Parenteral Medications
`"OIIIIIIB 1
`Second Edition, Revised and Expanded
`
`Edited by Kenneth E. Avis,
`Herbert A. liebermnn, and lean lnchmun
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`AstraZeneca Exhibit 2107 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017—00900
`
`

`

`Parenteral Medications
`ttolumet
`Serond Edition, Revised and Expanded
`
`Edited by
`
`Kenneth E. Avis
`
`The University of Tennessee
`Memphis, Tennessee
`
`Herbert A. liebermnn
`
`H.H. Lieberman Associates, inc.
`Consultant Services
`
`Livingston, New Jersey
`
`leon larhmun
`
`Lachman Consultant Services
`
`Wesrbunt, New York
`
`Marcel Dekker, Inc.
`
`New York I Basel - Hong Kong
`
`AstraZeneca Exhibit 2107 p. 2
`
`

`

`Library of Congress Cataioging - “1— Publication Data
`
`Pharmaceutical dosage forms, parenteral medications I edited by
`Kenneth E. Avis, Herbert A. Lieberman, and Leon Laohman. -- 2nd ed. .
`rev. and expanded.
`p.
`cm.
`
`Includes bibliographical references and index.
`ISBN 0-3243—8576-2 (v. 1 : elk. paper)
`1. Parenteral solutions.
`2. Pharmaceutical technology.
`Kenneth E.
`II. Lieberman, Herbert A.
`III. Laohman. Leon.
`[DNLM: 1. Infusions. Parenteral.
`WB 354 P536]
`RSZDI.P3TP48 1992
`615'. 19--dc20
`DNLMIDLC
`
`2. Technology, Pharmaceutical.
`
`I. Avis,
`
`for Library of Congress
`
`91 -38063
`CIP
`
`This book is printed on acid—free paper.
`
`Copyright © 1992 by MARCEL DEKKER, INC. All Rights Reamer!
`
`Neither this book nor 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.
`
`MARCEL DEKJCER, INC.
`270 Madison Avenue, New York, New York 10016
`
`Current printing (last_ digit):
`10 9 S 7 6 5 4 3 2 ]
`
`PRINTED IN TEE UNITED STATES OF AMERICA
`
`AstraZeneca Exhibit 2107 p. 3
`
`

`

`Contents
`
`Preface
`Contributors
`
`Contents of Pharmaceutical Dosage Forms: Parenteral Medications,
`Second Edition, Revised and Expanded, Volumes 2 and 3
`Contents of Pharmaceutical Dosage Forms: Tablets, Second Edition.
`Revised and Expanded, Volumes 1-3
`Contents of Pharmaceutical Dosage Forms: Dispense Systems,
`Volumes 1 and 2
`
`E.E:-
`
`xiii
`
`xv
`
`xvii
`
`Chapter 1 The Parenteral Dosage Form and Its Historical Development
`
`1
`
`Kenneth E. Arts
`
`1. The Dosage Farm
`11.. History of Parenteral Medications
`Appendix A: Glossary of Terms
`Appendix 3': Highlights in the History of
`Parenteral Medications
`References
`
`Chapter 2
`
`Parenteral Drug Administration: Routes. Precautions,
`Problems, Complications, and Drug Bel-Wary Systems
`
`Richard J. Dame. Michael J. Alters. and
`Salvatore J. Tums
`
`Introduction
`I. General Indications for Parenteral
`
`Administration of Drugs
`ll. Pharmaceutical Factors Affecting Parenteral
`Administration
`
`Specific Routes of Administration
`III.
`IV . Distribution of Parenterally Administered Agents
`
`1
`4
`12
`
`19
`15
`
`1'?
`
`1’?
`
`18
`
`19
`
`21
`39
`
`vii
`
`AstraZeneca Exhibit 2107 p. 4
`
`

