VISN 22 Drug Monograph TemplateWord下载.docx
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VISN 22 Drug Monograph TemplateWord下载.docx
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Thesedocumentswillbeupdatedwhennewdatawarrantadditionalformularydiscussion.DocumentswillbeplacedintheArchivesectionwhentheinformationisdeemedtobenolongercurrent.
ExecutiveSummary:
Ø
Indications:
Bovine,ovine,andhumanrecombinanthyaluronidasepreparationsareallindicatedasadjuvantstoincreasetheabsorptionanddispersionofotherinjecteddrugs;
forhypodermo-clysis;
andasadjuvantsinsubcutaneousurographyforimprovingresorptionofradioopaqueagents.Ovinehyaluronidasehasreceivedoff-labelstudyfortreatmentofvitreoushemorrhageandchronicpainattributedtopost-laminectomyfibrosis.
Efficacy:
Hyaluronidasepreparationshavebeenusedincombinationwithlocalanestheticagentsforophthalmicsurgerywheretheyhavebeendemonstratedtospeedonsetofanalgesiabyincreasingtissuepermeabilityandpromotingthedispersionoftheanesthetic,allowforsmallervolumesofanesthetictobeused,andimproveglobeandlidakinesia.Hyaluronidasehasalsobeenusedtomaintainadequatehydrationinpatientswhoareunabletotakeadequatefluidsorally,whoaremildlytomoderatelydehydratedandinwhomitisdifficultorimpracticaltoinsertanintravenousline.Hyaluronidase-augmentedsubcutaneousinfusionsoflactatedRinger’ssolutionenabledflowrates250to400%fasterthaninfusionswithouthyaluronidaseandreducededemaassociatedwithsubcutaneousinfusionoffluids.Thecombinedsubcutaneousadministrationofhyaluronidaseandsalinecansignificantlyreducetissueinjuryfollowingextravasationofanumberofdrugs,electrolytes,nutritionalanddiagnosticsubstancesincludingamphotericin,vancomycin,lipidemulsion,potassiumsolutions,totalparenteralnutritionsolution,andvincaalkaloids.AdministrationofmorphinewithrecombinanthyaluronidasehasbeenshowntoaccelerateTmaxandalterAUCofsubcutaneouslyadministeredmorphinetotheextentthattheywerecomparabletovaluesassociatedwithintravenousmorphineadministration.Intradermalhyaluronidaseinjectionshavebeenusedtotreatgranulomatousforeign-bodyreactionsorunwantedplacementassociatedwiththeinjectionofcross-linked,biosynthetichyaluronicacidproductsusedincosmeticdermalaugmentation.Theintravitrealinjectionofovinehyaluronidase55IUresultedinaclinicallysignificantimprovementinclearanceofvitreoushemorrhagesufficientfortheophthalmologisttoseetheunderlyingpathologyandcompletetreatment,significantlyincreasedthepercentageofpatientsattaining≥3linesinbestcorrectedvisualacuity,andsignificantlyreducedvitreoushemorrhagedensity.Repeatedcaudalepidermalinjectionofhyaluronidasereducedpainandincreasedqualityoflifemeasuresinpatientswithpost-laminectomyfibrosis.
Safety:
Themostfrequentadverseeventsreportedwithsubcutaneouslyadministeredhyaluronidasehavebeenlocalinjectionsitereactions.Hyaluronidaseisantigenicandrepeatedinjectionsofrelativelylargeamountsofhyaluronidasepreparationsmayresultintheformationofneutralizingantibodies.Allergicreactions,suchasurticariaandangioedema,havebeenreportedin<
0.1%ofpatientsreceivinghyaluronidase.Whilethehumanrecombinanthyaluronidaseproductisproposedtoalleviatetheallergy,immunology,andinfectiousrisksassociatedwithnonhumanproteinsderivedfromanimalsources,anaphylacticreactionstonon-recombinantpreparationsofhyaluronidasehavebeenrareandnocasesofanimalpathogens(includingtransmissiblespongiformencephalopathies)havebeenlinkedtoanimal-derivedhyaluronidasepreparations.Theintravitreousinjectionofovinehyaluronidasewasgenerallywell-tolerated;
transient,self-limited,sterileiritiswasthemostcommonocularadverseevent.Non-infectioushypopyonwereonlyseeninovinehyaluronidase-treatedeyesbutoccurredinfrequentlyandrespondedwelltotopicalanti-inflammatorytherapy.
Dose:
Forhypodermoclysis,initiationofsubcutaneousinfusionmaybefollowedbyinjectionof150unitsofhyaluronidaseintotheinfusionline.Alternatively,150unitsofhyaluronidasemaybeinjectedundertheskinpriortoclysis.Absorptionanddispersionofinjecteddrugsmaybeenhancedbyadding50-300units(usually150units)ofhyaluronidasetotheinjectionsolution.Incasesofextravasationinjury,aten-folddilutionofhyaluronidaseinnormalsalineismadetoaconcentrationof15units/ml,followedbyinjectionof1mldilutedsolutionthroughthecatheter(ifstillinplace),orsubcutaneouslyaroundthesite.Analternativemethodinvolvesdividingthedoseinto0.2mlsubcutaneousinjectionswhicharegiveninfoursitesequallyspacedaroundtheedgesoftheextravasationsite.Hyaluronidase150to200unitshasbeensuggestedastheamountrequiredforremovalofonecubiccentimeterofhyaluronicacidwhenunwantedreactionsorpoorcosmeticresultshaveoccurred.
