Parenteral Medications
`tlolumet
`Second Edition, Revised and Expanded
`
`Edited by Kenneth E. Avis,
`Herbert A. Lieberman, and Leon luchmun
`
`
`
`
`
`Serumconcentrationimuu,-me;
`
`40
`
`Ed 0
`
`M O
`
`—I O
`
`O
`
`
`
` "wt?
`
`..?‘~'
`_L
`__
`
`I.
`
`J
`
`1
`5
`
`1
`8
`
`Time {hours}
`
`__§_
`1t,_
`
`1
`Astrazeneca Ex. 2107 p.
`Mylan Pharms. Inc. v. Astrazeneca AB IPR2016-01326
`
`

`
`Parenteral Medications
`VIIIIIIIIB 1
`Second Edition, Revised and Expanded
`
`Edited by
`
`Kenneth E. Avis
`
`The University of Tennessee
`Memphis, Tennessee
`
`Herbert A. Lieberman
`
`H.H. Lieberman Associates, inc.
`Consultant Services
`
`Livingston, New Jersey
`
`Leon lutbman
`
`Lachman Consuitant Services
`
`Westbur}; New York
`
`Marcel Dekker, Inc.
`
`New York I Basel 0 Hong Kong
`
`Astrazeneca Ex. 2107 p. 2
`
`

`
`Library of Congress Cataloging -1n— Publication Data
`
`Phalmaceutical dosage forms. parenteral medic-art-ions I edited by
`Eienneth E. Avis. Herbert A. Lieberman, and Leon Lachman. -- ‘End ed. _,
`rev. and expanded.
`p.
`cm.
`Includes bibliographical references and index.
`ISBN 0-B24?-85'if3—-2 (V. 1 :- alk. paper)
`1. Parenteral solutions.
`2-". Pharmaceutical technology.
`Kenneth E.
`II. Iieberman, Herbert A.
`III. Lao-htoan. Leon.
`
`I. Avis,
`
`[DNLM:. 1. Infusions. Par'enteraI.. 2. ‘Technology, Pharmaceutical.
`WB 354 P5Sfi]
`RS201._P3TP48 1992
`615'. 19--de2D
`DNLM.-’DL(.-I
`for Library of Dongress
`
`91 -38083
`CIP
`
`This book is printed on acid-free paper.
`
`Copyright© 1992 by MARC}?-L DEKKEII, INC. All Righu Reserved
`
`Neither this book not any part may be reproduced or transmitted in any form
`or by any means. electronic or mechanical. including photocopying, micro-
`filming, and recording, or by any information storage and retrieval -system,
`without permission in writing from the publisher.
`
`MARCEI. DEKKER, INC.
`270 Madison Avenue, New York, New York [0016
`
`Current printing [last digit]:
`ID 9 8 7 6 5 4- 3 2 I
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`Astrazeneca Ex. 2107 p. 3
`
`

`
`Contents
`
`Preface
`Contributors
`Parenteral‘ Medications,
`Contents of Pharmaceutical Dosage Forms:
`Second Edition, Revised and Expanded, Volumes 2 and 3
`Tablets, Second Edition,
`Contents of Pharmaceutical Dosage Forms:
`Revised and Expanded, Volumes 1-3
`Contents of Pharmaceutical Dosage Forms:
`Ilisperse Systems.
`Volumes 1 and 2
`
`ii.Ea"
`
`JEV
`
`xvii.
`
`Chapter I. The Parenteral Dosage Form and Its Historical Development
`
`Kenneth E. Avis
`
`I.. The Dosage Form
`I]. History of Parenteral Medications
`Appendix A: Glossary of Terms
`Appendix '13: Highlights in the History of
`Parenteral Medications
`References
`
`Chapter 3
`
`Parenteral Drug Administration: Routes, Precautions,
`Problems, Complications, and Drug Delivery Systems
`
`Richard J. Burns, Michael J. Alters. and
`8aIvatore- J. Tm-no
`
`Introduction
`I. General Indications for Parenteral
`
`Administration of Drugs
`11 . Pharmaceutical Factors Affecting Parenteral
`Administration
`
`111.
`IV.
`
`‘Specific Routes of Administration
`Distribution of Pareuterally Administered Agents
`
`IADIDA1-‘
`
`14
`15
`
`1'7
`
`1?
`
`18
`
`19
`21
`-39
`
`vi!
`
`AstraZeneca Ex. 2107 p. 4
`
`

