DRUGS AND THE PH~ARMAc£uncAI. SCIENCES
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`VGLUME 12
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`CONTENTS
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`BLOOD
`cIIncuLAT:I_oN
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`MEMBREHE
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`editedI by
`1‘ Gilbert IS. Banker
`Christopher T. Rhodes
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`2}:
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`MYLAN PHARMS. INC. EXHIBIT 1037 PAGE 1
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`edited by
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`Gilbert 8. Banker
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`Iowa City, Iowa
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`ChristopherT. Rhodes
`University of Rhoda Isfand
`Kingston, Rhoda Isfand
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`MYLAN PHARMS. INC. EXHIBIT 1037 PAGE 2
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`

`
`Library nf Cnngrtsss Cataloging-in-Publication Data
`
`h4Vt}dL.”] p|1:trm::-::::1Ilics r‘ edited by Gilbert S. Banktzr. Christuphur T.
`Rhc:dc5.—3rd cd..
`I::\-'. and cxpartdcd.
`p.
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`lltclttdcs hibliugraphical rcfcrcnccts and indcx.
`ISBN Il—H2-17-9371-4 (alk. paper]
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`III. Sc.-riu.~..
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`In Special Sale5.-’I‘rut‘c5;sinn;t] Marketing, at the ttdtircss below.
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`Thizt hunk is printcc! mt uc1'd—fr::-.2 paper.
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`l‘J‘)t'i by Marcel Dckkcr. Inc. All Rights Rc:4«.-m.:tl.
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`PRINTED IN THE UNITED STATES OF AMERICA
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`MYLAN PHARMS. INC. EXHIBIT 1037 PAGE 3
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`

`
`I2
`
`
`Porenterol Products
`
`James C. Boylan
`Abbott Laboratories, Abbott Park, Illinois
`
`Alan L. Flies
`Fires Consulting, Greenwood, Indiana
`
`Steven L. Nail
`Purdue University, West Lafayette, Indiana
`
`I.
`INTRODUCTION
`The first official injection (morphine) appeared in the British Pharmacopoeia (BP) of 1867. It
`was not until 1898 when cocaine was added to the BP that sterilization was attempted. In this
`country, the first official injections may be found in the National Formulary (NF), published
`in 1926. Monographs were included for seven sterile glass-sealed ampoules. The United States
`Pharmacopeia (USP) published in the same year contained a chapter on sterilization, but no
`monographs for ampoules. The current USP contains monographs for over 400 injectable prod-
`ucts [1].
`Parenteral administration of drugs by intravenous (IV), intramuscular (IM), or subcutaneous
`(SC) routes is now an established and essential part of medical practice. Advantages for par-
`enterally administered drugs include the following: rapid onset; predictable effect; predictable
`and nearly complete bioavailability; and avoidance of the gastrointestinal tract (GIT), and
`hence, the problems of variable absorption, drug inactivation, and GI distress. In addition, the
`parenteral route provides reliable drug administration in very ill or comatose patients.
`The pharmaceutical industry directs considerable effort toward maximizing the usefulness
`and reliability of oral dosage forms in an effort to minimize the need for parenteral adminis-
`tration. Factors that contribute to this include certain disadvantages of the parenteral route,
`including the frequent pain and discomfort of injections, with all the psychological fears as-
`sociated with “the needle," plus the realization that an incorrect drug or dose is often harder
`or impossible to counteract when it has been given parenterally (particularly intravenously),
`rather than orally.
`In recent years, parenteral dosage forms, especially IV forms, have gained immensely in
`use. The reasons for this growth are many and varied, but they can be summed up as (a) new
`and better parenteral administration techniques; (b) new forms of nutritional therapy, such as
`intravenous lipids, amino acids, and trace metals; (c) the need for simultaneous administration
`of multiple drugs in hospitalized patients receiving IV therapy, (d) the extension of parenteral
`
`441
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`MYLAN PHARMS. INC. EXHIBIT 1037 PAGE 4
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`

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`442
`
`Boylon et al.
`
`therapy into the home; and (e) an increasing number of drugs that can be administered only
`by a parenteral route.
`Many important drugs are available only as parenteral dosage forms. Notable among these
`are biotechnology drugs; insulin; several cephalosporin antibiotic products; and drugs such as
`heparin, protamine, and glucagon. In addition, other drugs, such as lidocaine hydrochloride
`and many anticancer products, are used principally as parenterals. The reasons that certain
`drugs are administered largely or exclusively by the parenteral route are very inefficient or
`unreliable absorption from the GIT, destruction or inactivation in the GIT, extensive mucosal
`or first-pass metabolism following oral administration, or clinical need in particular medical
`situations for rapid, assured high blood and tissue levels.
