadm In rhe Pharma~utl.
`col lndU5try
`. . ... . _ .. . . . . . ... . . . . . •.•••.•••
`6 PharmacisTs in Gollemment .•••.•.•••••.••••.
`1 Drug InformaTion ••.•••••..•.•. • ••••••••.
`6
`I\.esearch ••.•••••.•.••••..•.•••.••••.
`
`Port 2
`
`Phormace-ulics
`
`9 ME'llology and CokuJatlon ................. .
`10 StaTisTics ••• • • • .•.•• . .•••.•.•.•.•••.•••.•..
`11 Computer Science • _ ••••••.•••.•.•••..... .. •
`12 COlculus . ............ . .............. . .... .
`13 Molecular Structure. Propenles and 5tQ~s of
`Maller •••••... . . • .•.. . .••••.•••.•.•••.•..
`14 Complex Formotion ........•.• • ••••••••• . •.
`15 Thll!'rmodynamlcs ••.••••.•.•••••••••••.• . ••.
`16 Solullons and Phose Eq uilibria ••• . •.. • ••..• . ..
`17
`IonIc Solutions and ElE'cttolytlc Equilibria •••••••.
`16 Reoction Kin e tics .• . •.•••••...... . ....••.
`19 Dispersll!' Systll!'ms ••.•••.• . .••.... . . . ..•..•••
`20 Rheology ..
`• ••...•••.•••.•.•••.••••
`
`PartS
`
`Inorganic Pharmaceutlcol Chemistry ••..••. .. .•
`2 1
`2:2 O rganic Phalmaceutical Chemistry .•••.•.•. • .•
`2.:1 Natulal ProdUCTS ••.••••••.•••••.•••.•••••.•
`24 Drug Nomll!'nciotullI!'_Unllll!'d Srotll!'s Adoptll!'d
`Names ••• •• . • ••. •• •••.•.•. • .•••.•.•• • .•••
`25 Stlucture.Acllylty Relotlonshlp and Drug
`Design •. • •. • ••. • •••••.••
`
`'art 4
`
`• .•••.•..••.•••.•.••••
`26 Analysis of Medicinals
`27 Biologicol TII!'stlng
`.. . ......... . . .. ..... .
`28 Clinical Anolysls ............... . .... . ..... .
`'19 ChIQlTlatoglaphy ••• , • ••••..• , .•.•• , .• • • .
`.:10
`)nslJumento! Memods of Ana lysis .. .• .. ••• .
`.:1 1 Dlssolullon •.•••••. • •••••.•••.•••.•.•...
`
`,
`• 20 ,.
`'" ,.
`
`49
`60
`
`69
`, 0-
`, :>8
`
`'"
`'''' 182
`, 91
`207 ". 247
`
`257
`"0
`
`412
`
`422
`
`4'"
`"" 495 ,,.
`'" "'9
`
`Parr ,
`
`"aillioisolop" in PhamMIcy ond Ml'dlclnl'
`
`.:12 Fundo~ntals of Radioisotopes. . • . • •• . • •• . • • •
`.:1.3 Medical Applications of Rodioisotopes •.• • •.•.•
`
`605
`624
`
`Pall'
`
`.:14 Diseases: Monilll!'SIOJlons and Patho.
`phys!ology •. . •••••••..•• . ..• . •.•• .
`.:15 Drug Absorption. Adion and Disposition •..••.••
`36 Basic Pharmocoklnt'tlcs , ••••••• ,.,., ••••• , •••
`.:17 Clinical Pharmacokinetics ...•..•.•...•...•.••
`.:18 Topkol Drugs •.•...•••••.•••. •. •••.•••.•.••
`.39
`Gostrolnt~ntlnal D/Ugs •••..•••.•• . ••• _ •.••.•.
`40 Blood. Fluids. ElvcJrolytes and Hemalologic
`Drugs .................................. ..
`41 CardioYascular Drugs ••.•.••.• . ..••. __ •• .. . .
`42 Respiratory Dl ugs .•.•.• • .•••.•.•••.•••.••.•
`4.:1 Sympathomimetic DIl,lgs ....... .. ... . .. . ... . .