`
`vlti
`
`Contents
`
`V. Precautions, Problems, Hazards. and
`Complications Associated with Parenteral Drug
`Administration
`
`W. Methods and Devices for Drug Delivery Systems
`VII.
`Summary
`References
`
`Chapter -3
`
`Biopharmaceutics of Injectable Medications
`
`Sol Motola
`
`1.
`
`Introduction
`
`1!.
`
`Phyaicochemical and.Phys1olog1ca1 Factors
`Affecting Drug Absorption by Injection: An
`U'V'E1‘V'i9W
`
`III. Application of Pharmacokinetics to Biopharma-
`ceutic Investigations: Pharmacokinetic Models
`IV. Examples of Biopharmaceuticflharmacokinetic
`Principles
`V. Regulatory Considerations for Bioequivalence
`Studies
`
`VI. Bioequivaience Study of Two Injectable Forms
`of the same Drug
`Summary
`References
`
`VII.
`
`Chapter 4
`
`Preformulation Research of Parenteral Medications
`
`Sol Match: and Shreeram N. Agharkcr
`
`I.
`
`Introduction
`
`11.. Drug. Substance Physieochemical Properties
`III. Accelerated stability Evaluation
`IV. General Modes of Drug Degradation
`V.
`Preforlmflation Studies for Proteins and Peptides
`VI. Preformulation Screening of Parenteral
`Packaging Components.
`Summary
`VII.
`VIII. Preformulation Worksheet
`References
`
`Chapter 5
`
`Forrnulstion of Small Volume Parenterala
`
`Patrick P. Dellucc and James C.. Boylan
`
`Introduction
`I.
`IL Formulation Principles
`III. Container Effects on Formulation
`11?.
`Stability Evaluation
`V.
`Process Effects
`References
`
`41
`49
`55
`5’?
`
`59
`
`59
`
`60
`
`77
`
`98
`
`108
`
`I119
`111
`112
`
`115
`
`115
`116
`140
`I50
`154
`
`158
`183
`163
`
`169
`
`173
`
`173
`I'M
`227
`234
`244
`245
`
`Astraleneca Ex. 2107 p. 5
`
`

`
`Contents
`
`inc
`
`Chapter 6
`
`Formulation of Large Volume Parents-rals
`
`Levit J. Demorest and Jeffrey G. Hamilton
`I.
`II.
`III.
`IV.
`V.
`
`Introduction ,
`Concepts of Formulation
`Formulation Development
`Solution Quality
`Summary
`References
`
`Chapter 7
`
`Parenteral Products of Peptides and ?roteins
`
`Yu~Chang John Wang
`
`I.
`II.
`III.
`IV.
`
`V.
`
`Introduction
`
`Characteristics of Proteins and Peptides
`Formulation Principles
`Compatibility with Packaging Components and
`Infusion Sets
`Formulation of Market Products
`References
`
`Chapter 8
`
`Sterile
`
`Diagnostics
`
`Leif E.
`
`Olsen
`
`Introduction
`
`III.
`IV.
`
`VI.
`VII.
`
`Diagnostic Products Defined
`Sterile Diagnostics
`Definitions
`
`Aseptic Manufacturing Considerations
`Validation Program
`Conclusion
`References
`
`Chapter 9
`
`Glass Containers for Parenterais
`
`R. Paul Abendroth and Robert N. Clark
`
`I.
`II.
`III.
`
`IV.
`V.
`VI .
`VII.
`VIII.
`
`Introduction
`The Nature of Glass
`
`United States Pharmacopeia Glassware
`Classifications
`The Manufacture of Glass Containers
`Chemical Performance
`Mechanical Performance
`
`The Container and Closure as a System
`Quality Assurance
`References
`
`2419
`
`249
`250
`273
`280
`281
`281
`
`283
`
`283
`284
`302
`
`310
`312
`317
`
`321.
`
`321
`321
`322
`325
`330
`351
`359
`359
`
`351
`
`361
`361
`
`362
`369
`375
`380
`380
`382
`384
`
`Astrazeneca Ex. 2107 p. 6
`
`