`Along with this astounding growth in the use of parenteral medications, the hospital phar-
`macist has become a very knowledgeable, key individual in most hospitals, having responsi-
`bility for hospital-wide IV admixture programs, parenteral unit-dose packaging, and often cen-
`tral surgical supply. By choice, by expertise, and by responsibility,
`the pharmacist has
`accumulated the greatest fund of information about parenteral drugs—not only their clinical
`use, but also their stability, incompatibilities, methods of handling and admixture, and proper
`packaging. More and more, nurses and physicians are looking to the pharmacist for guidance
`on parenteral products.
`To support the institutional pharmacist in preparing IV admixtures (which typically involves
`adding one or more drugs to large-volume parenteral fluids), equipment manufacturers have
`designed laminar flow units, electromechanical compounding units, transfer devices, and filters
`specifically adaptable to a variety of hospital programs.
`The nurse and physician have certainly not been forgotten either. A wide spectrum of IV
`and IM administration devices and aids have been made available in recent years for bedside
`use. Many innovative practitioners have made suggestions to industry that have resulted in
`product or technique improvements, particularly in IV therapy. The use of parenteral products
`is growing at a very significant rate in nonhospital settings, such as outpatient surgical centers
`and homes. The reduction in costs associated with outpatient and home care therapy, coupled
`with advances in drugs, dosage forms, and delivery systems, has caused a major change in the
`administration of parenteral products [2].
`
`II. ROUTES OF PARENTERAL ADMINISTRATION
`
`The routes of parenteral administration of drugs are (a) subcutaneous, (b) intramuscular, and
`(c) intravenous; other more specialized routes are (d) intrathecal, (e) intracisternal, (f) intra-
`arterial, (g) intraspinal, (h) intraepidural, and (i) intradennal. The intraderrnal route is not
`typically used to achieve systemic drug effects. The similarities and differences of the routes
`or their definitions are highlighted in Table 1. The major routes will be discussed separately.
`
`A. The Subcutaneous Route
`
`Lying immediately under the skin is a layer of fat, the superficial fascia (see Fig. 1 in Chapter
`8), that lends itself to safe administration of a great variety of drugs, including vaccines, insulin,
`scopolamine, and epinephrine. Subcutaneous (SC; also S0 or sub-Q) injections are usually
`administered in volumes up to 2 ml using a '/z- to 1-in. 22-gauge (or smaller) needle. Care
`must be taken to ensure that the needle is not in a vein. This is done by lightly pulling back
`on the syringe plunger (aspiration) before making the injection. If the needle is inadvertently
`located in a vein, blood will appear in the syringe and the injection should not be made. The
`injection site may be massaged after injection to facilitate drug absorption. Drugs given by this
`
`MYLAN PHARMS. INC. EXHIBIT 1037 PAGE 5
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`

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`Purentercn Producfs
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`443
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`MYLAN PHARMS. INC. EXHIBIT 1037 PAGE 6
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`

`
`444
`
`Boylctn at al.
`
`route will have a slower onset of action than by the IM or IV routes, and total absorption may
`also be less.
`
`Sometimes dextrose or electrolyte solutions are given subcutaneously in amounts from 250
`to 1000 ml. This technique, called hypoderrnoclysis. is used when veins are unavailable or
`difficult to use for further medication. Irritation of the tissue is a danger with this technique.
`Administration of the enzyme hyaluronidase can help by increasing absorption and decreasing
`tissue distention. Irritating drugs and vasoconstrictors can lead to abscesses, necrosis, or in-
`flammation when given subcutaneously. Body sites suitable for SC administration include most
`portions of the arms and legs plus the abdomen. When daily or frequent administration is
`required, the injection site can and should be continuously changed or rotated, especially by
`diabetic patients self—administering insulin.
`
`B. The Intramuscular Route
`
`The IM route of administration is second only to the IV route in rapidity of onset of systemic
`action. Injections are made into the striated muscle fibers that lie beneath the subcutaneous
`layer. The principal sites of injection are the gluteal (buttocks), deltoid (upper arm), and vastus
`lateralis (lateral thigh) muscles. The usual volumes injected range from 1.0 to 3.0 ml, with
`volumes up to 10.0 ml sometimes being given (in divided doses) in the gluteal or thigh areas
`(see Table 1). Again, it is important to aspirate before injecting to ensure that the drug will
`not be administered intravenously. Needles used in administering IM injections range from 1
`to 1'}: in. and 19 to 22 gauge, the most common being 11/: in. and 22 gauge.