`
`. "
`697
`725
`746
`757
`774
`
`aoo
`
`.," 060
`
`070
`
`"
`
`9' 94
`95 Long.Term COlli Focilltles ........... .. .. . ... . "'"
`
`Ambulotory Pallll!'nt Core
`InSlllu tlonal Patient Core
`
`1715
`1737
`
`96 The Pharmacllt and Publk Health ... . ..••••••.
`
`1773
`
`Apotex v. Abraxis -IPR20 18-00 151 , Ex. 1027, p.03 of 15
`
`

`

`97
`9'
`99
`"Xl
`.0,
`,02
`.0,
`.0,
`.0,
`
`Th~ POllen!: Behavioral D!!'lerminonls ...... . .. .
`Pallenl Communkolion
`Drug EdUCQllon
`Patient Compliance
`The PrelCripllon
`..... . . •••. .. • • • ..... .
`Drug InteraCTions ... .
`. .....• •• . . .. • • • ......
`Cllnkal Drvg LlrelotulE- .......•...... •• ..
`Heollh Accessories .......... •• ..
`'iu'gkal Supplies ............ .•• ..
`
`" .. m.
`" .. .07
`1659 , .. ,
`
`.0,
`
`"'00
`,.,. ,09
`
`1813
`
`1842
`
`1895
`
`. .... ....................... .
`Poison (onlfo!
`Lows Govemlng Pharmo<y .... .
`Community Pharmacy Economics and
`MonogemO!'nt
`... ...... .
`Denlo l Servla-s .. . .. . .......... .
`
`I"ft.x
`
`Alphabetic Index
`
`,90'
`
`1914
`
`1940
`
`,."
`
`'967
`
`Apotex v. Abraxis - IPR2018-00ISI, Ex. 1027, p.04 of IS
`
`

`

`CHAPTER 85
`
`Intravenous Admixtures
`
`Salvato •• J Turco. PharmD
`Prol.uor of ""',moer
`t ...... pl. Untven.lJy xhool at ~lIGrmocy
`PIlIIod.lphla. PA 19140
`
`It has been estimated that 40%of all drugs administered in
`hospitals are given in the form of injectiol1li and their use iii
`increasing. Part of this increase in parenteral therapy is due
`to the wider use of intravenous fluids (IV fluid!!), In th(llast
`de<:ade the use of TV fluids has doubled, increasing from 150
`million units to 300 million units annually. Not only do IV
`fluids continue t o serve as the means for fluid replal'ement,
`electrolyte·balance restoration and supplementary nutri(cid:173)
`tion, but they also are playing major roles as vehicles for
`administration of other drug substances and in total paren(cid:173)
`ter aJ nutrition (TPN) . TPN fluids are fi nding greater use3S
`the means of administering other drugs because of conve(cid:173)
`nience, the melIDll of reducing the irritation potential of the
`drugs and the desirability for continuous and intermittent
`drug therapy. The techniques for providing TPN parenter(cid:173)
`ally have imprO\'ed steadily in t he last decade, and such use
`is increasing markedly. The use of IV fluids for these pur(cid:173)
`jl'Oflcs requires the compounding of specific intravenous ad(cid:173)
`mixtures (parenteral prescriptions) to meet the clinical
`needs of a given patient. However, the combination of drug
`substances in an IV fluid can promote parcn~ral incompati(cid:173)
`bilities and give rise to conditions not favorable for drug
`stability. A new area of specialization h as been created for
`hospital pharmacists who can develop the expertise to pre(cid:173)
`par e these solutions-recognizing their compatibility and
`stability problems and the potential for contaminlltion(cid:173)
`and participate in the administration of the solutions. The
`romplex compounding of an order for TPN requires know(cid:173)
`ledgeable personnel capable of making accurate ca\cula(cid:173)
`tion.e., compounding and having a.e.eptic technique. The par(cid:173)
`enteral prescription is becoming increasingly important in
`hospitals. Centralized admixture progr ams are now found
`in 70% of the nation's hospitals having 300 beds or more.
`Equipment available for administering IV fluids has become
`mo re .e.ophistir..aterl, a nd has made possible increa.e.ed accura(cid:173)
`cy of dosage and l.:ld to till) d"vo.:lupWl'll t uf !Jew LvnL"I;!v 1ij a.m.l.