`
`1.‘
`
`Contents
`
`Chapter 10 Use of Plastics for Parenteral Packaging
`
`John M. Anes, Robert S. Nose, and
`Charles H. White.
`
`Introduction
`I.
`II. Fundamentals
`III. Fabrication Processes
`
`Important Criteria for Selection of Plastics
`IV.
`V. Plastics Used in Parenteral Packaging
`VI. Quality Assurance of Parenteral Containers
`References
`
`Chapter 11 Elastomeric Closures for Pa.-renterals
`
`Edward J. Smith and Robert J. "Noah
`
`1. Elastomeric Parenteral Packaging Components:
`A Physical Description
`Physical Description of ‘Rubber
`11.
`III. Types 01’ Rubber Used in Parenteral Packaging
`IV. Closure Design
`V. Rubber Compounding
`VI.
`vulcanization Process
`VII. Closure Manufacture and Control
`
`VIII. Closure Design Qualification
`IX. Regulatory Considerations
`X.
`Interaction of Drug Formulations with
`Rubber Closures
`
`XI. Contemporary Closure-Related Issues
`References
`
`Chapter 12 Parenteral Products in Hospital and Home Care
`Pharmacy Practice
`
`John W". Levchuk
`
`1.
`
`Introduction
`
`.11. The Preparation of Sterile Dosage Forms in the
`Hospital and in Home Care
`111. Dispensing and Compounding Processes
`IV. Technology of sterile Compounding in the
`Hospital Pharmacy
`1?. Clinical Supply and Use of Sterile Products
`VI. Quality Assurance
`VII. Conclusion
`
`Appendix: Abbreviated Sequence for Preparing 9.
`Series of Extemporaneously compounded IN’.
`- Admixturas
`References
`
`Index
`
`387
`
`387
`. 389
`398
`407
`422
`439
`443
`
`-145
`
`445
`450
`451
`482
`463.
`470
`477
`494
`503
`
`505
`507
`508
`
`513
`
`513
`
`513
`524
`
`532
`54'?
`552
`583.
`
`563'
`566
`
`569
`
`Astraleneca Ex. 2107 p. 7
`
`

`
`2 P
`
`arenteral Drug Administration: Routes,
`Precautions, Problems, Complications,
`and Drug Delivery Systems
`
`.
`
`Richard J . Durna
`
`Medical College of Virginia, Virginia Commonwealth University, Richmond.
`Virginia
`
`Michael J. Alters
`
`Eli‘ Lilly and Company. Indianapolis, Indiana
`
`Salvatore J . Turco
`
`Temple University, Philadelphia, Pennsylvania
`
`Parenteral, from porn enteron (Greek) , meaning “to avoid the intestines,"
`includes in its broadest sense. any drug‘ (or fluid) whose delivery does not
`utilize the alimentary canal for entry into body tissues. Although drugs 'ap~
`plied topically to the eye, ear, and skin, or even inhaled, may be broadly
`interpreted as parenternls, medical and pharmaceutical health care deliveries
`generally limit the definition to those drugs injected or infused directly into
`tissues, tissue spaces, vessels, or body compartments.
`The development of techniques for administering parenterals. coupled
`with innovative designs of new devices to achieve and monitor their delivery,
`occur almost daily and are enabling therapeutics to approach an exact science.
`In addition, parenteral therapy is not restricted to hospitals or clinics but is
`being increasingly employed, even in its most invasive forms of delivery (a. g. ,
`intravenous). to manage patients at home and in the work place. Most par
`tients readily accept or easily adapt to almost every form of parenteral ther-
`aplf. and many self-administer their own drugs, even when the route of de—
`livery is intravenous (e.g. , home infusion programs).
`Parenteral administration offers many advantages over therapy given by
`nonparenteral routes- Most notably, therapeutists can reliably predict with
`considerable accuracy the pharmacokinetica and pharmacology of the agents
`they prescribe; they can quickly interdict a rapidly progressive lethal pro-
`cess or disease; and, even though the physiology and pathology of patients
`may be complicated, they can "tine tune," stratify and quantitate results.
`However, despite these advantages. parenteral administration is not without
`
`1'?
`
`Astraleneca Ex. 2107 p. 8
`
`

