Pharmaceutical Properties of Paclitaxel and Their Effects
`on Preparation and Administration
`
`Lawrence A Trissel FASHP
`
`Paclitaxel
`
`is a mainstay in the treatment of ovarian and breast cancers and its
`use in other malignancies is being explored Although it has great clinical
`pose a number of challenges
`the drug and its formulation components
`utility
`to pharmacists and nurses Paclitaxel
`is insoluble in water and is formulated
`in an equal parts mixture of ethanol and Cremophor EL which disperses the
`of 0312 mgml paclitaxel
`drug in an aqueous medium At concentrations
`is stable for at least 2 days Additional
`research identified precipitation as the
`major limitation to longterm stability and supports the use of an inline filter
`infusions The formulation vehicle also leaches the plasticizer DEHP
`for all
`from polyvinyl PVC containing solution bags and administration sets This
`the amount of
`is dependent on the concentration of surfactant
`effect
`accessible DEHP and many other
`factors Health care practitioners must
`educate themselves regarding appropriate non PVC containers and
`administration sets for safe and convenient delivery of paclitaxel
`The
`compatibility of this and other drugs in solution is under
`investigation
`currently amphotericin B chlorpromazine hydroxyzine methylprednisolone
`sodium succinate and mitoxantrone have been determined to be physically
`incompatible with paclitaxel infusions
`Pharmacotherapy 1997175 Pt 2133S139S
`
`OUTLINE
`
`Formulation of Paclitaxel
`
`Stability in Solutions
`Extraction of DEHP Plasticizer from PVC Products
`Paclitaxel Does Not Undergo Sorption to PVC
`Compatibility with Other Drugs
`Future Directions
`
`Paclitaxel has become a mainstay in the
`treatment of ovarian and breast cancers and
`to investigate other
`studies are being conducted
`clinical applications of this unusual molecule
`Problems exist as a result of its pharmaceutical
`properties and present a challenge to pharmacists
`and nurses Some of the problems that paclitaxel
`
`From the Clinical Pharmaceutics and the Pharmaceutical
`Analysis Laboratory Division of Pharmacy University of
`Texas MD Anderson Cancer Center Houston Texas
`to Lawrence A Trissel FASHP
`Address reprint requests
`Division of Pharmacy Box 90 University of Texas MD
`Anderson Cancer Center 1515 Holcombe Boulevard
`Houston TX 77030
`
`shares with other parenteral drugs are stability in
`infusion
`compatibility with
`solutions
`administration equipment and compatibility and
`stability with other agents
`is rarely given alone Like other
`Paclitaxel
`is almost always part of a
`antineoplastics it
`complex regimen of infusion solutions delivery
`devices composed of various plastics elastomers
`metals and other materials pumping devices
`from complex machines to simple elastomeric
`pressure devices and multiple drug therapy that
`can consist of as many as 10 agents such as
`other antineoplastics
`symptomatic and
`supportive care drugs and antiinfectives
`To
`facilitate the complicated process of delivering
`many parenteral drugs with different and intense
`schedules multiple port administration sets
`multichannel pumps and Y and T connectors
`were developed to provide sufficient access
`Since these products are made of many different
`materials the opportunity
`for problems
`is great
`
`Abraxis EX2040
`Actavis LLC v Abraxis Bioscience LLC
`1PR201701101 1PR201701103 1PR201701104
`
`

`

`134S
`
`PHARMACOTHERAPY
`
`Supplement
`
`to Volume 17 Number 5 1997
`
`10 pm5
`do not reach clinically relevant size
`many drugs in infusion solutions have an
`intrinsic haze Because paclitaxel
`is not actually
`in solution however precipitation of clinically
`meaningful size particles eventually occurs the
`question is exactly when this will happen
`Outside influences can affect
`the rate of
`precipitation of the paclitaxel dilution The
`package insert states that the drug is stable in
`solution for 27 hours within the standard
`concentration range of 0312 mgm12 This is
`usually a safe working time frame for preparing
`and administering shortterm infusions of
`paclitaxel which are most commonly prescribed
`if 24 hour infusions or multiday
`However
`infusions which are currently being evaluated