`

`viii
`
`Contents
`
`V'. Precautions. Problems. Hazards, and
`Complication Associated with Parenteral Drug
`Administration
`
`VI. Methods and Devices for Drug Delivery Systems
`VII.
`Summary
`References
`
`_
`
`Chapter 3 Biopharmaceutics of Injectable Medications
`
`So! Motola
`
`I.
`
`Introduction
`
`II. Physioochemical and Physiological Factors
`Affecting Drug Absorption by Injection: An
`Overview
`
`111. Application of Pharmacokinetics to Biopharmr
`centic Investigations: Pharmacokinetic Models
`"IV. Examples of BiopharmaeeuticlPharmaeokmetio
`Principles
`V. Regulatory Considerations for Bioequivalence
`Studies
`
`VI. Bioequivolence Study of Two Injeotable Forms
`of the Same Drug
`Summary
`References.
`
`VII.
`
`Chapter 4
`
`Preformulation Research of Parenteral Medications
`
`So! Morale and Shreamm N. Aghorkor
`
`I .
`
`Introduction
`
`II. Drug Substance Physieochemical Properties
`III. Accelerated Stability Evaluation
`IV. General Modes of Drug Degradation
`V. Preformulatlon Studies for Proteins and Peptides
`VI.
`Preformulation Screening of Parenteral
`Packaging Components
`Summary
`VII.
`VIII. Preformulation Worksheet
`
`References
`
`Chapter 5
`
`Formulation of Small Volume Parenterals
`
`Patrick P. DeLuca and James C. Boylon
`
`I .
`
`Introduction
`
`Formulation Principles
`II.
`III. Container Effect-e. on Formulation
`1V. Stability Evaluation
`V.
`Process Effects
`References
`
`41
`
`49
`56
`5'?
`
`59
`
`59
`
`60
`
`7'?
`
`9%
`
`108
`
`109
`111
`112
`
`115
`
`115
`
`115
`140
`150
`154
`
`158
`183
`163
`
`169
`
`1'?3
`
`17 3
`
`174
`22?"
`234
`244
`245
`
`AstraZencca Exhibit 2107 p. 5
`
`

`

`Contents
`
`ix
`
`Chapter 6
`
`Formulation of Large Volume Parenterals
`
`Levit J. Demorest and Jeffrey G. Hamilton
`
`I.
`II.
`III.
`IV.
`V.
`
`Introduction ‘
`
`Concepts of Formulation
`Formulation Development
`Sqution Quality
`Summary
`References
`
`Chapter 7
`
`Parenteral Products of Peptides and Proteins
`
`YuHChong 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
`
`II.
`III.
`IV.
`
`VI.
`VII.
`
`Diagnostic Products Defined
`Sterile Diagnostics
`Definitions
`
`Aseptic Manufacturing Considerations
`Validation Program
`Conclusion
`References
`
`Chapter 9
`
`Glass Containers for Parenterals
`
`R. Poul 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
`
`249
`
`249
`250
`273
`280
`281
`281
`
`283
`
`283
`284
`302
`
`310
`312
`317
`
`321
`
`323.
`321
`322
`325
`330
`351
`359
`359
`
`351
`
`381
`381
`
`362
`369
`375
`380
`380
`382
`384
`
`AstraZeneca Exhibit 2107 p. 6
`
`