`
`18
`
`Damn. st at.
`
`certain, measurable risflcs and limitations that the professional must intelligent-
`ly weigh in terms of risks, benefits, and costs.
`This chapter will attempt to review and update the usage of parenteral
`administration in today's practice of medicine. However, since the subject is
`dynamic and the technology is -growing‘, the reader must appreciate that some
`of the material contained herein may become quickly outdated.
`
`I". GENERAL INDICATIONS FOR" PARENTERAL
`ADMINISTRATION OF DRUGS
`
`The parenteral routes of drug administration are mdicated for one or more
`of the following reasons:
`
`1. To ensure delivery of adequate concentrations of the drug in ques—
`tion to diseased tissues or target areas of the body, especially when
`inadequate or marginal transport of that drug into the tissues or tar-
`get areas is anticipated. Example: Direct intrsvrentricular injection
`of drugs (e.g. , antibiotics such as the aminoglycosides) which cross
`the "blood-brain-meninges barrier" poorly may be used in certain.
`patients with bacterial or fungal meningitis andior ventriculitis.
`2. To permit the user to exert direct control over certain pharmacologic
`parameters, such as the time of drug onset, serum peak and trough
`levels, tissue concentrations-, and rate of elimination of the drug from
`the body. Example:
`Intravenous or direct oardiointrsventriculsr
`routes may be desirable to achieve immediate effects in emergencies
`such as might occur in the control of life-threatening hypotension,
`hypertension, or arrhythmies; or in't1'amusc1J]ur routes may be desir-
`able to obtain protracted or sustained effects, such as the use of
`benssthine penicillin G in the treatment of infections.
`3. To allow the therapist. when outpatient management is desirable, to
`guarantee dosage and drug compliance, especially when the patient
`cannot be relied upon to sell’-mcdicate. Example: The use -of long-
`acting (montlaly) intramuscular pcnicillins may be used to manage
`children prophylactioally for rheumatic heart disease in order to pre-
`vent Group A streptococcal pharyngitis.
`4. To deliver a biologic effect that cannot be achieved through oral ad-
`ministration, perhaps because of nonsbsorbence from the alimentary
`canal or degradation by gastric acidity. Example: Therapeutic pep-
`tides and proteins such as insulin, human growth hormone. other
`products ti-om recombinant DNA technology, and polyene antibiotics
`(such as the entifungal agent smphotericin B).
`5. To administer a. drug when the desired route (_e.g., oral) may not be
`available. Example:
`In patients who are asptrsting or who have had
`the upper gastrointestinal tract stream diverted or removed (e.g'. .
`because of 5. -carcinoma). a parenteral route may be necessary.
`6. To provide a local effect when it is desirable to minimise or avoid sys-
`temic toxic effects or reactions. Example: Methotrexste may be given
`intrsthecally to patients with leukemia and leukemic. involvement of
`the meninges to avoid the systemic, toxic effects that would occur if
`an intravenous route was employed.
`
`Astrazeneca Ex. 2107 p. 9
`
`

`
`Parenteral Drug Administration
`
`19
`
`'7. To administer drugs to the unconscious. uncooperative, or uncon-
`trollable patient. Example: Patients with uncontrollable grand mal
`seizures often will not. cooperate in the oral administration of drugs
`or will be at risk to aspirate it compelled to take medicines by mouth.
`Similarly, patients unconscious from narcotic abuse, anesthetic usage,
`or trauma, or uncooperative patients such as those suffering delerium
`tremens or a psychosis, may be satisfactorily managed by using paren-
`teral routes.
`
`8. To permit rapid correction of fluid and -electrolyte imbalances and to
`supply short-- or long-term nutritional needs (hyperslimentation or
`parenteral feeding) . Example: Patients suffering severe dehydration
`or electrolyte depletion for a variety of reasons (e.g-. . heat stroke)
`can be rapidly corrected with intravenous electrolyte solutions; and
`patients whose intestinal tracts have been resected for one reason
`or another may be intravenously "fed" a complete diet of all the neces-
`sary amino acids, glucose, minerals, and vitamins for prolonged and
`indefinite periods of "time.
`9. To achieve a desired local effect. Example: Local anesthetics for
`tooth extractions or local anti-inflammatory agents for inflamed joints
`may be injected directly into the site in question to avoid systemic-
`effects or "systemic" dosages.
`
`II. PHARMACEUTICAL FACTORS AFFECTING
`PARENTERAL ADMINISTRATION
`
`Certain pharmaceutical characteristics dictate the method or route of peren-
`teral administration, and once the dosage form is injected or infused, influ-
`ence the rate and extent of drug availability. These characteristics will be
`reviewed briefly in this section, but the reader is also referred to Chapter 3
`for a more detailed treatment of the hiopharmsceutical factors affecting peren-
`teral drug availability.
`
`A. Solubility of the Drug and Volume of the Injection
`
`A drug must be completely solubflised, preferably in water, before it can be
`administered by intravenous injection. Both the extent of drug solubility in
`its intended vehicle and the dose required for the desired therapeutic effect
`will determine the volume of the injection. Parenteral routes other than the
`intravenous one have limitations regarding" the maximum volume of medication
`administered Ce.g'. , intradermal, intramuscular. intraoculsr. intreventricular,
`and intrathecal, to name a few).
`
`B. Vehicle Characteristics
`
`Drugs in aqueous vehicles may be administered by any parenteral route,
`whereas drugs in nonaqueous vehicles, which may or may not be water mis-
`cible, are administered most frequently by the intramuscular route. The in-
`travenous route may be used for a few drugs in mixed solvent systems (e.g.,
`did-ZEPBFH; digoxin, and phenytoin} . but precautions must be BPP.1ied in adjust-
`ing the rate of drug infusion to avoid drug precipitation at the site of infusion.
`
`Astraleneca Ex. 2107 p. 10
`
`