`are required the maximum 27 hour stability
`is approached and possibly exceeded
`limit
`Normal time delays in everyday clinical
`practice often occur before actual drug
`administration such as in preparation storage in
`the pharmacy until delive0 transit time to the
`use site and storage at the use site after delivery
`Therefore the 27 hour stability limit can mean
`having to prepare two 12 hour doses for each 24
`hour period with associated effects on cost and
`workload Furthermore several container
`changes associated with long infusions of
`for the patient and
`paclitaxel are inconvenient
`potentially increase the risk of microbiologic
`contamination
`due to these system breaks
`Therefore longer stability of
`the drug is
`desirable especially when it
`is to be infused over
`24 hours or longer
`
`Stability in Solutions
`
`In the first
`report of paclitaxels stability in
`infusion solutions beyond 27 hours the drug was
`chemically stable for 48 hours° Furthermore no
`gross precipitation was reported however
`the
`formation of subvisual particles was not assessed
`The stability limit was not determined because
`this study ended at 48 hours
`In an attempt
`to determine a longer stability
`period paclitaxel was stored over 31 days
`Concentrations of 01 and 1 mgml which are
`most commonly administered were evaluated in
`solutions of both 5 dextrose and 09 sodium
`chloride Samples were stored at 4 22 and 32°C
`and evaluated for both chemical and physical
`stability including subvisual phenomena
`Chemical stability was analyzed by a validated
`stability indicating highperformance
`liquid
`chromatography HPLC assay Physical
`
`with compatibility and stability to occur as drugs
`come in contact with these materials
`
`Formulation of Paclitaxel
`
`is soluble in a variety of organic
`Paclitaxel
`solvents such as ethanol methanol benzene
`chloroform methylene chloride and others
`most of which are unsuitable for human
`administration It
`is insoluble in water and
`aqueous solutions a common attribute of many
`Because aqueous solutions are
`natural products
`the best vehicles for intravenous delivery in
`terms of ease and tolerability extraordinary steps
`were taken to prepare paclitaxel as an aqueous
`solution
`The drug is formulated in an equal parts
`mixture of ethanol and Cremophor EL surfactant
`a polyoxyethylated derivative of castor oil
`Cremophor EL is used in this and other
`formulations to disperse insoluble drugs in an
`aqueous medium by forming tiny micellar
`particles3 Consequently paclitaxel
`is never
`aqueous solution rather it
`is a microdispersion
`distributed throughout an aqueous medium
`Similar to soapy water paclitaxels dispersion
`appears slightly hazy which can be observed by
`through the dispersion The haze
`shining a light
`is concentration dependent but not
`level
`linear4
`Haze increases
`as the concentrated product
`diluted and micellar dispersion forms achieving
`maximum haziness at paclitaxel concentrations
`of 0309 mgml which are commonly
`administered in clinical practice Figure 1
`Turbidity declines as the product becomes more
`and more diluted to low concentrations
`The
`haze itself
`is not a concern as long as the particles
`
`in
`
`is
`
`001
`
`8 7
`
`6
`
`5
`
`4
`
`3
`
`H
`
`2
`
`1 I
`
`0
`
`NTU
`
`Turbidity
`
`Figure 1 Natural
`
`iiIIIi1
`
`09
`03
`0075
`Concentration mgmL in D5W
`turbidity in paclitaxel admixtures4
`
`24
`
`

`

`PREPARATION AND ADMINISTRATION OF PACLITAXEL Trissel
`
`135S
`
`stability was tested using a multistep approach
`that assessed visual appearance in both normal
`diffuse light and using a Tyndall beam changes
`in turbidity and the formation of clinically
`relevant size particulates4
`No chemical decomposition of
`the paclitaxel
`molecule occurred at any storage temperature in
`either dextrose or sodium chloride solution at
`either concentration
`Paclitaxel was stable
`under these conditions until
`it precipitated
`precipitation was identified as the primary
`stability limitation in infusion solutions No
`changes in natural haziness were observed in the
`test samples However microcrystalline
`precipitation of needlelike crystals formed in
`some samples after 3 days of storage Gross
`white flocculent precipitation was present
`in