`methods of nutrition and drug therap.,Y.
`
`Intravenous Fluids
`
`Large-volume injections intended to be administered by
`intuvenous infusion commonly are called IV fluids and are
`included in the group of sterile products referred to as large(cid:173)
`vol ume parenterals. These consist of single-dose injections
`having a volume of 100 mL or more and containing no added
`substances. Intravenous fluids are packaged in containers
`having a capacity of 100 to 1000 mL. Minitype infusion
`containers of 250-mL capacity are available with 50- and
`too-mL partial fills for solution of drugs when used ill the
`"piggyback" technique (ie, the administration of a second
`solution through a Y -tube or gum -rubber connection in the
`adminilitrstion ~et or the first intravenoUli fluid, thus avoid(cid:173)
`ing the need for another injection site).
`In addition to t he
`IV fluids. this group also includes irrigat ion !IOlution!l and
`solutions for dialysis.
`Intravenous fluids are ster ile solutions of simple chemi-
`
`caw s uch as sugars, amino acids or electrolytes_materials
`which easily can be carried by the circulatory system and
`assimilated. Prepared with Water for Injection USP. the
`solutions are pyrogen-free. Because of the large volumes
`administered intravenously, the absence of particulate mat·
`ter assumes a significant role in view of pofl.'lible biological
`hazards resulting from insoluble particles. Absence of par(cid:173)
`tkulate matwr or darity of IV fluids i~ Ill; important at the
`time of administration following their manipulation in the
`hospital as it is at t he time of manufacture of the injection.
`Limita for part iculate matter occurring in IV fluids, or
`large-VOlume injections used for single-dose infusion, are
`defined in the USP. This represents the first regulatory
`attempt to define limita for partkulate matter in paren(cid:173)
`teraLs. Limits also apply to multiple·dose injections, small(cid:173)
`volume injections or injections prepared by reconstitution
`from sterile solids. The USP dcfines particulate matter as
`extraneous, mobile, undissolved substances, othe.r than goo
`bubbles, unintentionally present in parellteral solutions.
`The total numbers of particles having effective linear di(cid:173)
`mensionsequal to or larger than 10.um and larger than 25 "m
`are counted. The IV fluid meeta t he requirement of the test
`if it contains not more than 50 particles per mL whkh are
`equallo or larger than 10 "m, and not more than 5 particles
`per mL which are equal to or larger than 25 "m in linear
`dimellllion.
`Intravenous fluids commonly are used for a number of
`clinical rondition9. Th&se include
`C<>rred;on of dillturOOr""," in ~l"drol)le bHldn<:e.
`COfr«tinn of dilltUfbancU in b<XIy fluirls (fluid ,..,placement).
`The lneR nA nfprovirling b~l;k nutri tinn
`The OO$ i. fnr the prll(tice of prnvirling TPN.
`Use "" "ebides (OJ nthe. <i .. " . "b:otance$.
`
`In both of the latter two cases it has become common prac(cid:173)
`t ice to add other drugs to certain IV fluid s to meet the
`clinica l needs of the patient. Using IV fluids as vehicles
`. offers the advantages of convenience, the means of reducing
`the irritation potential of the drug and a method for continu(cid:173)
`ous drug therapy. However, the practice require.e. that care(cid:173)
`ful consideration be given to the stability and compatibility
`of additives present in the IV fluids serving as t he vehicles.
`This approach also demands strict adherence to aseptic
`techniques in adding the drugs, as well as in the administra(cid:173)
`tion of the IV fluid s. Theile procedures are discussed later
`in the chapter. The IV nuids commonly used for parcnter(cid:173)
`als are shown in Table I.
`Many dil;ease states result in el~trolyte depletion and
`loss. P roper electrolyte concentration and balance in plas(cid:173)
`ma and t issues are critical for proper body fun ction. Elec(cid:173)
`trolyte restoration and balance are achieved most rapidly
`through administration of IV fluids. Required electrolytes
`include sodium IUld chloride ions, which in normal saline
`moreciosely approximate the composition of t he extracellu(cid:173)
`lar fluid than solutions of any other single salt; potaasium.