`
`20
`
`Duma ct oi.
`
`Large volume parenteral fat emulsions are also available by the intravenous
`route. Nonaqueous vehicles that are more viscous than water vehicles will
`affect the rate of injection through a small-gouge needle and the rate of ab-
`sorption from the injection site.
`
`C.
`
`pH and Dsmolaiity of lnjectable Solutions
`
`Ideally, administered injections should be formulated at 21 pH and osmololity
`similar to that of biological fluids. Unfortunately, this is not possible for
`many parenteral dosage forms, as many parenteral drugs are unstable at neu-
`tral pH. Therefore, such drugs are formulated at the pH at which they are
`most stable. For example, diazcxide (e. ncndiugre-tic benzothiadiazine deriva-
`tive) is formulated at :2». pH of 11.6, the pH at which it is most stable. Many
`parenteral druga are salt forms of weak bases. Thus the pH of a dosage form
`containing the salt of a weak base may be as low as 2.0 (e.g. , tetracycline
`hydrochloride), or the pH of a dosage form containing the salt of a weak acid
`may be as high as 12.0 (e.g‘. , Dilentin) in order to maintain the active in»
`gradient in solution. Although dosage forms with extreme pH values may be
`administered by any parenteral route, the rate and volume of injection must
`be controlled to minimize iooin and irritation to the patient and damage to the
`surrounding tissues.
`Certain parenteral formulations are hype-rosmotic with biological fluids
`and contain a relatively high dose of active ingredienus) in order to achieve
`a desired level of biological ectivity. For example, water—solub1e contrast
`media, spinal anesthetics, ophthalmic sodium sulfacetamide, diazoxide, and
`osmotic diuretics are a few hypertonic parenteral formulations containing high
`drug concentrations to achieve an appropriate biological action(s).
`‘Products
`of parenteral nutrition are formulated or admixed with high concentrations
`of amino acids, dextrose, and other essential ingredients, resulting in very
`hypertonic solutions. These solutions, called hyperolimentetion solutions,
`are so hypertonic that they must be administered vie a large vein such as the
`subclovian. The blood in this vein enters directly into the heart, which allows
`the hypertonic solution to be rapidly diluted by a still larger volume of blood.
`Generally, hypertonic parenteral dosage forms are contraindicated for
`subcutaneous or intramuscular injections. Whereas the vitreous humor, can
`tolerate only very narrow ranges of osmotic values from an injected medication.
`Therefore, although stability and solubility problems may Qrevent dosage forms
`from being formulated at physiological pH, they should be formulated with
`solute contents approximately equal to those of biological fluids.
`
`D. Type of Dosage Form
`
`Parenteral dosage forms include solutione, suspensions, and sterile solids
`for reconstitution.
`If the dosage form is a suspension, it may be administered
`only by the intramuscular or suiicutaneous route. Particles should not be
`present in dosage forms administered intravenously or by other parenteral
`routes in which the medication enters directly into a biological fluid or semi»
`tive tissue (e.g. , brain or eye). Reconstitutecl solids should be completely
`dissolved in the reconstituting diluent before they are administered intraverr
`ously.
`
`Astrazeneca Ex. 2107 p. 11
`
`

