What is Alfaxan® ?

References1. JuroxandRicera,Aninvitrostudyevaluatingthebindingofalfaxaloneto

variousnuclearreceptors(RiceraStudyNo.AA94464).RecordsinHouse,2010.

2. JuroxandRicera,Aninvitrostudyevaluatingthebindingofalfaxalonetovarious abuse receptors (Ricera Study No. AA94047). Records in House,2010.

3. Child,K.J.,etal.,MetabolismandexcretionofCT1341intherat.InSteroidAnaesthesia,1972.RoyalCollegeofPhysicians,London.

4. Selye, H., Anaesthetic effects of steroid hormones. Proceedings of theSocietyforExperimentalBiology,1941.46:p.116.

5. Phillips, G.H., Structure-activity relationships in steroid anaesthetics. J.SteroidBiochem.,1975.6(5):p.607-613.

6. ChildK.J.,etal.,ThepharmacologicalpropertiesinanimalsofCT1341–anewsteroidanaestheticagent.Br.J.Anaesth.,1971.43(1):p.2-13.

7. Krantz, J.C. et al., XXVI. Pharmacodynamic studies of polyoxyalkylenederivativesofhexitolanhydridepartialfattyacidesters.J.Pharmacol.Exp.Ther.,1948.93(2):p.188-195.

8. Brewster, M.E. et al., Development of a non-surfactant formulationfor alfaxalone through the use of chemically-modified cyclodextrins.J.Parenter.Sci.Technol.,1989.43(6):p.262-5.

9. Brewster,M.E.,etal.,Anintravenoustoxicitystudyof2-hydroxypropyl--cyclodextrin,ausefuldrugsolubilizer,inratsandmonkeys.Int.J.Pharm.,1990.59:p.232-243.

10. NADA141-342Alfaxan®zIntravenousinjectableanestheticforuseincatsanddogs.

11. Heit,M.C.,etal.,SafetyandefficacyofAlfaxan®CDRTUadministeredoncetocatssubcutaneouslyat10mg/kg.InACVIM,2004.

12. Muir, W., et al., Cardiorespiratory and anesthetic effects of clinical andsupraclinical doses of alfaxalone in dogs. Veterinary Anaesthesia andAnalgesia,2008.35(6):p.451-462.

13. Muir, W., et al., The cardiorespiratory and anesthetic effects of clinicalandsupraclinicaldosesofalfaxaloneincats.VeterinaryAnaesthesiaandAnalgesia,2009.36(1):p.42-54.

14. Whittem,T.andPasloske,P.,RD9604.03–H005.Eightdaytargetanimalsafetystudyof intravenousAlfaxan®CDRTUindogsadministeredeveryotherday.2004,JuroxPty.Ltd.

15. Pasloske, K. and Whittem, T., JX9604.07-H004. A target animal safetystudyincatsafteradministrationofAlfaxan®CDRTUassingle,repeatedinjectionsondays0,2and5atdosesof5,15or25mg/kg.2004,0nfileatJuroxPtyLtd.

16. NADA141-342:Dogfieldstudy(JX9604.03-C009)p.22.17. NADA141-342:Catfieldstudy(JX9604.07-C006)p.11.18. Metcalfe,S.,etal.,Amulti-centreclinicaltrialevaluatingtheefficacyand

safety of Alfaxan® administered to bitches for induction of anaesthesiaprior tocaesareansection. In33rdWorldsmallAnimalCongress.2008.Dublin,Ireland:WSAVA/FECAVA.

19. Pasloske, K., et al., Plasma pharmacokinetics of alfaxalone in bothpremedicated and un-premedicated Greyhound dogs after single,intravenous administration of Alfaxan at a clinical dose. Journal ofVeterinaryPharmacologyandTherapeutics,2009.32:p.510-513.

20. Mesens, J.L., et al., Pharmaceutical applications of 2-hydroxypropyl--cyclodextrin. In New trends in cyclodextrins and derivatives. (Editor: D.Duchene).1991:Paris.P.369-407.