`the principal intracellula r cation of most body tissues and an
`essential for the func tioning of the nervous and muscular
`
`1570
`
`Apotex v. Abraxis - IPR20 18-001 5 1, Ex. 1027, p.05 of 15
`
`

`

`INTRAVENOUS ADMIXTlJRES
`
`1571
`
`Table I-Fluids Used Commonly lor IV Use
`."
`
`Concenlralion (% I
`
`,
`
`5
`
`3.5; 7
`8.5
`3.5; 5.5; 8.5
`2.14
`
`10
`10
`
`6
`6
`2.5-'<)
`Varying conen of dextr(l$e
`from 5-20 with varying
`concn of sodium chlo(cid:173)
`ride from 0.22-0.9
`5,10
`
`0.6
`0.03
`0.02
`0.3
`5
`10
`15
`20
`
`0.86
`0.03
`0.033
`5
`0.45; 0.9;
`3; 6
`116 M
`
`4.5
`
`5.25
`6.6
`GO
`1.5-6.0
`
`5 •
`5 • 3.5-6.5
`
`3S-tJ.S
`
`'.0
`
`6.0-7.5
`
`Sedative, BMllfeo;;c, calorie~
`Sedative, analgesic, calories
`Fluid and nutrient replenisher
`
`Metabolic alkaloids
`Priming nuid for utracor'
`pOreal circulation
`PTiming nuid for extraoor(cid:173)
`poreal circulation
`
`PIa..ma volume upander
`Plnsma volume upander
`Fluid and nutrient replenisher '
`Fluid, nutrient nnd electrolyte
`",plenisher
`
`Fluid and nutrient replenisher
`
`Systemic alkali:.ec; fluid and
`electrolyt'l replenisher
`
`5.0-1.0
`
`Osmotic diuresis
`
`Fluid and electrolyte
`replacement
`
`Fluid and electrolyte
`replenisher
`
`Metabolic acidosis
`Fluid and electrolyte
`replenisher
`Fluid snd electrolyte
`replenisher
`Diluent
`
`5.0-7.5
`
`8
`4.5-7.0
`
`6.3-7.3
`
`5.5
`
`Alcohol
`with I);)/W~
`with oslW in NSS·
`Amino Acid (Synthetic)
`Aminosytl fI (A..bb(>u )
`FreAminc III (McGaw)
`Travll!501 (Da.tler)
`Ammonium Chloride
`Outran 40
`in NSS
`in D5/W
`
`Oextrnn 70
`in NSS
`in J)5!W
`DulrOSC (Glucme, 05/W)
`De~t:rO$tl and Sodium
`Chloride
`
`Invert Sugar
`(F ructose and Dextr06C)
`lActated Ringer's
`(Hartlll8nn'sj
`NaCI
`KCI
`CoCl1
`Lactate
`Mannitol
`al!lO in comhination with
`dutJ'Oie or sodium
`chloride
`Multiple electrolyte
`.olutions
`varying combination$ of
`eleetrolyte$, dntrQ'Oe,
`fructo6e, invert sugar
`Hing.,r's
`NaCI
`KCI
`CaCI2
`Sodium Bicarbonate
`Sodium Chloride
`
`Sodium Lactate
`
`Sterile Water for Jnj~t ion
`• G" DUlrOOIe in water .
`• NOrmllJ Saline Solution.
`
`systems as well as the heart; magnesium, as a nutritional
`~upplement especially in TPN solutions and phosphate iOn,
`important in a variety of biochemical reactions. In addition
`to the number of standard electrolyte fluids shown in Table
`I, a large number of combinations of electrolytes in varying
`concentrations are available commercially. Some of these
`electrolyte fluids also contain dextrose.
`Dextrose Injection 5% (D5(W) is the most frequently used
`it is
`IV fluid, either tor nutrition Or fluid replacement.