`
`Parenteral Drug Administration
`
`21
`
`‘E. Formulation lrtgredlerlts
`
`As discussed in Chapter 5, parenteral formulations may contain various active
`and inactive excipients other than the main therapeutic agent, for a variety
`of reasons. For molt-idose parenterals, antimicrobial agents are added to the
`formulation for the preservation of sterility. However-. these agents may be
`contraindicated in medications to be administered into the cerebrospinel fluid
`or intrsocular fluid because of the toxicity tlley may produce. Several paren-
`teral formulations. contain surface-active agents (such as polysot-bate 80) to
`maintain drug solubility in the solution vehicle-. Surface-active agents are
`known to alter membrane permeability, so their presence must be recognized
`when administering such dosage forms by the subcutaneous or intramuscular
`routes.
`
`The expanding field of sustained and prolonged release of drug‘ delivery
`employs various formulations and additives that at times aid in achieving the
`desired duration of drug‘ action. These additives are primarily high-molecular‘-
`weight polymers or oily solvents. Formulations containing’ these macromole-
`cules are administered by the subcutaneous or intramuscular routes to permit
`the delayed release of the active ingredient within deeper tissues of the body.
`
`Ill. SPECIFIC ROUTES OF ADMINISTRATION
`
`Three primary routes of parenteral administration are commonly -employed:
`intramuscular. intravenous, and subcutaneous. These three routes satisfy‘
`to a large extent the four principal reasons for administering psrenterals:
`(1) for therapy (definitive or palliative) , (2) for prevention, (3) for diagnosis,
`and (4) for temporarily altering’ tissue functiontsl in order to facilitate other
`forms of therapy. Besides these three primary routes, additional ones are
`utilized under special circumstances:
`for example ,. subconjunctival, intra-
`ocular, intrathecal, intro-articular, and so on.
`In the sections to follow,
`the primary and special routes of parenteral administration are reviewed in
`alphabetical order. Each review will include four subheadings: description,
`indications. precautions . and method of drug’ or fluid delivergr.
`
`A. Primary Routes
`
`Intramuscular
`
`Description.
`
`Injection directly into the ‘body of a relaxed muscle.
`
`Indications. The intramuscular (i.m.) route is one of the most popular
`and convenient routes available, ‘both for the administrator and for the patient
`[1] . especially for a child [2]. Therefore, whenever it is possible and prac-
`ticable. the intramuscular route is used. The intramuscular route provides
`a‘ means for prolonged release of drugs formulated as aqueous or oily solutions
`or suspensions. The intramuscular route is preferred over the subcutaneous
`route when a rapid rate of absorption is desired and over the intravenous
`route when for one reason or another the drug cannot be administered direct-
`1y into the vascular compartment.
`Many factors affect the rate of drug absorption from an intramuscular
`injection [Z]; they will be discussed later in this chapter. Drug commonly
`
`Astralencca Ex. 2107 p. 12
`
`

`
`22
`
`Emma et al.
`
`injected by intramuscular administration include lidoczfine, cephalosporins,
`aminoglycosides. cliazepam, insoluble salts of penicillin G (procane penicillin
`G}, corticosteroids, narcotics, narcotic antagonists, and contraceptive steroids,
`to name a few.
`
`Precautions. Although intramuscular injections are much easier to ao:l—
`minister than other injections, the main precaution is to avoid entering a blood
`vessel (especially an artery), which might lead to infusionlof a toxic agent
`or a toxic vehicle directly to an organ or tissue. This can be prevented usu-
`ally by pulling heel: on the plunger of the syringe; if blood does not appear,
`the needle is probably not in a vessel. Also, the accidental striking of or
`injection into a peripheral nerve may result in a peripheral nerve palsy with
`or without sensory damage. Ciccasionally, when :3 large bolus of drug is in»
`jected into the muscle, local damage or muscle infarction may result, lending
`to El sterile abscess or to elevation of serum levels of muscle enzymes. The
`latter complication may present confusing diagnostic problems, especially in
`patients under suspicion of having a myocardial infarction or hepatitis.
`If materials contaminated with microorganisms are injected, a septic abscess
`may result. Therefore, appropriate precautions must be taken to e1‘aSu1‘£3.Stl3I"
`ility prior to injection.
`In patients with poor hygiene or skin care, microorga-
`nisms from the slain flora may he punchedin by the needle at the time of in-
`jection. resulting in stagrnhylococcal or streptococcal abscesses; and rarely in
`such situations as gas gangrene [3] (especially if epinephrine is injected)
`or tetanus [4] .
`the intramuscular route should never be
`An important note of caution:
`employed in patients with significant heart failure or shock, when uptake into
`the vascular compartment new be expectently poor. This caution should be
`followed especially if immediately high serum or plasma concentrations of the
`drug are desired or if rapid distribution to a distal organ is mandatory.
`
`Method. Various muscle sites are available for delivery (Fig. 1) , includ~
`ing the gluteal, deltoid, triceps, pectoral, an-:1 vnstus laterelis muscles.
`In
`adults the site of choice often is the gluteal muscle, because large volumes
`of drug may be injected and tolerated. However, the vastus Iateralis of the
`thigh may aiso be used because it not only tolerates large volumes of medica-
`tififl. but it is also away from any major vessels or nerves. For rapid absorp~
`tion and small volumes (<2 ml} , the deltoid muscle is preferred, as some stud-
`ies suggest that blood flow in the deltoicl muscle is 7% greater than that of
`the vastns lateralis and 17% greater than that of the gluteus maxi;-nus [5] .
`For this reason. in adults the cleltoid is the preferred site for vaccine admin-
`istration.
`In infants and small children, the vaetus. lateralis of the thigh is
`often preferreefl because it is better developed than other muscle groups, de-
`pending on the site selected. The skin is first cleaned with alcohol or a suit“
`able disinfectant, and the plunger on the syringe is always retracted prior
`to injeciton to be sure that the needle is not in a vessel. For deep intramus~
`cular injections, as might be used for irritating medications such as iron prep-
`oration.-3, El "z~tr£_-Lek" injection method is employed.
`
`Intravenous
`
`Description.
`
`Injections or infusions directly into a vein.
`
`Astrazeneca Ex. 2107 p. 13
`
`