21. Pasloske, K., et al., A multicentre clinical trial evaluating the efficacyand safety of Alfaxan®-CD RTU administered to dogs for inductionand maintenance of anaesthesia. In British Small Animal VeterinaryAssociationCongress.2005.Birmingham,UK.

22. Pasloske, K., et al., A multicentre clinical trial evaluating the efficacyand safety of Alfaxan®-CD RTU administered to cats for inductionand maintenance of anaesthesia. In British Small Animal VeterinaryAssociationCongress.2007.Birmingham,UK.

23. Ambros, B., et al., Comparison of the anesthetic efficacy andcardiopulmonary effects of continuous rate infusions of alfaxalone in2-hydroxypropyl--cyclodextrin and propofol in dogs. Am. J. vet. Res.,2008.69(11):p.1391-8.

24. Heit,M.C.,etal.,CardiovascularandrespiratorysafetyofAlfaxan®CDRTUin cats premedicated with acepromazine, medetomidine, midazolam orbutorphanol.InACVIM.2004.

25. Amengual, M., et al., An evaluation of anaesthetic induction in healthydogsusingrapidintravenousinjectionofpropofoloralfaxalone.VeterinaryAnaesthesiaandAnalgesia,2012:p.n/a.

26. Herbert, G.L., et al., Alfaxalone for total intravenous anaesthesia indogs undergoing ovariohysterectomy: a comparison of premedicationwith acepromazine or dexmedetomidine. Veterinary Anaesthesia andAnalgesia,2012:p.n/a.

27. Jansen, K.S. and Uilenreel, J.J., A comparison between alfaxalone andpropofol continuous rate infusions in a total intravenous anaesthesiaprotocolforcaninesurgicalpatients.2009,FacultyofVeterinaryMedicine–UniversityofUtrecht.

28. Jimenez, C.P., et al., Evaluation of the quality of recovery afteradministration of propofol or alfaxalone for induction of anaesthesiain dogs anaesthetized for magnetic resonance imaging. VeterinaryAnaesthesiaandAnalgesia,2012.39(2):p.151-159.

29. Maddern,K.,etal.,Alfaxaloneinductiondosefollowingadministrationofmedetomidine and butorphanol in the dog. Veterinary Anaesthesia andAnalgesia,2010.37(1):p.7-13.

30. Martinez Taboada, F. and Murison, P.J., Induction of anaesthesia withalfaxaloneorpropofolbefore isofluranemaintenance incats.VeterinaryRecord,2010.167(3):p.85-89.

31. Mathis,A.,etal.,Comparisonofqualityof recovery fromanaesthesia incats induced with propofol or alfaxalone. Veterinary Anaesthesia andAnalgesia,2012.39(3):p.282-290.

32. Murison,P.J.andMartinezTaboada,F.,Effectofpropofolandalfaxaloneonpainafterovariohysterectomyincats.VeterinaryRecord,2010.166(11):p.334-335.

33. Psatha,E.,etal.,Clinicalefficacyandcardiorespiratoryeffectsofalfaxalone,ordiazepam/fentanyl for induction of anaesthesia indogs that are apooranaestheticrisk.VeterinaryAnaesthesiaandAnalgesia,2011.38:p.24-36.

34. Zaki, S., et al., Clinical evaluation of Alfaxan-CD® as an intravenousanaestheticinyoungcats.AustralianVeterinaryJournal,2009.87(3):p.82-87.

TheFOIstatementforAlfaxan®(NADA#141-342)canbereviewedat:http://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/UCM326904.pdf

INDICATIONS:Alfaxan®is indicatedfortheinductionandmaintenanceofanesthesiaandforinductionofanesthesiafollowedbymaintenancewithaninhalantanesthetic,incatsanddogs.