`isotOnic and administered intravenously into a peripheral
`vein; 1 g ot dextrose provides 3.4 cal i1lld 1 L of 1)5(W
`supplies 170 caL The bOOy utilizes dcxtrose ata rate of 0.5 g
`per kg of body weight per hr. More rapid administration
`can result in glycoouria. Therefore, 1 L of D51W requires
`114 hours for lissimillitiOD. The pH range of D5/W Clin vary
`from 3.5 to 6.5. The wide range permitted is due to t he free
`sugar acids present and formed during the sterilization and
`storage of the injection. To avoid inCOInJUltibilities whe n
`other drug substances are added to Dextrose injection, t he
`poosible low pH should be considered in using itas a vehicle.
`
`More concentrated solutions of dextrose are available and
`provide increll.lled calorie intake with less fluid volume. Be(cid:173)
`ing hypertonic, the more concentrated, solutions may be irri(cid:173)
`ta ting to peripheral veins. Highly concentrated solutions
`are admi nistered in a larger central vein. Other I V fluids
`used for intravenous admixtures and providing calories in(cid:173)
`clude solutions C(lntaining invert sugar. There is some evi(cid:173)
`dcnce that fructose, unlike dextrose, may be used in diabetic
`patients: the 10% injection is hy pertonic and provides 375 cal
`per L . Invert sugar consists of equal parts of dextrose and
`fructose ; i~ is claimed that the preSt:uce offructOllC promot~
`more rapid utilization of dextrose.
`Intravenous fluids containing crystalline amino acids Clln
`provide biologically usable .amiuoacids for protein synthesis
`(Chapter 51). Protein contributes to tissue growth, wound
`repair and resistance to infection. The protein requirement
`for the normal adult is 1 g per kg per day; children and
`JUltients under stress require greater amounts. Attempts
`are made to maintain a positive nitrogen balance, indicating
`that the protein administered is being utilized properly and
`
`Apotex v. Abraxis - IPR20 18-00 151, Ex. 1027, p.06 of 15
`
`

`

`1572
`
`CHAPTER 85
`
`not broken down and eliminated through the urine 88 creati(cid:173)
`nine and urea, which are normal waste products. In a posi(cid:173)
`tive nitrogen balance patienu are uking in more nitrogen
`than they are eliminating. In a negative nitrogen balance
`there is more nitrogen being eliminated through the urine
`regularly than is being administered intravenously. This
`means that tissues are continuing to be torn down and repair
`i9 not necessarily taking place. Amino Acid Injection can
`afford the Wtal body requirements (or proteins by the proce(cid:173)
`dure known 88 TPN (dis~ below) or be used for ~ upvle­
`mental nutrition by peripheral administ ration. In addition
`to the amino acids, these nutritional injections also may
`oontain dutrose, electrolytes, vitaming and insulin. Fat
`emulsion (lntralipid, Kabi Vitrum AB; Liposyn II, Abbott
`and Trauamul,ion; Travenol) sometimes is used concur(cid:173)
`rently but usually administered at another site.
`
`PacJ;.aging Sy.dems
`
`Containers for intravenous fluids must be designed to
`maintain solution sterility, clarity (freedom from particulate
`matter) and nonpyrogenicity from the time of preparation,
`through storage and during clinical administration. Con(cid:173)
`tainer cl06Ul\l8 mWjt be dt!!lignlld to facilitate insertion of
`administration sets through which the injections are admin(cid:173)
`iste~, at a regulated flow-rate, into suitable "eim.
`IV
`fluids are available in gla!',.'! and plastic containen; the latter
`may be made from either a flexible or semirigid plastic mate(cid:173)
`rial.
`IV fluids are supplied in lOOO-mL, SOO-mL and 250-
`mL sizes in addition to 25(}..mL capacity containers pack(cid:173)
`aged wit h 50 or 100 mL of DS/W or Sodium Chloride Injec(cid:173)
`tion for piggyback use.
`IV flu ids in gla!',.'! oontainers are
`packaged under vacuum, which must be dissipated prior to
`use_ For fl uid to leave the IV glass container and fl ow
`through the administration set, some mechanism is neces(cid:173)
`Mry to permit a ir to enter the-eontainer. Current fluible
`plutic systems do not require air introduction in order to
`function. Atmospheric pressure pressing on the oontaincr
`forces the fluid to flow_
`AJllllass and plastic containers are single-dose and should
`be discarded after opening even if not used. Intravenous
`flu ids are packaged with approximately 3% excess fm to
`allow for removal of air from the administration set and
`permit the labeled volume to be delivered from the contain ·
`er. The containers are graduated at 20-mL increments on
`scales t hat permit the volume in container to be determined.