`
`Parenteml Drug Administration
`
`23
`
`tlpper
`some common sites employed for intramuscular injections.
`Figure ‘I
`left: posterior gluteal. located in the outer upper quadrant about 2 in. below
`the iliec crest. Upper right: deltoid located about 2 in. below the aorornion
`process. Lower left: ventrogluteal. located in the triangle formed by one
`finger on the anterior superior 'iliac spine and the other on the flisc crest.
`Lower right: vastus lateralls. located along the middle third and lateral as-
`pect of the thigh. ‘The "bull's-eye" indicates the approxjnaate site of injection.
`
`Intravenous (1.v.) administration of drugs. fluids, and for
`Indications.
`electrolytes is one of the most common parenteral routes employed in hospitals
`today.
`It is especially convenient for rapidly infusing large volumes of fluid.
`The most common indication for use of this route are:
`(1) to guarantee de-
`livery and distribution when hypotension or snack exists; (2) to restore rapid-
`ly electrolyte and fluid balance: (3) to achieve an immediate phermecologic
`effect, especially in emergencies , -such as the treatment of certain arrythmias
`or of seizures; (4) to treat serious, life-threatening infections or conditions;
`(5) to. provide continuous nutrition (hyperafimentation) when patients are
`unable to be fed by mouth; and (B) to avoid complications which might result
`if other administration routes were employed (e.g. , hemetomas at the site of
`intramuscular injections in a patient with a bleeding diathesis).
`In addition.
`the intravenous route may be used for a variety of other purposes, such as
`plesmapheresis. blood transfusion, and hemodynamic monitoring. to name a few.
`
`Astraleneca Ex. 2107 p. 14
`
`