`

`a:
`
`Contents
`
`Chapter 10 Use of Plastics for Parenteral Packaging
`
`John M. Anes. Robert S. Nose, and
`Charles H. White
`
`I.
`II.
`III.
`IV.
`V.
`VI.
`
`Introduction
`Fundamentals
`Fabrication Processes
`
`Important Criteria for Selection of Plastics
`Plastics Used in Parenteral Packaging
`Quality Assurance of Parenteral Containers
`References
`
`Chapter 11 Elastomeric Closures for Parenterals
`
`Edward J. Smith and Robert J. Nash
`
`II
`
`II.
`III.
`IV.
`V.
`VI .
`VII.
`VIII.
`IX .
`
`XI.
`
`Elaetomeric Parenteral Packaging Components:
`A Physical Description
`Physical Description of Rubber
`Types of Rubber Used in Parenteral Packaging
`Closure Design
`Rubber Compdunding
`Vulcanization Process
`Closure Manufacture and Control
`
`Closure Design Qualification
`Regulatory Considerations
`Interaction of Drug Formnlations with
`Rubber Closures
`
`Contemporary Closure-Related Issues
`References
`
`Chapter 12 Parenteral Products in Hospital and Home Care
`Pharmacy Practice
`
`John W. Levchuk
`
`1.
`II.
`
`III.
`IV.
`
`V.
`VI.
`VII.
`
`Introduction
`
`The Preparation of Sterile Dosage Forms in the
`Hospital and in Home Care
`Dispensing and Compounding Processes
`Technology of Sterile Compounding in the
`Hospital Pharmacy
`Clinical Supply and Use of Sterile Products
`Quality Assurance
`Conclusion
`
`Appendix: Abbreviated Sequence for Preparing a
`Series of Extemporaneously Compounded LV.
`Admixtures
`References
`
`Index
`
`387
`
`387
`. 389
`398
`407
`422
`439
`443
`
`445
`
`445
`450
`451
`462
`463
`470
`477
`494
`503
`
`505
`50'?
`503
`
`513
`
`513
`
`513
`524
`
`532
`547
`552
`562
`
`56 3
`566
`
`569
`
`AstraZencoa Exhibit 2107 p. 7
`
`

`

`2 P
`
`arenteral Drug Administration: Routes,
`Precautions, Problems, Complications,
`and Drug Delivery Systems
`
`.
`
`Richard J. Burns
`
`Medical College of Virginia. "Virginia Commonwealth University, Richnond,
`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;r into body tissues. Although drugs ap-
`plied topically to the eye, ear, and skin, or even inhaled, may be broadly
`interpreted as parenterals, medical and pharmaceutical health care deliveries
`generally limit the definition to those drugs injected or infused directly into
`tissues, tissue spaces, vessels, or hody 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 (e. g. .
`intravenous), to manage patients at home and in the work place. Most pa-
`tients readily accept or easily adapt to almost every form of parenteral ther-
`apy. and many self-administer their own drugs, even when the route of ties
`livery is intraVenous (e.g., home infusion. programs).
`Parenteral administration offers many advantages over therapy given by
`nonparenteral routes. Most notably , therapeutlsts can reliably predict with
`considerable accuracy the pharmaeokineties. 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 "fine tune," stratify and quantitate results.
`However. despite these advantages. parenteral administration is not without
`
`17
`
`AstraZeneca Exhibit 2107 p. 8
`
`

`

`18
`
`Damn at cl.
`
`certain. measurable risks 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 indicated 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. Brainple: Direct intraventricular injection
`of drugs (eng. , antibiotics such as the aminoglycosides) which cross
`the "blood—brain—meninges barrier" poorly may be used in certain
`patients with bacterial or fungal meningitis and/or 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 cardiolntraventricular
`routes may be desirable to achieve immediate effects in emergencies
`such as might occur in the control of life-threatening hypotension,
`hypertension, or arrhythmias; or intramuscular routes may be desir-
`able to obtain protracted or sustained effects, such as the use of
`beneathine 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 self-medicate. Example: The use of long~
`acting: (monthly) intramuscular penicillina may be used to manage
`children prophylactically for rheumatic heart disease in order to pre—
`vent Group A streptococcal pharyngitis.
`4. To deliver a biologic effeo’t that cannot be achieVed through oral ad-
`ministration, perhaps because of nonahsorbanCE from the alimentary
`canal or degradation by gastric acidity. Example: Therapeutic pep-
`tides and proteins such as insulin, human growth hormone. other
`products from recombinant DNA technology, and polyene antibiotics
`(such as the antifungal agent .amphotericin B).
`5. To administer a drug when the desired route (a. g. , oral) may not be
`available. Example:
`In patients who are aspirating or who have had
`the upper gastrointestinal tract stream diverted or remOVed (e.g. ,
`because of a carcinoma) a parenteral route may be necessary.
`6. To provide a local effect when it is desirable to minimize or avoid sys—
`temic toads effects or reactions. Example: Methotrexate may be given
`intrathecally 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.
`
`AstraZencca Exhibit 2107 p. 9
`
`