Important Alfaxan® Risk Information: Warnings, Precautions and Contraindications:Whenusingalfaxalone,patientsshouldbecontinuouslymonitored,andfacilitiesforthemaintenanceofapatentairway,artificialventilation,andoxygensupplementationmustbeimmediatelyavailable.Alfaxan®doesnotcontainanantimicrobialpreservative.Donotuseifcontaminationissuspected.Strictaseptictechniquesmustbemaintainedbecausethevehicleiscapableofsupportingtherapidgrowthofmicroorganisms.Carefulmonitoringofthepatientisnecessaryduetopossibilityofrapidarousal.Alfaxan®iscontraindicatedincatsanddogswithaknownsensitivitytoalfaxaloneoritscomponents,orwhengeneralanesthesiaand/orsedationarecontraindicated.Adverse Reactions:Themostcommonsideeffectsofalfaxaloneincluderespiratoryandcardiovascularderangements,suchasapnea,hypotensionandhypertension.Appropriateanalgesiashouldbeprovidedforpainfulprocedures.

For more information contact:

Jurox Inc.

American Century Tower II, 4520 Main Street, Kansas City, MO 64111

Enquiries +1-844-ALFAXAN alfaxan@jurox.com

® Registered Trademark of Jurox Pty Limited.

Repeatable. Reliable. Relax.

What is Alfaxan® ?

References1. JuroxandRicera,Aninvitrostudyevaluatingthebindingofalfaxaloneto

variousnuclearreceptors(RiceraStudyNo.AA94464).RecordsinHouse,2010.

2. JuroxandRicera,Aninvitrostudyevaluatingthebindingofalfaxalonetovarious abuse receptors (Ricera Study No. AA94047). Records in House,2010.

3. Child,K.J.,etal.,MetabolismandexcretionofCT1341intherat.InSteroidAnaesthesia,1972.RoyalCollegeofPhysicians,London.

4. Selye, H., Anaesthetic effects of steroid hormones. Proceedings of theSocietyforExperimentalBiology,1941.46:p.116.

5. Phillips, G.H., Structure-activity relationships in steroid anaesthetics. J.SteroidBiochem.,1975.6(5):p.607-613.

6. ChildK.J.,etal.,ThepharmacologicalpropertiesinanimalsofCT1341–anewsteroidanaestheticagent.Br.J.Anaesth.,1971.43(1):p.2-13.

7. Krantz, J.C. et al., XXVI. Pharmacodynamic studies of polyoxyalkylenederivativesofhexitolanhydridepartialfattyacidesters.J.Pharmacol.Exp.Ther.,1948.93(2):p.188-195.

8. Brewster, M.E. et al., Development of a non-surfactant formulationfor alfaxalone through the use of chemically-modified cyclodextrins.J.Parenter.Sci.Technol.,1989.43(6):p.262-5.

9. Brewster,M.E.,etal.,Anintravenoustoxicitystudyof2-hydroxypropyl--cyclodextrin,ausefuldrugsolubilizer,inratsandmonkeys.Int.J.Pharm.,1990.59:p.232-243.

10. NADA141-342Alfaxan®zIntravenousinjectableanestheticforuseincatsanddogs.

11. Heit,M.C.,etal.,SafetyandefficacyofAlfaxan®CDRTUadministeredoncetocatssubcutaneouslyat10mg/kg.InACVIM,2004.

12. Muir, W., et al., Cardiorespiratory and anesthetic effects of clinical andsupraclinical doses of alfaxalone in dogs. Veterinary Anaesthesia andAnalgesia,2008.35(6):p.451-462.

13. Muir, W., et al., The cardiorespiratory and anesthetic effects of clinicalandsupraclinicaldosesofalfaxaloneincats.VeterinaryAnaesthesiaandAnalgesia,2009.36(1):p.42-54.

14. Whittem,T.andPasloske,P.,RD9604.03–H005.Eightdaytargetanimalsafetystudyof intravenousAlfaxan®CDRTUindogsadministeredeveryotherday.2004,JuroxPty.Ltd.

15. Pasloske, K. and Whittem, T., JX9604.07-H004. A target animal safetystudyincatsafteradministrationofAlfaxan®CDRTUassingle,repeatedinjectionsondays0,2and5atdosesof5,15or25mg/kg.2004,0nfileatJuroxPtyLtd.