`several samples within 714 days The HPLC
`showed
`that microcrystalline
`analysis
`precipitation did not
`lead to substantial
`loss of
`from the solution indicating that only
`paclitaxel
`small amounts of drug were involved However
`when gross precipitation was present paclitaxel
`losses of up to 50 were determined by chemical
`analysis The precipitate was identified as
`essentially pure paclitaxel
`Of importance paclitaxel precipitation was
`The microcrystalline precipitation that
`erratic
`occurred after 3 days was observed in only a few
`samples The gross precipitation that occurred in
`14 days in most samples still
`left some samples
`with no precipitate at all There is no doubt that
`precipitation will occur but
`the timing remains
`results from
`highly variable This uncertainty
`many factors for which there is little
`control and
`For example the inherent particle
`recognition
`burden in aliquots of solutions could be a factor
`Higher particle burdens or solutions with
`larger or smaller particles could seed
`somewhat
`The shape and composition of
`precipitation
`The
`such particles also may be important
`interior configuration of container surfaces could
`provide a stimulus for precipitation
`that many other factors remain unknown
`Paclitaxel precipitation leads to obvious issues
`in drug delivery Besides precipitation in the
`inline precipitation may occur even
`container
`when the drug remains in solution in the bag or
`bottle According to anecdotal
`reports9 10 this
`may occur unpredictably during administration
`even within the 27hour stability period stated in
`insert2 Anecdotal
`reports from our
`the package
`indicate
`that
`inline
`institutions clinic
`to be
`precipitation is sufficiently frequent
`to the
`It usually occurs just distal
`meaningful
`
`is likely
`
`It
`
`pumping mechanism of a mechanical pump
`furthermore its frequency is much higher with
`pumps that use a peristaltic drive to move
`solutions through the line In our institution
`paclitaxel delivery using a piston driven pump
`resulted in only one reported case of
`inline
`In contrast use of portable
`precipitation
`peristaltic pumps for continuous drug delivery
`increased the number of reports of inline
`precipitation from our clinics
`is uncertain how the pumping mechanism
`It
`it can be surmised that
`affects precipitation but
`the compression and crushing action of a
`peristaltic pump is more mechanically traumatic
`to micellar dispersions than a piston pump In
`laboratory experiments we found that high shear
`mechanical
`forces applied to a paclitaxel
`dispersion can easily generate a precipitate
`as 1 hour after mixing LA
`sometimes in as little
`Trissel unpublished data 1993 Based on
`variability in precipitation and to ensure that
`the
`precipitate is not delivered to the patient an
`inline filter 022 pm is required with all
`
`paclitaxel
`
`infusions
`
`Extraction of DEHP Plasticizer from PVC
`Products
`
`Like other drugs that use a surfactant
`in their
`formulation paclitaxel
`injection leaches
`extracts the plasticizer diethylhexyl phthalate
`DEHP from polyvinyl chloride PVC solution
`containers administration sets and extension
`from
`sets Plasticizer extraction does not occur
`glass containers or from nonplasticized plastics
`such as the polyolefins Polyethylene present
`in
`Excel and PAB McGaw containers and
`in many plastic syringes
`polypropylene present
`have no plasticizers to leach and are suitable for
`administering paclitaxel Glass containers may
`a problem because
`create
`the paclitaxel
`dispersion can wet
`the air vent of rigid glass
`bottles and cause leakageil Many other plastic
`materials may come in contact with solutions
`trimellitate TOTMplasticized
`including trioctyl
`PVC ethylene vinyl acetate Silastic and
`The drugs compatibility with
`polyurethane
`these materials has yet to be evaluated
`The surfactant not
`leaches
`the paclitaxel
`DEHP8 The amount of DEHP leached from PVC
`on several variables The
`materials is dependent
`concentration
`the surfactant whether
`of
`Cremophor EL or polysorbate 80 in the solution
`is crucial with higher surfactant concentrations
`resulting in more leached DEHP when all other
`
`

`

`136S
`
`PHARMACOTHERAPY
`
`Supplement
`
