By James Ruble, PharmD, JD
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`Premixed IV Products
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`Impact Safety, Efficiency, and
`the Bottom Line With
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`Premixed IV Products
`
`he availability of premixed W products and their role in the health
`care environment have grown exponentially with the release ofthe
`widely known institute of Medicine (IOM) report, as well as the
`USP and Joint Commission's increased expectations regarding
`sterile product compounding and medication management.
`litigation may also make the utilization of premixed W products an attractive
`option. However, decisions to use premixed products should not be made with-
`out due diligence.
`The terms premixed, ready—to—use (RTU), and point-of—care (FCC) are often
`med synonymously; however, they may describe slightly different products.
`Premixed products generally involve an absolutely RTU container of medica-
`tion. The product may be frozen to extend beyonchrse dating. A POC
`product's container may use an isolation technology that sepa-
`rates the drug and diluent until admin'uu'an'on.
`Examples include ADD-Vantage, Mini-Bag
`Pius, Duplex, and Vial-Mate. Tl'rcre are sev-
`eral reputable manufacturers of premixed,
`RTU, and POC products, inchrding B. Bruno,
`Baxter, and Hospira.
`A variety of factors may be involved in the
`decision to use premixed, RTU, and FCC IV
`products. Accordingly, this article will examine
`premixed IV products in regard to safety, consider—
`ations specific to concentrated elecuolytesand par-
`enteral nutrition, dosagestandardization, labeling
`V
`concerns,barcodingoptions,changestoinventory
`3
`management and dispensingworldiow,sraffeduca—
`.35? ""3" T?” m_ tion, and finally, decision analysis.
`[January-ion. limos unnugnom
`“I all "will"! ofPTH'I Safety Concerns
`Decisions to purchase andstoclt prembted prudllfls
`often rally around the flag of safety. Extemporaneous compounding of N admix-
`tures has been shown to lead to error in 9% of doses compounded, and 2% of
`extemporaneously compounded [V products may involve clinically si
`‘
`1
`errors. In contrast, ready-rouse pharmaceutical products are suggested to have
`an error rate ofless than 1%.'
`
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`
`On the other hand, premixed products also present some safety concerns.
`Many of the safety concerns with these products are not related to their phar-
`maceutical production, but rather their packaging and labeling, which can lead
`to product selection errors during dispensing. For instance, several years ago,
`confusion resulted between a manufacturer's premixed esmolol and dopamine
`infusion producrs, both of which were contained within a foil overwrnp that
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`listed the drug name on one side .
`only; when tl're bags rested with I
`the identity side facing down, the
`products could be mistaken for
`one another. As a partial solution
`to this problem, the manufac-
`turer issued special
`labels to _
`be affixed to both sides of the
`esmoiol over-wraps upon dis-
`pensing from the pharmacy. In
`addition, there were recommen-
`dations to avoid storing these
`products on the care units.
`Another safety concern was identified with glass hordes of dextrose 5% in
`wait: (DSW) and premixed nitroglycerin bottles, both ofwhich featuredsirniiar
`Ethel colors and lettering. In this circumstance, there were isolated mesofnurses
`hanging a bottle of DEW that was assumed to be premixed nitroglycerin. This
`problem was addressed primarily through staff education.
`[bolt-alike premixed bags can easily be confused for one another, and ulti—
`mately. the wrong medication can be dispensed. Ciproiloxacin (5 my’mL) and
`fluconamle (2 mg/mL) premixed products are available in approximatelyZOl]
`mL volumes and have similar overvwrap packaging. While both are anti-infec-
`tive agents, their misapplication could have profound consequences in a criti-
`cally ill patient. To avoid these errors, physically separate these products in drug
`storage areas.
`Another premixed product prone to dispensing errors is heparin. Some of
`these producm have red lettering on their labels and can be confused with pre-
`mixed potassium chloride, which also features red lettering. Premixed heparin
`products have also been confused with herastarch products. In spite of these
`observations, there remains general agreement that premixed products and POC
`technologies do result in fewer errors.z
`
`Potassium ChlorideIMagneslum Sulfate and TPN
`Hemolyte homeostasis in clinical care often invokes potassium and magne-
`sium supplementation. These agents can be simultaneously viewed as critical
`agents in patient care and erronprone W products. Vials of concentrated
`potassium chloride and magnesium sulfate are frequently used to prepare elm:-
`trolyte replacement solutions. Compounding errors can result in a replam-
`ment therapy of a higher dose or concentration than intended. Thejoint
`Commission (TJC) now Frohibits floor stuck storage of any concentrated
`potassium chloride product in patient care units. The institute for Safe
`Medication Practices (ISMI’) has further recommended that only premixed
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`in grant
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`Premixed IV Products
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`solutions or commercially outsourced admixed solutions be made available in
`these areas.J
`There has been much debate over the benefits of premixed versus cus-
`tomized parenteral nutrition formulations.