`either from an upright or inverted position. Glass contain(cid:173)
`ers have aluminum a nd plastic bands for hanging, while
`plastic containers ha .... e eyelet openings or plastic straps for
`attachment to IV poles.
`
`Tabl. II-N Fluid Syste ms
`
`""-
`
`G ...
`
`Plastic
`
`Gto..
`
`Plastic
`
`G ....
`
`Pintie
`
`.... ~
`
`Buttr
`
`&lIlter (Vitl/lu)
`
`McGaw
`
`McCaw (A.ecumtd)
`
`Ab"""
`
`Abbott (Liftcart)
`
`• Pu. otlKlminln ... tion oet.
`
`C ...... acleristlQ
`
`VllCUum
`Air tube
`Polyvinyl chloride
`Flexible
`Non" "'ntcd
`Vacuum
`Air tube
`Polyolcfin
`Semirigid
`Vacuum.
`Air fi lter"
`Polyvinyl chloride
`Flexible
`Nonvent.:d
`
`Fluids for IV U9C are available from t hree sources; all
`provide both glass and plastic containers. The glass-eon(cid:173)
`lainer 'yt.tem. of ila'lt.er and McGaw are similar. The char(cid:173)
`acteristiCli of current packaging systems are summarized in
`Table 11
`
`Adminiltration Seu
`Admininration seta used to deliver fluids intravenously
`a re sterile, PYl"OKen-Cree and disposable. Although these
`sets are supplied by different manufacturers, each for ita
`own ~y~tem , they have certain basic components.
`'Ibese
`include 4 plastic spike tCl pie rce the rubber closure or plastic
`seal on t he IV container, 4 drip (sight) chamber to trap air
`and permit adjustment of flow rate and a length (150 to 450
`cm) of polyvinyl chloride tubing terminating in a gwn-rub(cid:173)
`ber injection port. At the tip of the port i.s a rigid needle or
`catheter adapter. An adjttstable clamp (screw or roller
`t ype) on t he tubing pinches the t uhing to regulate flow.
`Sin<'"e the gum-rubber port is self-scaling, additional medica(cid:173)
`tion ca.n be added to the IV system at these ports of entry.
`Glass containers that have no air tubes require air-inlet
`filters designed. 11.8 part of the administration set (Abbott).
`Sec Figs 85-1 to 85-5.
`
`Administration ProcedUl"e5
`
`In the administration of I V fluids, the primary IV contain(cid:173)
`er providea for fluid replacement. eleetrruyte replenishment,
`
`/ ." ~ ,
`
`-
`
`S~l k.
`
`- Clo""
`
`Fig 85- 1. P(l(\S of bilslc admlnlstr!llion sets.
`
`(for tV spike)
`
`Slop,,,
`(canllOl be penetrllted
`by ooodle)
`
`, . ..(cid:173)
`~_MM
`D
`
`.00 "'-
`
`Fig 85-2. AbbOtt tV glass container. The air venting Is provided
`tlV'ough the alf jirter located in the spike of the administration set
`Soo Fig 85-1.
`
`Apotex v. Abrax is - IPR20 18-00 15 1, Ex. 1027 , p.07 of 15
`
`

`

`Sofely
`5",
`
`Pu n C lu ~ Proot
`Seo l( Al um,nlJll\)
`
`,
`
`INTRAVENOUS ADM IXTURES
`
`1513
`
`o
`
`=
`
`6
`
`A(!d ili ve
`
`.. ,,'
`
`Spi ke
`
`500mL.
`
`1000 n'\..
`
`250mL. Copaclly
`( PiQ~yba c" )
`Fig 85-3. Baxter and McGaw glass containers. The plastic air tube
`allows the air to enter the bottle as lt1e flukl Is In/used into the patient.
`The ~p ik e 01 the administrat ion set is not vented. See Fig 85-1.
`
`,
`
`drug therapy or nutrition; the fluid can be infused over a 4-
`to 8-hr period. In some r:ase.~ an IV fluid is infu.o.ed slowly
`for the purpose of keeping the \'ein open (KVO). This will
`allow additional drugs to be administered when required.