`
`24
`
`Damn et cl.
`
`Precautions. A large number and variety of complications may occur us-
`ing the intravenous route. A few of these are:
`(1) thrombosis with or with-
`out complicating irlfection at the site of injection or infusion; (2) injection. of
`microorganisms, toxins, particulate matter, or air; (3) the occurrence of phys-
`ical or chemical incompatibilities between agents prior to or at the ‘lzime of in-
`jection“; (4) uncontrolled or excessive administration of drugs or fluids; and
`(5) extravasation of injections. or infusions at the site of administration. When
`indwelling catheters are utilized, rarely the catheter tip may break off and
`lodge in a major vessel, in the heart. or in the lung-.
`
`Method. The upper extremities are chosen whenever possible for the
`site of injection or infusion. As many venous sites as possible should be pre-
`served for future use: thus the most peripheral veins (e.g'. , those over the
`hand) are selected for initial use. When arm sites are no longer available.
`the leg veins (femoral and saphenous) or dorsal foot veins may be utilized;
`and in small children the scalp veins.
`Selection of a vein depends on the size of the needle or catheter intended
`for use-. type of fluids to be infused. flow rate anticipated, volume to be re-
`ceived, concomitant medications to be given, degree of patient mobility de-
`sired, and of course the skill of the person performing the venipuncture or
`catheterization. The veins in the ante-cubital fossa are among the most com-
`monly chosen. because they are large and readily punctured. other veins
`utilized commonly are oasllic. cephalic. radial at the wrist, and the metacarpal
`and dorsal venous plexuses.
`Although the risk of infection appears to be less with needles than with
`indwelling intravenous catheters [6]. an 8-111. long intravenous, plastic cathe-
`ter is commonly used for delivery of fluids via peripheral Veins. Such cathe—
`tors reduce the risk of infiltration considerably. thus providing more comfort
`to the patient. reducing time and labor costs of nursing in managing the in-
`fusion , rendering pharmaooldnetic predictions more reliable, and -avoiding
`If
`adverse side effects, such as cellulitis and occasionally tissue slouglning.
`peripheral insertion sites become exhausted, surgical cut-downs of deep ‘trains
`with implantation of indwelling catheters may be performed. When long-term,
`repeated, or prolonged usage is anticipated, the subclavlan or internal jugu-
`lar (central) veins in the upper chest may be utilised. These veins are es-
`pecially useful if hyper-osmolar fluids are to be infused, as physicochemioal
`irritation and venospasm produced by the lryperosmolarity or chemical formu-
`lation of the fluids may be reduced or negated.
`In -such instances, silaetic
`tunnelled, implanted, central venous access catheters ('e.g. . Broviac, I-Iic‘k~
`man, Groshong. Port-A-Oath} tailored to each patient so that the tip of the
`catheter rests just above the right atrium, are often utilised. These devices
`are designed so that they can remain in place and be maintained indefinitely
`for the life of the patient.
`If needles are to be used for intravenous infusion, a 1- to 2-in. long,
`beveled. 18 to 22 gauge (Table 1), stainless steel needle is commonly used.
`Whether using a catheter or needle, the device is inserted percutaneously
`into the vein only after thoroughly cleaning the skin.-insertion site and pre-
`paring it aseptically. Since infections appear to be more commonly associated
`with indwelling intravenous catheters than with needles, more time and care
`needs to be given to skin preparation with catheter use than with needle in-
`sertion. Such aseptic practices -are especially important when “long-term"
`
`Astralencca Ex. 2107 p. 15
`
`

`
`Parenteral Drug Adminis trct-ion
`
`Table 1 Needle Selection
`
`25
`
`Injection site
`
`Length range (in.)
`
`Gauge range
`
`Intrs—abdominal
`
`Intro.-articular
`
`Intrscardiac
`
`Intradermal
`
`Intraocu1s.r-
`Anterior chamber
`Intravitreal
`Retrobulhsr
`
`subeonjunctial
`
`Intrapleursl
`
`Intrathecal
`Adult
`Pediatric
`Neonatal
`
`Intravenous
`Metal needle
`
`Winged needle
`Plastic needle
`Intracatheter
`
`In—1ying'- catheter
`silestio catheter
`
`Hy-podermoclysis
`Adult
`Pediatric
`
`Subcutaneous
`
`4-6
`
`1-3
`
`4-5
`
`134-5.58
`
`3—5
`
`1-1}
`112-1
`
`1-2
`
`3!4—1l
`3&5
`
`s~111
`12,.26
`13-33
`
`2
`
`1-1:}
`
`1:"4-518
`
`14-18
`
`19-22
`
`1B—21
`
`24-26
`
`'25
`25
`25
`25
`
`13-18
`
`‘-10- 22
`25
`37
`
`15-25
`16- 23
`15-21
`15-21
`
`14, 15
`12-19
`
`19
`20-22
`
`24-25
`
`Eilsstic catheters inserted into the subelavian vein or vena cava. are utilised
`(‘wide supra). The mechanics of insertion usualljr involve a tourniquet being
`applied proximal to the site of insertion in order to congest the vein (thus,
`expanding the vein), so that the device may be easily inserted.
`If a. cstheter
`Afterwards .
`is used. it is inserted over a needle used for the initial puncture.
`the needle is removed, and the catheter is left in place.
`The indwelling aesthe-
`ter or needle, whichever is utilised, is anchored to the extremity or body
`by means of appropriate, sterile occlusive or nonooclusive dressings, often
`impregnated with antibiotic ointments to reduce the risk of a. complicating in-
`fection.
`Indwelling catheters often contain heparin locks to ensure against
`clotting and loss of potency from venous thrombosis.
`
`Subcu tcneous
`
`Injection into the loose connective and adipose tissue beneath
`Description.
`the skin (dermis).
`
`Astraleneca Ex. 2107 p. 16
`
`

`
`26
`
`Damn et cl.
`
`Indications. This route may be utilized if drugs cannot be administered
`orally because of lack of absorption from or inactivation. by the contents of
`the gastrointestinal tract, if the patient is unable to ingest medications by
`mouth or if self-medication of parenterals (e.g. , insulin) is desired. Dru