`The major clinical problem arising from [M injections is muscle or neural damage, the
`injury normally resulting from faulty technique, rather than the medication.
`Most injectable products can be given intramuscularly. As a result, there are numerous
`dosage forms available for this route of administration: solutions, oil—in-water (olw) or water-
`in-oil (wio) emulsions, suspensions (aqueous or oily base), colloidal suspensions, and recon-
`stitutable powders. Those product forms in which the drug is not fully dissolved generally
`result in slower, more gradual drug absorption, a slower onset of action, and sometimes longer-
`lasting drug effects.
`Intramuscularly administered products typically form a “depot” in the muscle mass from
`which the drug is slowly absorbed. The peak drug concentration is usually seen within 1-2
`hr. Factors affecting the drug—re|case rate from an IM depot include the compactness of the
`depot (the less compact and more diffuse, the faster the release), the rheology of the product
`(affects compactness), concentration and particle size of drug in the vehicle, nature of the
`solvent or vehicle, volume of the injection, tonicity of the product, and physical form of the
`product.
`
`C. The Intravenous Route
`
`Intravenous medication is injected directly into a vein either to obtain an extremely rapid and
`predictable response or to avoid irritation of other tissues. This route of administration also
`provides maximum availability and assurance in delivering the drug to the site of action.
`However, a major danger of this route of administration is that the rapidity of absorption makes
`antidoting very difficult, if not impossible, in most instances. Care must also be used to avoid
`too rapid a drug administration by the IV more because irritation or an excessive drug con-
`centration at the target organ (drug shock) can occur. The duration of drug activity is dependent
`on the initial dose and the distribution: metabolism, and excretion properties (pharmacokinetics)
`of the drug. For most drugs, the biological half-life is independent of the initial dose, because
`the elimination process is first-order. Thus, an intravenous drug with a short half-life would not
`
`MYLAN PHARMS. INC. EXHIBIT 1037 PAGE 7
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`

`
`Parenteral Products
`
`445
`
`provide a sustained blood level. The usual method of administration for drugs with short half-
`lives is to use continuous IV drip. Intravenous injec'tions (vein puncture) normally range from
`1 to 100 ml and are given with either a 20- or 22-gauge 11/2-in. needle, with an injection rate
`of 1 ml/10 sec for volumes up to 5 ml and I ml/20 sec for volumes over 5 ml. Only drugs in
`aqueous or hydroalcoholic solutions are to be given by the IV route.
`Large proximal veins, such as those located inside the forearm, are most commonly used
`for IV administration. Because of the rapid dilution in the circulating blood and the genera]
`insensitivity of the venous wall to pain, the IV route may be used to administer drugs that
`would be too irritating or caustic to give by other routes (e.g., nitrogen mustards), provided
`that proper dosing procedures are employed. The risk of thrombosis is increased when extrem-
`ity sites such as the wrist or ankle are used for injection sites, or when potentially irritating
`IV products are used, with the risk further increasing in patients with impaired circulation.
`The [V infusion of large volumes of fluids (100— 1000 ml) has become increasingly popular
`(Figs. 1 and 2). This technique, called venoclysis, utilizes products known as large-volume
`parenterals (LVPS). It is used to supply electrolytes and nutrients, to restore blood volume, to
`prevent tissue dehydration, and to dilute toxic materials already present in body fluids. Various
`parenteral drug solutions may often be conveniently added to the LVP products as they are
`being administered (Figs. 3 and 4), or before administration, to provide continuous and pro-
`longed drug therapy. Such drug additions to LVP has become very common in hospitals.
`Combining parenteral dosage forms for administration as a unit product is known as IV ad-
`mr'xrures. Pharmacists practicing such IV additive product preparation must be very knowl-
`edgeable to avoid physical and chemical incompatibilities in the modified LVP, creation of any
`therapeutic incompatibilities with other drugs being given parenterally or by any other route,
`or loss of sterility or addition of extraneous matter.