`to Volume 17 Number 5 1997
`
`Table 1 Extraction of DEHP by Formulation Components
`at Various Concentrations
`
`rate at which plasticizer can migrate from the
`exterior to the interior of the container or tubing
`through the plastic matrix may contribute to the
`maximum amount of DEHP that can be leached
`from any particular administration setup Rate of
`infusion administration fluid contact
`time
`solution temperature and administration set bore
`size also affect DEHP leaching
`The timeconcentration pattern of DEHP
`extraction from PVC varies with concentration
`We studied test solutions of paclitaxel
`injection
`vehicle corresponding to paclitaxel
`injection of
`03 and 12 mgml delivered in triplicate over 24
`hours At the higher concentration we extracted
`a large amount of DEHP initially as a spike with
`extraction tapering off apparently as accessible
`DEHP was depleted Figure 211
`In contrast
`a
`rate of extraction occurred
`relatively constant
`with 03 mgml Figure 311
`These results indicate that frequent changes of
`administration sets by health care workers
`because of set
`incompatibility may actually
`enhance DEHP leaching and delivery problems
`by replenishing the DEHP pool Also rapid
`administration of a concentrated dispersion of
`the need for a
`does not circumvent
`paclitaxel
`non PVC administration set Based on our
`results the bulk of DEHP delivery would occur
`in the first 34 hours of administration
`Although DEHP is not an acutely toxic
`substance13 there are concerns about potential
`
`0 Bag 1
`Bag 2
`A Bag 3
`
`300
`
`250
`
`200
`
`150
`
`100
`
`50
`
`DEHPConcentrationµgmL
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`14
`
`16
`
`18
`
`20
`
`22
`
`24
`
`26
`
`Hour
`Figure 2 Extraction of DEHP from a standard
`administration set by the paclitaxel vehicle equivalent
`paclitaxel 12 mgml Originally published in Trissel LA
`XU Q Kwan J Martinez JF Compatibility of paclitaxel
`injection vehicle with intravenous administration and
`extension sets Am J Hosp Pharm 199451280410 c
`1994 American Society of Hospital Pharmacists Inc All
`rights reserved Reprinted with permission R9697
`
`to
`
`DEHP Extracted
`in 24 Hours pgm1
`195
`
`179
`
`36
`
`157
`
`227
`
`232
`
`Concentration
`
`5 5 1 5
`
`10
`
`25
`
`Component
`Cremophor EL
`Polysorbate 80b
`Polysorbate 80
`Polysorbate 80
`Polysorbate 80
`Polysorbate 80
`Admixed in 50 ml PVC bags of 5 dextrose injection USP
`bPlus ethanol 5
`
`From reference 12
`
`Table 2 Extraction of DEHP by Drugs Containing
`Cremophor EL
`
`Cremophor EL
`Concentration
`
`5
`39
`3
`
`1
`
`DEHP Extracted in
`24 Hours pgm1
`195
`
`102
`
`65
`
`21
`
`Drug
`
`Paclitaxel
`
`Cyclosporine
`Miconazole
`
`Teniposide
`
`From reference 12
`
`factors remain equal Ethanol
`in the paclitaxel
`formulation may also contribute to surfactant
`if any is minor Other
`leaching but
`its effect
`common organic solvents such as polyethylene
`to have no
`glycol and propylene glycol appear
`DEHPleaching potentia112
`A study of DEHP leaching by a variety of
`comparable amounts of DEHP leaching by 5
`nonaqueous
`agents
`reported
`parenteral
`Cremophor EL and 5 polysorbate 80 each in
`combination with 5 ethanol Table 112 Over a
`from
`range of polysorbate 80 concentrations
`125 the amount of DEHP leached from PVC
`increased with
`increasing
`concentration This concentration dependent
`effect was documented with several surfactant
`
`containing drugs Table 2 The amount of
`DEHP leached increased only a small amount
`when the surfactant concentration was increased
`from 10 to 25 This suggests that the amount
`of DEHP that
`is accessible also may influence the
`extent of its leaching
`Typically flexible PVC bags and tubing contain
`to approximately 2530 of
`DEHP equal
`total
`mass to provide adequate flexibility
`Pumping
`segments for peristaltic pumps may contain a
`higher concentration and hard PVC connectors
`The concentration of DEHP
`may contain none
`in PVC total mass of PVC available surface area
`surface configuration and
`of solution contact
`
`surfactant
`
`

`

`PREPARATION AND ADMINISTRATION OF PACLITAXEL Trissel
`
`137S
`
`Table 3 Unacceptable
`Administration Set
`manufacturer model
`Vented nitroglycerin set
`Baxter 2C7552S
`
`Equivalent Paclitaxel