`
`I Arguments against premixed TPN include:
`IMay limit the ability to fine tune electrolyte homeostasis
`'May limit the ability to optimize calorie needs of patient
`IMaymalte prescribers feel a loss ofconrrol in patient care
`0 Difficulty in gaining prescriber acceptance may increase inventory,
`should both premixed and customized TPN he offered by pharmacy
`
`NDCmmbu-Jdmymarufamuershavcmovodbeyonddrisufinhmunmqfimnem
`to include the lot mother-and beyonduse date in the product's bar code.
`The FDA requires that barcodes be present on a drug product's overwrap, as
`well as on its inunediare container, unless theimmediate container‘s bar code
`readilyvisible and machinoreadable through the overwrap (such as an overwrap
`with a transparent section over the label bar code). To prevent medication errors,
`a bar coded overwrap is important, even if the over-wrap will be removed prior
`to administration, because hospital personnd may need to scan the bar code at
`several points in the dispensing process and prior to administration. Some insti-
`tutions use software to generate bar coded, patient-specific medication labels
`for premixed products.
`
`I Arguments in favor of premixed TPN include:
`'May reduce compoundingworkload and simplify USP <797> compliance
`'May allow for greater variability in start/hang times, regardless of phar-
`macy's compoundingworkflow (In many institun'ons, hang times are stan-
`dardized to evening/late evening hours. lfpremixedTPNis beingurilized,
`TPN could start at nearly any time of the day.)
`0 May lead to decreased product contamination (Pharmacyprepared prod-
`nets are subiect to variability in the staffing/environment of the corn-
`pounding area.)
`
`Dosage Standardization
`There are often legitimate clinical reasons for relatively small changes to the
`dosages and concentrations of IV medications or for orders for atypical
`dosages. Nevertheless, these who routinely work in IV admixture services fre-
`quently observe these highly customized products being returned unused to
`phannacywithin 24 to 48 hours. Premixed and RTU products can both reduce
`mate and serve to establish reasonable limitations for dosage standardization.
`Pharmacy, in conjunction with the PM conunittee, may decide roimplemrnt
`a standardized dosage program utilizing premixed 1V products. The hospital may
`srill compound non—standard doses, but the availability of predetermined pre-
`mixed products may channel providers into more cost-effective orders.
`
`Labeling Concerns
`Manyhealth care enterprises encounter errors associated wilh the mislabeling
`of W medications. While premixed and RTU products are not immune from
`these types of errors. many now undergo substantial scrutiny of their packaging
`prior to market release. Specialists in human factors engineering may be
`involved to identify packag‘ng or processes that would Contribute to such errors.
`Thought should be given to the placement of patient-specific labels on pre-
`mixed IV products that require overJWtap packaging to maintain optimal stor-
`age conditions. Removal of the over—map may subiect the product to dosage
`concentration changes resulting from the evaporation ofwater or exposure to
`lifirt. Whenever possible. the pharmacy should defer to manufacturer recom-
`mendations on over-wrap packaging. In some circumstances, over—“raps may
`be partially opened and rescaled so that a patient-specific label can be placed
`on the immcdiate container.
`
`Bar Coding Options
`The use of barcoded medication administration (BCMA) technology is mowing
`exponentially in hospitals and is contributing to favorable cost-benefit analyses and
`substantially reducing errors.‘ FDA regulations now require that pharmaceutical
`products contain a machine readable bar code, which, at a minimum, conmins the
`
`Changes to Inventory Management and Dispensing World'iovr
`Automated dispensing cabinets (ADCs) are a natural fit with the dispensing of
`oral and topical medications. However, the placement of extemporaneously
`compounded Wlnedimu'ons into ADCs is complicated hystorage temriremmts
`andshorrened beyond-use dating. Some ADCs have refrigerated oompamnems,
`buteven so, sotrreoompounded medications mayallow forWOfmllyawa
`daynnmkingdreiravailabilityinADCslessdran optimal. hmnmpranhred
`and POCprndum are ideally suited for incorporation into ADCs.‘
`Premixed products often have extended beyond-use dating and. therefore,
`may be kept in ADC: for longer times, providing a shelf-life that will Iiltely
`resultin clinical utilization and reduce medication wastage. Pharmacy can
`monitor unit-based ADCs to optimize inventory par levels and ensure prod-
`uct availability.