`

`Parenteral Drug Administration
`
`'
`
`19
`
`'2. 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 if 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 paran-
`teral routes.
`
`8. To permit rapid correction of fluid and electrolyte imbalances and to
`supply short— or long-term nutritional needs (hyperalimentation or
`parenteral feeding). Example: Patients suffering severe dehydration
`or electrolyte depletion for a variety of reasons (eug. , 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. Emma: 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.
`
`H. PHARMACEUTICAL FACTORS AFFECTING
`PAR‘ENTERAL ADMINISTRATION
`
`Certain pharmaceutical characteristics dictate the method or route of paren-
`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 biopharmaoeutical factors affecting paren—
`teral drug availability.
`
`A. Solubility of the Drug and Volume of the Injection
`
`A drug must be completely colubflized, prefers.ny 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 (sag. . intradermal, intramuscular, intrsocular. intraventricular,
`and intrathecai, to name a few) .
`
`B. Vehicle Characteristics
`
`Drugs in aqueous vehicles may be administered by any parenteral route,
`whereas drugs in nonaqucous vehicles. which may or may not be water mis-
`cible, are administered most frequently by th intramuscular route. The in-
`travenous route may he used for a few drugs in mixed solvent systems to. g. ,
`diazepam, digoxin, and p'henytoin) , but precautions must be applied in adjust-
`ing the rate of drug infusion to avoid drug precipitation at the site of infusion.
`
`Asnachcca Exhibit 2107 p. 10
`
`

`

`20
`
`Sumo at at
`
`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 smoll~geuge needle and the rote of ab-
`sorption from the injection site.
`
`C.
`
`pH and Osmolality of lnjectable Solutions
`
`Ideally, administered injections should be formulated at a pH and osmolality
`similar to that of biological fluids. Unfortunately , this is not possible for
`many parenteral dosage forms, as many parenteral drugs are unstable at new
`trsl pH. Therefore, such drugs are formulated at the pH at which they are
`most stable. For example, diszoxide (s nondiuretic benzothiadiezine deriva-
`tive) is formulated at e pH of 11.6, the pH at which it is most stable, Many
`parenteral drugs are salt forms of weak bases. Thus the pH of a dosage form
`Containing the salt of a weak base may he as low as 2.0 (mg. , tetracycline
`hydrochloride), or the pH of a dosage form containing the salt of a weak acid
`may he as high as 12.0 (9.33;. , Dilontin) 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 pain and irritation to the patient and damage to the
`surrounding tissues.
`Certain parenteral formulations are hyperosmotic with biological fluids
`and contain a relatively high dose of active ingredienfis) in order to achieve
`a desired level of biological activity. For example, water—soluble contrast
`media, spinal anesthetics, Ophthalmic sodium sulfncetamidc, diazoxide, and
`
`osmotic diuretics are a few hypertonic parenteral formulations contsining high
`drug concentrations to achieve on appropriate biological action(s). Froducts
`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 hyperslimentstion solutions,
`are so hypertonic that they must be administered via a large vein such as the
`subclavian. 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 prevent dosage forms
`from being formulated at physiolOgicol pH, they should be formulated with
`solute contents approximately equal to those of biological fluids.
`
`D. Type of Dosage Form
`
`Parenteral dosage forms include solutions, suspensions, and sterile solids
`for reconstitution.
`If the dosage form is a suspension, it may be administered
`only by the intramuscular or subcutaneous 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 sensi»
`tive tissue (mg. , brain or eye). Roconstituted solids should be completely
`dissolved in the reconstituting diluent before they are administered intrsvenw
`ously.
`
`AstraZeneca Exhibit 2107 p. 11
`
`

`

`Parenteral Drug Administration
`
`21
`
`E. Formulation Ingredients
`
`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 multidose 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 they may produce. Several paren-
`teral formulations contain surface- active agents (such as polysorbste 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 soldering the
`desired duration of drug action. These additives are primarily high-molecular-
`weight polymers or oily solvents. Formulations containing theso 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 0F 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 parenterals:
`(1) for therapy (definitive or palliative) , (2) for prevention, (3) for diagnosis.
`and (4] for temporarily altering tissue iunctionts) in order to facilitate other
`forms of therapy. Besides these three primary routes, additional ones are
`utilised 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 delivery.
`
`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 pmlonged 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—
`ly into the vascular compartment.
`Many factors affect the rate of drug absorption from an intramuscular
`injection [2]; they will be discussed later in this chapter. Drugs commonly
`
`AstraZoneca Exhibit 2107 p. 12
`
`