`Commonly administered large-volume parenterals include such products as sodium chloride
`injection [USP] (0.9% saline), which replenish fluids and electrolytes, and 5% dextrose injec-
`tion [USP], which provides fluid plus nutrition (calories) or various combinations of dextrose
`and saline. In addition, numerous other nutrient and ionic solutions are available for clinical
`use, the most popular of which are solutions of essential amino acids or lipid emulsions. These
`solutions are modified to be hypertonic, isotonic, or hypotonic to aid in maintaining both fluid,
`nutritional, and electrolyte balance in a particular patient according to need. Indwelling needles
`or catheters are required in LVP administration. Care must be taken to avoid local or systemic
`infections or thrombophlebitis owing to faulty injection or administration technique.
`
`D. other Parenteral Routes
`
`Other more specialized parenteral routes are listed and described briefly in Table 1. The intra-
`arterial route involves injecting a drug directly into an artery. This technique is not simple and
`may require a surgical procedure to reach the artery. It is important that the artery not be
`missed, since serious nerve damage can occur to the nerves lying close to arteries. Doses given
`by this route should be minimal and given gradually, since, once injected, the drug effect
`cannot be neutralized. As shown in Table 1, the intra-arterial route is used to administer ra-
`
`diopaque contrast media for viewing an organ, such as the heart or kidney, or to perfuse an
`antineoplastic agent at the highest possible concentration to the target organ.
`The intrathecal route is employed to administer a drug directly into the cerebrospinal fluid
`at any level of the cerebrospinal axis. This route is used when it is not possible to achieve
`sufficiently high plasma levels to accomplish adequate diffusion and penetration into the cere-
`brospinal fluid. This is not the same route used to achieve spinal anesthesia, for which the
`drug is injected within the dural membrane surrounding the spinal cord, or in extradural or
`
`MYLAN PHARMS. INC. EXHIBIT 1037 PAGE 8
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`

`
`Parenteral Products
`
`C. Vehicles
`
`Aqueous Vehicles
`
`457
`
`“Water for injection" (WFI) is the most widely used solvent for parenteral preparations. The
`requirements for WFI are generally the same throughout the world- Companies involved in
`intemational markets must be assured that their products comply with the applicable standards.
`The most common means of obtaining WFI is by the distillation of deionized water. Water
`for injection must be prepared and stored in a manner to ensure purity and freedom from
`pyrogens.
`
`Microorganisms, dissolved organic and inorganic substances, and foreign particles are the
`most common contaminants found in water. New purification methods and systems are con-
`tinually being investigated to improve the quality of water for parenteral use. Inorganic com-
`pounds are commonly removed by distillation, reverse osmosis, deionization, or a combination
`of these processes. Membrane and depth filters are used to remove particulate contaminants,
`and Charcoal beds may be used to remove organic materials. Filtration, chilling or heating, or
`recirculation of water are used to reduce microbial growth and to prevent pyrogen formation
`that will occur in a static deionization system. To inhibit microbial growth, WFI must be stored
`at either 5°C or 60—9D°C if it is to be held for over 24 hr.
`
`The USP also lists sterile water for injection and bacteriostatic water for injection, which
`unlike WFI, must be sterile. Higher levels of solids are allowed in these vehicles because of
`the possible leaching of glass constituents into the product during high-ternperatur-e sterilization
`and subsequent storage. Bacteriostatic water for injection must not be placed in containers
`larger than 30 ml. This is to prevent the administration of large quantities of bacteriostatic
`agents (such as phenol) that could become toxic if large volumes of solution were administered.
`Other aqueous vehicles that may be used in place of sterile water for injection or bacteriostatic
`water for injection for reconstitution or administering drugs include 5% dextrose, 0.9% sodium
`chloride, and a variety of other electrolyte and nutrient solutions, as noted earlier.
`
`Noncqueous and Mixed.‘ Vehicles
`
`A nonaqueous solvent or a mixed aqueous—nonaqueous solvent system may be necessary to
`stabilize drugs, such as the barbiturates, that are readily hydrolyzed by water, or to improve
`solubility (e.g., digotoxin). Nonaqueous solvents must be carefully screened and tested to en-
`sure that they exhibit no pharmacological action, are nontoxic and nonirritating, and are com-
`patible and stable with all ingredients of a formulation.
`A major class of nonaqueous solvents is the fixed oils. The USP [1] recognizes the use of
`fixed oils as parenteral vehicles and lists their requirements. The most commonly used oils are
`corn oil, cottonseed oil, peanut oil, and sesame oil. Because fixed oils can be quite irritating
`when injected and may cause sensitivity reactions in some patients, the oil used in the product
`must be stated on the label.