`Concentration mgme
`03
`12
`
`Extraction of DEHP from Administration Sets by the Paclitaxel Vehicle
`DEHP Concentration in
`Effluent pgm1a
`63 ± 05
`685 ± 30
`74 ± 04
`821 ± 120
`85 ± 02
`816 ± 28
`72 ± 02
`626 ± 35
`68 ± 07
`585 ± 17
`
`03
`12
`
`03
`12
`
`03
`12
`
`03
`12
`
`Vented basic solution set
`Baxter 1C8355S
`Horizon pump vented nitroglycerin iv set
`McGaw V7450 original
`Horizon pump vented nitroglycerin iv set
`McGaw V7450new
`Intelligent pump vented nitroglycerin iv set
`McGaw V7150
`Mean ± SD n=6
`Note No paclitaxel was present Diluent
`From reference 11
`
`tested equivalent
`
`to 03 and 12 mgpl
`
`of
`
`At this time there are no definitive acceptable
`amounts of DEHP that can be infused with
`paclitaxel or any other drug solutions For
`research purposes we established benchmarks
`for DEHP based on the acceptability of certain
`types of administration sets by the Food and
`Drug Administration as listed in the paclitaxel
`package insert The use of conventional PVC sets
`to administer paclitaxel
`injection is not
`recommended Thus an unacceptable amount of
`DEHP was approximately 100 pgml or more
`leached from a 24
`because that was the amount
`hour infusion through those sets
`The paclitaxel package insert specifies the use
`IVEX2 filter
`sets Abbott
`to prevent
`These sets are made
`precipitate administration
`with about 20 cm of PVC tubing Approximately
`20 igm1 of DEHP was leached during a 24hour
`infusion of paclitaxel 12 mgml through the
`IVEX2 set and IVEXHP Therefore leached
`DEHP levels exceeding approximately 20 pgml
`at maximum paclitaxel concentrations were
`considered unacceptable lower amounts were
`considered
`but
`they can be avoided
`acceptable
`through careful selection of administration sets
`Using these benchmarks we studied 50
`administration and extension sets Although
`the study was not comprehensive it offers
`pharmacists and nurses an information base on
`which to make selection decisions Twentysix
`administration sets that were represented by their
`as potentially compatible with
`manufacturers
`paclitaxel and 24 extension sets were evaluated
`for the amount of DEHP leached by paclitaxel
`concentrations of 03 and 12 mgml The
`infusions were run over 24 hours in
`paclitaxel
`triplicate for each set and the effluent was
`
`In humans prolonged exposure to
`exposure
`DEHP leached into blood products was not
`associated with specific toxicitiesi4 However in
`animals changes in hepatocellular structure and
`liver function and development of hepatocellular
`carcinoma occurred with DEHP exposure15
`Teratogenicity and cardiotoxicity were reported
`with DEHP and its metabolite mono2ethyl
`19 Consequently
`hexylphthalate respectively18
`knowingly delivering such an extraneous
`material when it could be easily avoided by
`careful selection of drug delivery equipment
`both undesirable and unprofessional
`
`is
`
`0 Bag 1
`El Bag 2
`
`Bag 3
`
`DEHPConcentrationµgmL
`
`8
`
`10
`
`12
`
`14
`
`16
`
`18
`
`20
`
`22
`
`24
`
`26
`
`Hour
`Figure 3 Extraction
`of DEHP from a standard
`administration set by the paclitaxel vehicle equivalent
`paclitaxel 03 mgmi Originally published in Trissel LA
`XU Q Kwan J Martinez JF Compatibility of paclitaxel
`injection vehicle with intravenous administration and
`extension sets Am J Hosp Pharm 199451280410 c
`1994 American Society of Hospital Pharmacists Inc All
`rights reserved Reprinted with permission R9697
`
`to
`
`

`

`138S
`
`PHARMACOTHERAPY
`
`Supplement
`
`to Volume 17 Number 5 1997
`
`collected for DEHP analysis using the method of
`Waugh et al
`Most of the administration and extension sets
`were compatible with paclitaxel
`infusions even
`several so
`at high concentrations
`However
`called non PVC sets leached unacceptable
`levels
`of DEHP Table 3 These are constructed so that
`plastics other than PVC contact
`the drug solution
`for the pumping segments the pumping
`except
`segments are made of heavily plasticized PVC to
`provide the necessary pliability for use with the
`pumping drive They contain much higher levels
`of DEHP than conventional PVC tubing as much
`as 60 of the total mass of the pumping segment
`This provides a large accessible pool of DEHP to
`infusion and
`be leached into the paclitaxel