`

`22
`
`Bums et at.
`
`injected by intramuscular administration include liooceine, cephslosporins,
`eminoglycosides. diezepam, insoluble salts of penicillin G (procsne penicillin
`G) , corticosteroids, narcotics, narcotic antagonists, and contraceptive steroids,
`to name a few.
`
`Precautions. Although intramuscular injections are much easier to ad—
`minister then other injections, the main precaution is to avoid entering e blood
`vessel (especially an artery) , which might lead to infusion of a toxic agent
`or e. toxic vehicle directly to an organ or tissue. This can be prevented usu-
`ally by pulling back 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 s peripheral nerve may result in a peripheral nerve palsy with
`or without sensory damage. Occasionally, when s large bolus of drug is in»
`jected into the muscle, local damage or muscle infarction may result, leading
`to e sterile abscess or to elevation of serum levels of muscle enzymes. The
`latter complication may present confusing diagnostic prehlems, 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 ensure ster-
`ility prior to injection.
`In patients with poor hygiene or skin care, microorga-
`nisms from the skin flora may he punched in by the needle at the time of in“
`jection, resulting in staphylococcal 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 may he expectsntly 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) , include
`ing the glutesl, deltoid, triceps, pectoral, and vestus laterelis muscles.
`In
`adults the site of choice often is the gluteel muscle, because large volumes
`of drug may be injected and tolerated. However, the vestus leterelis of the
`thigh may also be used because it not only tolerates large volumes of medics-
`tion, but it is also away from any major vessels or nerves. For rapid absorp~
`tion and small volumes (<2 ml) , the deltoid muscle is Freierred, as some stud-
`ies suggest that blood flow in the deltcitl muscle is 7% greater than that of
`the vsstus lsterelis and 17% greater than that of the gluteus maximize [5] .
`For this reason, in adults the cleltoicl is the preferred site for vaccine sdmirr
`istretion.
`In infants and small children, the vastus lsterslis of the thigh is
`often preferred because it is better dvloped than other muscle groups. de~
`pending on the site selected. The skin is first cleaned with alcohol or e suit~
`sle disinfectant, end the plunger on the syringe is always retracted prior
`to injeciton to he sure that the needle is not in a vessel. For deep intramus~
`culsr injections, as might be used for irritating medications such as iron prep-
`arations, e "miracle" injection method is employed.
`
`Intravenous
`
`Description.
`
`Injections or infusions directly into a vein.
`
`AstraZeneca Exhibit 2107 p. 13
`
`

`

`Paren re re! Drug Administration.
`
`23
`
`
`
`Figure. 1 Some common sites employed for intramuscular injections. Upper
`left: posterior gluteal. located in the outer upper quadrant about 2 in. below
`the iliac crest. Upper right: deltoid located about 2 in. below the acromion
`process. Lower left: ventrogluteal, located in. the trianng formed by one
`finger on the anterior superior iliac spine and the other on the iliac crest.
`Lower right: vastus lateralis, located along the middle third and lateral as—
`pect of the thigh.
`"bull's—eye" indicates the approximate site of injection.
`
`Intravenous finer.) administratlcm of drugs, fluids. audio:-
`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 shock exists; (2) to restore rapid-
`ly electrolyte and fluid balance; (3) to achieve an imrnediate pharmacologic
`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 (hyperalimentation) when patients are
`unable to be fed by mouth; and (6) to avoid complications which might result
`if other administration routes were employed (e.g'. , hematomas 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
`Plasmaphercsis, blood transfusion. and hemodynamic monitoring, to name a few.
`
`AstraZoneca Exhibit 2107 p. 14
`
`