`The primary IV fluid also can serlle as a vehicle for other
`drugs to be administered, thus beeoming an intrallenous
`admixture (IV drip) and results in continuous blood lellols of
`added drugs once the steady state has been rcachcd.
`In preparing an IV fluid for administration, the following
`pro(;edure is used.
`
`AdditIve
`PO! I
`(A) Abba" (Ufecare ) polyvinyl Chloride flexib le container:
`Fig 85-4.
`(8) Baxter (Viaflexj polyvinyl chloride flexible oonl aincr: McGaw
`(AcclXll6d) polyolefln semirigid container. front and side ~iews.
`These contalnelS take nonvented administration sets. See Fig 85-1.
`
`A" ,." •. _
`'e'''''''.'
`
`( 00<1."0'
`
`Venl.~
`5 ..
`
`Non·Venled
`So>
`
`Fig 85_5. SeUing up a primary IV fluid tor adminislratiOfl.
`
`Apotex v. Abraxis - IPR20 18-00151 , Ex. 1027, p.08 of 15
`
`

`

`1574
`
`0iAPTER 85
`
`I. The apike ..... pter nl the .dm;n;'tnotiOll I14't ;. ;1"III4',ud ;nw the
`atoppe, or _I 01 !.he IV cont.a'I14'" ~ Fi,. 86·s..
`2.. TMIV "llid is 1111"1 00. a,-,nd.t bedside .nd .ir i, pU'led from
`the .dnliniftrlliun Kt by open,,,, the d .. mp until "uid COrnell IIU~ of
`nMdle. The wbine if; IMn etllmped off. 5H t'ic: M·~
`3. The venipuncture is made by ..... mlle, oIthe IV tom. floor nuOM
`or physlcilon.
`<t. Tbe ;nrusioln no~ is Iodjlllud by IIIowIy openi",.nd clCJ&;", the
`clfomp until the d8i.-M drop no~, viewed in the drip chamt-. "' ob·
`'-'ined. The ........ ) runninrlimeif;4 to8ht (\I& ..... lIyl2:1 OI.L .. ,d~I;V"fred
`;n I h,). Orup....,h .. he-pa,;n, inlulin.lidoaiil14' or dopfImi .... ...., be
`pruent in !.he IV d,ip. When pOtent drop .. re p'eten\, the now ' "tft
`.. ill ~.ry depend on the clinic .. 1 condition of the Plltient, Seta are
`~I(ulat.td todeliw:r 10, 15,20, SO or 60 drop!! pe' mL dtptndin, on the
`menU(ae\II'e,. See Fic: &·5.
`inlermitlent administration of an antibiotic and other
`drul' can be achieved by any of three methods:
`(I) direct
`intravenous injection (IV bolUil or push), (2) addition of the
`drug to a predelermi ned volume of fluid in a yolume·control
`device or (3) use of R second container (minibottle, minibag)
`with an already hanging IV fluid (piggybacking).
`Direcl lntravcnous In;cetion-Small volumes (I to 50
`rnL) of drugs are injected into the vein over a short period of
`time (I to {; min). The injection also can be made through a
`rese81able gum·rubller injection site or an already hanging
`IV nuid. This method is suitable for a limited number of
`drugs but too hazardoUil for most drugs.
`Vo!ume-CoDlroJ Method- Volume-control seta provide
`a means Cor inwrmittentinrUilion of drug IIOlutions in precise
`quantities, at controlled rates of now. T hese units consist of
`calibrated, plastic, fluid chambers placed in a direcl line
`under an eatablished primary IV container or more often
`attached to an independent nuid supply. In either C&Se, the
`drug to be administered is first reconstituted if it is a SlerHe
`solid and injected into the gum.rubber injection port of the
`volume-eontrol uniL It is then further diluted to 50 to ISO
`mL with the primary nuid or the separate fluid reservoir.
`Administration of the total drug·containing solution rc(cid:173)
`quirea30 to 60 min and produces a peak concentration in the
`blood rollowed by a valley if the dosage iadiacontinued. The
`following volume-control seta are available commercially:
`Sollaet, Abbotti Buretrol, Baxter and Metrnet, McGaw.