16. NADA141-342:Dogfieldstudy(JX9604.03-C009)p.22.17. NADA141-342:Catfieldstudy(JX9604.07-C006)p.11.18. Metcalfe,S.,etal.,Amulti-centreclinicaltrialevaluatingtheefficacyand

safety of Alfaxan® administered to bitches for induction of anaesthesiaprior tocaesareansection. In33rdWorldsmallAnimalCongress.2008.Dublin,Ireland:WSAVA/FECAVA.

19. Pasloske, K., et al., Plasma pharmacokinetics of alfaxalone in bothpremedicated and un-premedicated Greyhound dogs after single,intravenous administration of Alfaxan at a clinical dose. Journal ofVeterinaryPharmacologyandTherapeutics,2009.32:p.510-513.

20. Mesens, J.L., et al., Pharmaceutical applications of 2-hydroxypropyl--cyclodextrin. In New trends in cyclodextrins and derivatives. (Editor: D.Duchene).1991:Paris.P.369-407.

21. Pasloske, K., et al., A multicentre clinical trial evaluating the efficacyand safety of Alfaxan®-CD RTU administered to dogs for inductionand maintenance of anaesthesia. In British Small Animal VeterinaryAssociationCongress.2005.Birmingham,UK.

22. Pasloske, K., et al., A multicentre clinical trial evaluating the efficacyand safety of Alfaxan®-CD RTU administered to cats for inductionand maintenance of anaesthesia. In British Small Animal VeterinaryAssociationCongress.2007.Birmingham,UK.

23. Ambros, B., et al., Comparison of the anesthetic efficacy andcardiopulmonary effects of continuous rate infusions of alfaxalone in2-hydroxypropyl--cyclodextrin and propofol in dogs. Am. J. vet. Res.,2008.69(11):p.1391-8.

24. Heit,M.C.,etal.,CardiovascularandrespiratorysafetyofAlfaxan®CDRTUin cats premedicated with acepromazine, medetomidine, midazolam orbutorphanol.InACVIM.2004.

25. Amengual, M., et al., An evaluation of anaesthetic induction in healthydogsusingrapidintravenousinjectionofpropofoloralfaxalone.VeterinaryAnaesthesiaandAnalgesia,2012:p.n/a.

26. Herbert, G.L., et al., Alfaxalone for total intravenous anaesthesia indogs undergoing ovariohysterectomy: a comparison of premedicationwith acepromazine or dexmedetomidine. Veterinary Anaesthesia andAnalgesia,2012:p.n/a.

27. Jansen, K.S. and Uilenreel, J.J., A comparison between alfaxalone andpropofol continuous rate infusions in a total intravenous anaesthesiaprotocolforcaninesurgicalpatients.2009,FacultyofVeterinaryMedicine–UniversityofUtrecht.

28. Jimenez, C.P., et al., Evaluation of the quality of recovery afteradministration of propofol or alfaxalone for induction of anaesthesiain dogs anaesthetized for magnetic resonance imaging. VeterinaryAnaesthesiaandAnalgesia,2012.39(2):p.151-159.

29. Maddern,K.,etal.,Alfaxaloneinductiondosefollowingadministrationofmedetomidine and butorphanol in the dog. Veterinary Anaesthesia andAnalgesia,2010.37(1):p.7-13.

30. Martinez Taboada, F. and Murison, P.J., Induction of anaesthesia withalfaxaloneorpropofolbefore isofluranemaintenance incats.VeterinaryRecord,2010.167(3):p.85-89.

31. Mathis,A.,etal.,Comparisonofqualityof recovery fromanaesthesia incats induced with propofol or alfaxalone. Veterinary Anaesthesia andAnalgesia,2012.39(3):p.282-290.

32. Murison,P.J.andMartinezTaboada,F.,Effectofpropofolandalfaxaloneonpainafterovariohysterectomyincats.VeterinaryRecord,2010.166(11):p.334-335.

33. Psatha,E.,etal.,Clinicalefficacyandcardiorespiratoryeffectsofalfaxalone,ordiazepam/fentanyl for induction of anaesthesia indogs that are apooranaestheticrisk.VeterinaryAnaesthesiaandAnalgesia,2011.38:p.24-36.