`

`24
`
`Damn at al.
`
`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 infection 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 time of in-
`jection; (4) unsontrolled 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 men};r venous sites as possible should be pre-
`served for future use; thus the most peripheral veins (mg. , those over the.
`hand) are selected for initial use. When arm sites are no longer available,
`the leg veins (femoral and saphenoue} 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 venipuneture or
`catheterization. The veins in the snte-oubltsl fossa are among the most com—
`monly chosen, because they are large and readily punctured. Other veins
`utilized commonly are basilic, cephalic, radial at the wrist, and the metacarpal
`and dorsal venone plexuses.
`Although the risk of infection appears to be less with needles than with
`indwelling intravenous catheters [E] , an a-in. long intravenous, plastic cathe-
`ter is commonly need for delivery of fluids via peripheral value.
`such cathe-
`ters 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, renderlng pharmaookinetic predictions more reliable, and avoiding
`If
`adVerse side effects. such as cellulitis and occasionally tissue sloughing.
`peripheral insertion sites become exhausted, surgical cut-downs of deep veins
`with implantation of indwelling catheters may be performed. When long-term,
`repeated, or prolonged usage is anticipated, the subolavian or internal jugu~
`lar (central) veins in the upper chest may be utilized. These veins are es-
`pecially useful if hyperosmolar fluids are to be infused, as physioochemioel
`irritation and. venospasm produced by the hyperosmolsrity or chemical formu-
`lation of the fluids may be reduced or negated.
`In such instances, silastic
`tunnelled, implanted, central venous access catheters (mg. , Broviac, Hick-
`man, Gros‘hong, Port-A-Cat‘h) tailored to each patient so that the tip of the
`catheter rests just above the right atrium, are often utilized. 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 l) , 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 narcotic-us appear to be more commonly associated
`with indwolling 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"
`
`AstraZeneca Exhibit 2107 p. 15
`
`

`

`Parenteral Drug Administration
`
`Table 1 Needle Selection
`
`25
`
`Injection site
`
`Length range (in . }
`
`Gauge range
`
`Intro-sh dominal
`
`Intro: articular
`
`Intraca'rdiec
`
`Intradermsl
`
`Intrsoculer
`Anterior chamber
`Intravitreal
`Retrobulb or
`
`Subconjunetial
`
`Intra'pleural
`
`Int-rathecsl
`Adult
`Pediatric
`Neonatal
`
`Intravenous
`Metal needle
`
`Winged needle
`Plastic needle
`Intrscatheter
`
`III-lying catheter
`Silastic catheter
`
`Hypodermoclysis
`Adult
`Pediatric
`
`Subcutaneous
`
`é—S
`
`l-3
`
`4-6
`
`It'll-538
`
`1-3
`1-3
`
`15
`1%
`
`5-8
`
`3—5
`1-1}
`122-1
`
`1-2
`Mil-Ii
`
`8- 1111
`12. 26
`13-23
`
`2
`
`1-H
`
`Nil-5M
`
`1448
`
`19* 22
`
`18~ 21
`
`24- 26
`
`25
`25
`35
`
`25
`
`13-18
`
`20- 22
`25
`27
`
`15- 25
`1.3- 23
`15- 21
`15- 21
`
`14.. 15
`12-19
`
`19
`20-22
`
`24- 25
`
`silastic catheters inserted into the snbclavian vein or vena cava are utilized
`
`Wide. supra) . The mechanics of insertion usually involve a tourniquet being
`applied proximal to the site of insertion in order to oongest the vein. (thus ,.
`If a catheter
`expending the vein) , so that the device may be easily inserted.
`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 cathe—
`ter or needle. whichever is utilized, is anchored to the extremity or body
`by means of appropriate, sterile occlusive or nonocclusive dressings, often
`impregnated with antibiotic ointments to reduce the risk of a complicating in-
`fection. 1ndwe11ing catheters often contain heparin locks to ensure against
`clotting. and loss of potency from venous thrombosis.
`
`Subcutaneous
`
`Description.
`the skin (dermis).
`
`Injection into the loose connective and adipose tissue beneath
`
`Assacheca Exhibit 2107 p. 16
`
`

`

`28
`
`Dumc et at.
`
`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, it the patient is unable to ingest medications by
`mouth or if self-m