`The procedure for setting up an intermittent IV infusion
`wi th a volume·control set is 8S follows:
`
`I. UBI", aoeptic teehni'llM!, the Ipike 01 the voIUfIW!·oontroi let ..
`inserud inlO the prim • • y IV fluid or 11II4'PII .. ~fluid 000r..a1114'" See FiB
`M·.
`Z. Air Is llUrted (rom lubl", ohbe \'OIume-alf1trol KI. 11)' open;", the
`cI.m~ until fluid oomMlh,,,,,,h.
`3. The cI.mp Is opened above the.caJibtllfd cha",~r and it iltilled
`with 25 to 50 IIll. fluid from the primary IV roI"Il.Biner til ~'81.t "uid
`c:ontail14" .
`4. The ca."'p iI c'-!above the clwnbe, .
`6. The medi(.lion it! i n~tfd th."",h !.he JIlm·rubber pOf1. 01 the
`YO!lIme-controi un;\.
`6. The ca.",p .. boY. tbe chambe, if; Opened to comple~ the dilotion
`10 the d",i"d VQlume (SO to ISO mL), tMn clo8ed.
`flow oommeR(Q ""hen the ca.",p bel"",' the ' -oillme-controillnit ill
`7.
`
`""' .....
`
`Piggyback Method-The piggyback method (Figs 85·7
`8nd 85·8) refen to the intermittent IV drip of 8 second
`IOlution, the reconstituted drug, through the venipuncture
`site of lin established primary IV system. With this setup
`
`~OflOOm
`LVP' .... d
`
`~"
`,"""'Det
`
`the Intetminent admlnlstrahon 01 II
`Fig 85--1. Plggybaclc method:
`second soMIon Ihrough the venipuncture 8M 01 an established
`prim&ry IV system.
`
`fig 8H. Volorne-conttol set
`
`Fig 85-8. p~ administration setl,l]).
`
`Apotex v. Abrax is -I PR201 8-001 5 1, Ex. 1027, p.09 of 15
`
`

`

`the drul!: can be thought of as entering the vein on "top" of
`the primary IV fluid, hence the designation "piggypack."
`The piggyhack technique not only eliminates the need for
`another venipuncture, but also achieves drug dilution and
`peak blood levels within a relatively shon time span, usually
`30 to 60 min. Drug dilution helps to reduce irritation, and
`early high serum levels are an important consideration in
`serious infection requiring IIggressivc drug therapy. These
`advantages hUve popularized the piggyback method of IV
`therapy, especially for the intermit tent administration of
`antibiotics. In using the piggyback technique, the secon(cid:173)
`dary unit is purged of air and 'its needle inserted into a Y(cid:173)
`injection site of the prima]"y set or into the injection site at
`the end of the primary set. The piggyback infusion is then
`started. Once it is completed, the primary fluid infusion
`will be restarted. See Fig 85-8.
`Primary IV administration sets are available that have a
`built-in check valve for use in piggyback administration.
`When the piggyback is connected to one of these sel.'! and
`started, the check valve automatically closes off the primary
`infusion. When the piggyback runs out, the check valve
`automatically opena, thereby restarting the primary infu(cid:173)
`sion. The check valve works because of pressure differ(cid:173)
`ences. To achieve this difference, the primary container is
`hung lower than the seoondary bottle by means of an uten(cid:173)
`sion hanger, Sec Fig 86-9.
`Manufacturers have introduced minibottleti prefilled with
`various antibiotic products; each container is provided with
`a plastic hanger for direct suspension from an IV pole as the
`piggyback solution is administered through the resealahle
`gum-r ubber injection site or Y -type facility of an existing IV
`s~'t!tem. Rec()nstitution of piggyback units requires only the
`addition of a small volume of compatible diluent. Since
`reconstitution and administration proceed from the same
`bottle, no drug transfer is involved, 110 transfer syringes and
`additional IV oontainen are not necessary. Prefilled 'd rug
`container~ offer ~ignificant auvantages to hospitals. Time·
`saving, less potential for error and cQntamination and cQnve(cid:173)
`nience are outstanding qualities of this type of packaging.
`The need exists