`subsequently delivered to the patient
`Practitioners must be aware that heavily
`in some non
`plasticized PVC may be present
`PVC sets Furthermore they should verify that
`is compatible with paclitaxel before use
`the set
`
`Paclitaxel Does Not Undergo Sorption to PVC
`
`Practitioners sometimes confuse the issue of
`leaching of plasticizer with sorption of drug to
`PVC or other materials but
`the processes are
`Leaching of plasticizer
`involves
`very different
`extracting a material from the plastic into the
`drug solution from which it may be administered
`to the patient Sorption involves loss of drug
`from the solution onto the surface adsorption
`or into the matrix absorption of PVC or other
`material Original work demonstrated that
`paclitaxel does not undergo adsorption or
`absorption to PVC therefore the drug is not
`lost from infusions due to either sorption
`phenomenon8
`
`Compatibility with Other Drugs
`
`be
`should
`intravenous
`drugs
`Ideally
`administered through separate lines to avoid
`Since this is difficult
`for
`incompatibilities
`patients with cancer who receive many drugs
`intravenously practitioners must be familiar with
`This helps to
`the compatibility of solutions
`avoid administering incompatible combinations
`and to find combinations that are convenient and
`comfortable for the patient to receive
`Paclitaxel 12 mgml was evaluated for physical
`simulated Y site
`compatibility
`during
`administration with 59
`selected
`agents
`symptomatic and supportive care drugs anti
`infectives other antineoplastics with which it
`The drugs were
`likely to be coadministered420
`
`is
`
`Table 4 Physical Incompatibilities of Paclitaxel with
`Other Drugs
`
`Drug
`Amphotericin B
`
`Incompatability
`
`Increased turbidity separation into
`two layers
`
`Chlorpromazine HC1
`
`Decreased natural turbidity
`
`Hydroxyzine HC1
`
`Decreased natural turbidity
`
`Methylprednisolone
`sodium succinate
`
`Decreased natural
`
`turbidity
`
`Mitoxantrone HC1
`
`Decreased natural
`
`turbidity
`
`From references 4 and 20
`
`tested at high concentrations which tend to be
`more problematic than low concentrations and
`were mixed in a 11 ratio to simulate the mixing
`that occurs during Ysite administration through
`a common line In clinical practice the contact
`two drug solutions in a common line is
`time of
`approximately 1530 minutes in patients
`receiving very slow infusions eg children the
`time may reach 1 hour
`contact
`In these
`evaluations samples were evaluated over 4 hours
`to provide a margin of safety to observe potential
`incompatibilities Samples were monitored both
`visually and electronically for turbidity changes
`precipitate formation color changes and gas
`evolution all parameters of physical compatibility
`the 59 drugs studied only 5 showed
`Of
`incompatibilities with paclitaxel Table 4 Of
`
`natural
`
`interest 4 of the 5 caused substantial decreases
`in
`turbidity of paclitaxel which constitutes
`incompatibility
`In addition to physical compatibility testing
`the chemical stability of paclitaxel with other
`antineoplastics is the subject of continuing
`research Unlike simultaneous administration
`through a Yinjection site with minimal solution
`times combining drugs into the same
`contact
`solution container exposes the agents to a greater
`risk of chemical decomposition that would occur
`during infusion Performing simple physical
`is not sufficient when
`compatibility evaluations
`evaluating admixtures of 2 or more drugs in the
`same solution In such cases the chemical
`integrity of each agent must be assured using
`stability indicating assay technology most
`commonly HPLC8
`Studies are evaluating the stability of paclitaxel
`at high and low concentrations with carboplatin
`cisplatin and doxorubicin HC1 over 7 days
`The tests are being conducted in both 5
`for cisplatin and 09
`
`dextrose injection except
`
`

`

`PREPARATION AND ADMINISTRATION OF PACLITAXEL Trissel
`
`139S
`
`References
`
`sodium chloride injection in polyolefin
`containers
`Three sample infusions of each
`combination are being stored at 4 23 and 32°C
`Preliminary results indicate that paclitaxel 03
`and 12 mgml were chemically stable in all
`samples with each of the three drugs for the
`entire study period As in earlier studies