`
`Sesame oil is the preferred oil for most of the official injections in oil. This is because it is
`the most stable (except in light.) and, thus, will usually meet the official requirements. Fixed
`oils must never be administered intravenously and are, in fact, restricted to IM use.
`The USP usually does not specify an oil, but states that a suitable vegetable oil can be used.
`The main use of such oils is with the steroids, with which they yield products that produce a
`sustained-release effect. Sesame oil has also been used to obtain slow release of fiuphenazine
`esters given intramuscularly [4]. Excessive unsaturation of an oil can produce tissue irritation.
`The use of injections in oil has diminished somewhat in preference to aqueous suspensions,
`
`MYLAN PHARMS. INC. EXHIBIT 1037 PAGE 9
`
`

`
`453
`
`Bovlon et at.
`
`which generally have less irritating and sensitizing properties. Benzyl benzoate may be used
`to enhance steroid solubility in oils if desired.
`Water-miscible solvents are widely used in parenterals to enhance drug solubility and to
`serve as stabilizers. The more common solvents include glycerin, ethyl alcohol. propylene
`glycol. and polyethylene glycol 300. A common esanrplc of an injectable product formulated
`with nonaqueous solvents is IV ‘Valium. which contains 4ll% propylene glycol and 10% ethanol.
`Mixed-solvent systems do not exhibit many of tlte disadvarttttges observed with the fixed oils,
`but may also be irritating or increase toxicity, especially when present in large amounts or in
`high concentrations. A solution containing a high percentage of ethanol will produce pain on
`injection.
`The formulator should be aware of the potential of nonaqueous solvents in preparing. a
`solubilized or stable product that may not have been otherwise possible. The reader is directed
`to comprehensive reviews of uonaqucous solvents for additional information [lilo].
`
`V. DOSAGE FORMS
`
`A. Solutions
`
`inject-able products are solutions. Solutions of drugs suitable for
`The most common of all
`parenteral administration are referred to as r'njecrimi.s‘. Allltuttglt usually aqueous. they may he
`mixtures of water with glycols, alcohol, or other nunaqucous solvents. Many injectable solit-
`[ions are manufactured by dissolving the drug and a preservative. adjusting the pH. sterile
`filtering the resultant solution through a 0.22-u.m—membrane filter and. when possible. auto-
`claving the final product. Most solutions have a viscosity and surface tension very similar to
`water, although streptomycin sulfate injection and ascorbic acid injection. for example. are
`quite viscous.
`Sterile filtration, with subsequent aseptic filling. is common because of the heat sensitivity
`of most drugs. Those drug solutions that can withstand heat should be terminally autoclave-
`sterilized after filling, since this better assures product and package sterility.
`Large-volume parenterals (LVPS) and small-volume parenterals (SVPS) containing no anti-
`microbial agent should be terminally sterilized. It is standard practice to include an antimicro-
`bial agent in SVPs that cannot be terminally sterilized or are intended for multiple-dose use.
`The general exceptions are products that pass the USP Antimicrobial Preservative Effectiveness
`Test [1] because of the preservative effect of the active ingredient. vehicle. pH. or a combination
`of these. For example. some barbiturate products have a pH of 9-10 and a vehicle that includes
`glycol and alcohol.
`Injections and infusion lluids must be manufactured in a manner that will minimize or
`eliminate haze and color. Parenteral solutions are generally filtered through 0.22-um-
`membrane filters to achieve sterility and remove particulate matter. Prefiltration through a
`coarser filter is often necessary to maintain adequate flow rates, or to prevent clogging of the
`filters during large—sc-ale maritifacturittg. A tale or carbon filtration aid (or other filter ititlfil mil)’
`also be necessary. If tale is used.
`it should be pretreated with a dilute acid solution to remove
`surface alkali and metals.
`The formuiator must be aware of the potential for binding when filtering protein solutions.
`Because of the cost—availability of most protein materials. a membrane should be used that
`minimizes protein adsorptiott to the membrane surface. Typical filter media that minimize this
`binding include hydrophllic polyvinylidene difluoride and lrydror-:yl-modified hydrophilic poly-
`amide membranes [17]. Filter suppliers will evaluate the compatibility of the drug product with
`their membrane media and also validate the selected membrane.
`
`MYLAN PHARMS. INC. EXHIBIT 1037 PAGE 10