`murmuredinventory management systems [melt producturilimlion and can
`help pharmacy contain costs associated with excess inventory levels. Data is
`most often captured when nurses remove a product from an ADC prior to
`patient adminisu'arion and either scan the product's bar code or record it as
`removed using the ABC’s on—board computer. Furthmnore, by stocking pre-
`mixed and POC medications in ADCs,hospimls stand to improve their medicar
`lion delivery and administration times.
`Even for hospitals not using ABC!) to dispense meditations on the nursing
`units, premixed IV products can present several inventory management bene-
`fits. For instance, pharmacies maywitness a decrease in the ancillary products
`required for the production of [V medications, and medication wasragc may
`decrease due to the extended beyond-use dating offered hypremised products,
`in comparison to sterile preparations compoundedin the pharmacy. Moreover,
`some inslirmiors may heavily depend on hatch production ofoommon dosages,
`such asoefazolin l g. nafcillin 2 g, andvancomydn i g. Substiuuion ofprearixed
`products for some of these products may result in reduced cleanroarn—rclaled
`costs. The reduction in overhead may result from a smaller portion of space
`dedicated to compounding, reduction ofsraff hours needed for compounding
`and reductions in ancillary costs for compounding equipment and supplies.
`
`Nursing Education
`Nurses remain primarily raponsible for the administration of medication prod-
`ucts; however, physicians and other prescrihers also need to be considered in
`the education process. Premixed and RTLl products typically require no signif-
`icant difference in education compared to theirextemporaneous counterparts.
`Howwer, POC products that utilize isolation technologies require additional
`training. as they are prone to improper activation. For example, ADD-Vantage
`systems require diy'tal manipulation of a latex stopper to allow the mixture of
`the diluent and drug. Unfortunateiy, it remains possible for nursing personnel
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`EKR Therapeutics, LLC Exhibit 2012 Page 2
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`Premixed IV Pl'CidLlL’LiS
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`III administer the diluent without Fully activating the drug. likewise. Mini-Bagle
`andVial—Mate systems roquirebendinga connecting wmula to allowmiadngofdmg
`and diluent. If the mixture is not accomplished first, the patient typically mceives a
`small salinem or isotonic fluid belus, without any medication. Problems will:
`improper aetivation can be minimized or entirely overcome through nursing edum
`tion and the use of secondary labels, placed nearby the patient-specific label, that
`remindnursee to activate the product prior to hanging ir.
`
`cists to dedicate their time to other Worthwhile tasks, both within and outside
`the walls of the pharmacy department. I
`
`Will! more than 20 years’ experience in heirltb care. joules Ruble,
`”11th1D, is niunager ofinfilsr'orr services ii» the pharmacy depart-
`mm: a» Uniwrsity ofUtah. In addition. he murderpharmacy law
`andelbior instruction finr the University ofSombem Nemfa audit on
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`Doclslon Analylls
`To date there are no largo-scale liner-acute analyses of the economic impact of pre—
`mixed, RTU, and FCC products. Asmall phannacoeconomic analysis on the mar-
`savings from RTU products was conducted in Belgium. This studywas limited to
`the use ofdobutamine (urtemporaneous compounded versus prem'med} in cardiac
`Slum patients Overall, the investiyrors Found a 60% cost-reduction from using
`premixed dobmamine versus com-entional admixture.‘
`In addition, Kenneth Witte and his colleagues developed a decision analysis
`model forfiuzen premixed meducmprimarilyfmun cefazofinThqrdevelopod
`a nine-point, wru'giued decision pmccss.’ The decision analysis demonsnatedtheir
`'mstirution could save apprtudmately $5,000 byufilizingfrazen, premixed ccfazolin
`products. Accounting for-inflation, this would amount to approurirnatelya $10M
`swing! noday.
`Carl Geberbauer described general guidelines to considcrwhcn purdiasiugpre—
`mixed prodlm'Al'avmable cost-Immagement outcome can be adiievodbylm'liring
`premixed, small-volume parenteral products. With the use of small-volume par-
`enleral products, Geberbauer observed better inventorycontrol (feweriremsto pur—
`chase); a reduction in waste, equipment costs, and the need for Specializnd corn-
`poundingsmffing; and improved quality assurance for parenteral products.
`
`Summary
`Many health care enterprises are making decisions to utilize premixed, RTU,
`and [’06 IV products instead of performingin—house compounding. in order to
`improve safety, case USP and TJC compliance burdens, improve medication
`delivery times, and reduce medication wastage. Furthermore, by reducingyom-
`compoundingworldoad, the use of premixed IV products can promote quality
`assurance for your institution's IV products, reduce the costs associated with
`compounding supplies and [V product components. and allow your pharma-
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`EKR Therapeutics, LLC Exhibit 2012 Page 3
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