`subvisual microcrystals formed in some of
`the
`samples after 3 days of storage In the presence
`of paclitaxel 12 mgml cisplatin 02 mgml had
`losses of about 8 in 4 hours and about 20 in
`24 hours at 23 and 32°C21 At 4°C cisplatin loss
`was 10 in 24 hours In combination with
`paclitaxel concentration of 03 mgml cisplatin
`exhibited 610 loss in 7 days at each of
`the
`Results for
`the
`storage temperatures
`doxorubicin HC1 admixture should be available
`in the near future
`
`Future Directions
`
`Although much research on the pharmaceutical
`aspects of paclitaxel has been conducted more
`remains to be done Screening for physical
`compatibility with other drugs is rather limited
`in scope This is partly the result of severe
`supply restrictions imposed during early days of
`paclitaxels availability Candidates for additional
`physical and chemical compatibility studies
`ifosfamide mesna
`include cyclophosphamide
`and etoposide phosphate
`The compatibility of paclitaxel with a variety
`of plastic materials currently available is
`unknown Questions regarding its compatibility
`with TOTMplasticized PVC ethylene vinyl
`various elastomers and
`acetate containers
`polyurethane and Silastic catheters are quite
`common Other plastic materials may require
`evaluation as well
`Examining ways to extend the stability of
`infusions is warranted
`The need for
`paclitaxel
`repeated changes of container and administration
`sets with longer infusions is not convenient
`for
`patients or health care workers and can lead to
`inadvertent
`contamination
`of the infusion
`solution
`
`investigational
`
`injection
`
`assessment of the
`
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`4 Trissel LA Bready BB Turbidimetric
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`6 Chin A Ramakrishnan RR Yoshimura NN Jeong EWS Nii
`LJ DiMeglio LS Paclitaxel stability and compatibility in
`polyolefin containers Ann Pharmacother 199428356
`in 5
`7 Xu Q Trissel LA Martinez JF Stability of paclitaxel
`dextrose injection or 09 sodium chloride injection
`at 4 22
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`8 Waugh WN Trissel LA Stella VJ Stability compatibility and
`plasticizer extraction of paclitaxel NSC125973
`injection
`diluted in infusion solutions and stored in various containers
`Am J Hosp Pharm 19914815204
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`10 Cronquist SE Daniels M Precipitation of paclitaxel during
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`11 Trissel LA Xu Q Kwan J Martinez JF Compatibility of
`injection vehicle with intravenous administration
`paclitaxel
`and extension sets Am J Hosp Pharm 199451280410
`12 Pearson SD Trissel LA Leaching of diethylhexyl phthalate
`from polyvinyl chloride containers
`by selected drugs and
`formulation components Am J Hosp Pharm 19935014059
`13 Calley D Autian J Guess WL Toxicology of a series of
`phthalate esters J Pharm Sci 19665515862
`14 Harris GW Conference on phthalate Washington DC US
`Department of Health and Human Services 198118992
`15 Kevy SV Jacobson MS Hepatic effects of phthalate
`ester
`leached from polyvinyl chloride blood bags
`plasticizer
`following transfusion Environ Health Perspect 1982455764
`16 Gray TJ Beamand JA Lake BG et al Peroxisome proliferation
`in cultured rat hepatocytes
`produced by clofibrate and
`phthalate ester metabolites Toxicol Lett 1982102739
`17 Warren JR Lalwani ND Ready JK Phthalate
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`peroxisome proliferator carcinogens Environ Health Perspect
`1982453540
`18 Peters JW Cook RM Effect of phthalate esters on
`reproduction in rats Environ Health Perspect 19733914
`19 Rock G Labow RS Franklin C Burnett R Tocchi M
`mono2ethylhexylphthalate MEHP a contaminant of
`stored blood N Engl J Med 19873161218
`20 Trissel LA Martinez JF Turbidimetric assessment of the
`compatibility of paclitaxel with 42 other drugs during
`simulated Y site injection Am J Hosp Pharm 1993503004
`21 Xu Q Zhang YP Trissel LA Gilbert GL Martinez JF
`Compatibility and stability of paclitaxel combined with
`cisplatin and with carboplatin in infusion solutions Ann
`Pharmacother In press
`
`Hypotension
`
`and cardiac arrest
`
`in rats following infusion of
`
`