Cost:
Bovinehyaluronidaseproductsareavailableforapproximately$13fora150USPunitvialwhile200USPunitsofovinehyaluronidaseis$16.35/vial.Humanrecombinanthyaluronidaseis$45.89fora150USPunitvial.
PlaceinTherapy:
Thepromotionofabsorptionanddispersionofinjecteddrugs,biologicfluids,ormedicaldevicesbyhyaluronidaseappearstobeaclinicallyusefulproperty,especiallyregardingophthalmicanddermatologicproceduresandextravasationevents.Hyaluronidasecanacceleratesubcutaneousinfusionoffluidsandthusaugmentthisalternativerouteforhydrationwhenoralorintravenousreplacementisnotpossibleorimpractical.
Introduction
Thepurposesofthismonographareto
(1)evaluatetheavailableevidenceofsafety,efficacy,cost,andotherpharmaceuticalissuesthatwouldberelevanttoevaluatingbiologicsource-specificpreparationsofhyaluronidaseforpossibleadditiontotheVANationalFormulary;
(2)defineitsroleintherapy;
and(3)identifyparametersforitsrationaluseintheVA.
Pharmacology1-4
Hyaluronidaseisaspreadingordiffusingsubstancethatmodifiesthepermeabilityofconnectivetissuethroughthedepolymerizationofhyaluronicacid,mucopolysaccharides,andthechondroitinsulfatesAandC.Hyaluronicacidisapolysaccharidefoundintheintracellulargroundsubstanceofconnectivetissueandofcertainspecializedtissues,suchastheumbilicalcordandvitreoushumor.HyaluronidasehydrolyzeshyaluronicacidbysplittingtheglucosaminidicbondbetweenC1oftheN-acetylglucosaminemoietyandC4ofaglucuronicacid.Thistemporarilydecreasestheviscosityofthecellularcementandpromotesdiffusionofinjectedfluidsorlocalizedtransudatesorexudates,thusfacilitatingtheirabsorption.
Whennospreadingfactorispresent,amaterialinjectedsubcutaneouslyspreadsveryslowly,buthyaluronidasecausesrapidspreading,providedlocalinterstitialpressureisadequatetofurnishthenecessarymechanicalimpulse.Suchanimpulseisnormallyinitiatedbyinjectedsolutions.Therateofdiffusionisproportionatetotheamountofenzyme,andtheextentisproportionatetothevolumeofsolution.
Thereconstitutionofthedermalbarrierremovedbytheintradermalinjectionofhyaluronidase(20,2,0.2,0.02,and0.02units/ml)toadulthumansindicatedthatat24hourstherestorationofthebarrierisincompleteandinverselyrelatedtothedosageoftheenzyme;
at48hours,thebarrieriscompletelyrestoredinalltreatedareas.2
TheFDAconsidersallhyaluronidaseproductsasdistinctentitiesduetovariationsamongtheirsourcesandchemicalcompositions;
as‘biogenerics’approvedasfollow-onproteinproductsundersection505(b)
(2)oftheFood,Drug,andCosmeticActtheyareconsideredtobesimilarbutnotinterchangeable5,6.Hydase™andAmphadase™arepreparationsofpurifiedbovinetesticularhyaluronidase1,3;
whileVitrase™isanovine(ram)testicularproduct(table1).4Theseanimal-sourcehyaluronidaseproductshaveamolecularweightofapproximately55,000Daltons.7,8Hylenex™(alsocalledrHuPH20)isapreparationoftheenzymerecombinanthumanhyaluronidaseproducedbygeneticallyengineeredChineseHamsterOvarycellscontainingaDNAplasmidencodingforasolublefragmentofhumanhyaluronidase.Thepurifiedrecombinanthyaluronidasehasanapproximatemolecularweightof61,000Daltons.2
Table1:
Biologicsources,dosageforms,andcostsofcommerciallyavailablepreparationsof
hyaluronidase1-4
Sourceofhyaluronidase
Tradename
DateofFDA
Approvala
AvailableDosageformb
Costc
Bovine
Amphadase™d
Oct26,2004
150USPunitsperml,2mlviale
$12.78/vial
Hydase™
Oct25,2005
$12.36/vial
Ovine
Vitrase™
May5,2004
200USPunitsperml,2mlviale
6200USPunitsperkitf
$16.35/vial
$557.71/vial
Human
recombinant
Hylenex™
Dec2,2005
150USPunitsperml,2mlviale
$45.89/vial
aSource:
OrangeBookathttp:
//www.fda.gov/cder/ob/default.htm
bUnlessotherwisespecified,productsareavailableasaclear,colorless,readyforusesolution
cPricesfromAugust2008,allFSS
dAmphadase™containsthimerosalasapreservative;
allotherhyaluronidaseproductslistedarepreservative-free
e1mlhyaluronidaseina2mlvial;
storeunopenedvialinrefrigeratorat2-8º
C(35-46º
F)
f6200USPunitsoflyophilizedovinehyaluronidaseinasingle-use5mlvial;
one1mlsterilepolycarbonatesyringe;
o
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