34. Zaki, S., et al., Clinical evaluation of Alfaxan-CD® as an intravenousanaestheticinyoungcats.AustralianVeterinaryJournal,2009.87(3):p.82-87.

TheFOIstatementforAlfaxan®(NADA#141-342)canbereviewedat:http://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/UCM326904.pdf

INDICATIONS:Alfaxan®is indicatedfortheinductionandmaintenanceofanesthesiaandforinductionofanesthesiafollowedbymaintenancewithaninhalantanesthetic,incatsanddogs.

Important Alfaxan® Risk Information: Warnings, Precautions and Contraindications:Whenusingalfaxalone,patientsshouldbecontinuouslymonitored,andfacilitiesforthemaintenanceofapatentairway,artificialventilation,andoxygensupplementationmustbeimmediatelyavailable.Alfaxan®doesnotcontainanantimicrobialpreservative.Donotuseifcontaminationissuspected.Strictaseptictechniquesmustbemaintainedbecausethevehicleiscapableofsupportingtherapidgrowthofmicroorganisms.Carefulmonitoringofthepatientisnecessaryduetopossibilityofrapidarousal.Alfaxan®iscontraindicatedincatsanddogswithaknownsensitivitytoalfaxaloneoritscomponents,orwhengeneralanesthesiaand/orsedationarecontraindicated.Adverse Reactions:Themostcommonsideeffectsofalfaxaloneincluderespiratoryandcardiovascularderangements,suchasapnea,hypotensionandhypertension.Appropriateanalgesiashouldbeprovidedforpainfulprocedures.

For more information contact:

Jurox Inc.

American Century Tower II, 4520 Main Street, Kansas City, MO 64111

Enquiries +1-844-ALFAXAN alfaxan@jurox.com

® Registered Trademark of Jurox Pty Limited.

Repeatable. Reliable. Relax.

Alfaxalonebindstoasiteonthereceptorresultingintheopeningofthechloridepore,allowingentryofchlorideions.[1,2]Thiscauseshyperpolarizationoftheneuroneandinhibitionofimpulsetransmissionwhichgivesthemoleculeitsanestheticproperties.

Alfaxalone is short-acting and is rapidly cleared from the circulation[3] and Alfaxan® is suitable for use as an induction, and/or maintenance, anesthetic agent.

The development history of Alfaxan®

Intheearlypartofthetwentiethcenturytherewasagrowingrecognitionofthepotentialofcertainendogenoushormonestoactasagentsofsedation.Systematicresearch,beginninginthe1940s,producedanumberofcandidatecompoundsamongwhichalfaxaloneshowedmostpromiseintermsofsafetyandefficacy.[4,5,6]

Initialattemptsatdevelopmentandmarketingofananestheticbasedonthealfaxalonemoleculewerenotsuccessfulastheactiveingredientisnotsolubleinaqueoussolutionandwasconsequentlyformulatedinsuspensionwithacastoroilderivative,Cremophor.Thiscompoundproducedundesirablesideeffectswhichmanifestedasallergic-typereactions.[7]Thetwoproductscontainingalfaxalonewhichwerethenavailable,AlthesininhumananesthesiaandSaffaninveterinaryanesthesia,werewithdrawnfromthemarket.

However,workcontinuedtodevelopaformulationthatdidnotcausetheaboveeffects.[8,9]Finallyinthelate1990salfaxalonewasformulatedincyclodextrin,acomplexsugarthatallowedsolubilizationinaqueoussolutionwithouttheeffectsseenwiththeearlierproducts.

ThisformulationisnowmarketedacrosstheglobeasAlfaxan®.ItiscurrentlyregisteredandmarketedinAustralia,NewZealand,SouthAfrica,France,theUK,

theRepublicofIreland,Germany,theNetherlands,Spain,Canada,BelgiumandThailand.Alfaxan®isnowalsoavailableintheU.S.

Alfaxan®isa1%(10mg/mL)clear,colourless,aqueous,pHneutral,iso-osmolarsolutionofalfaxaloneincyclodextrinandsterilewater.Itcontainsnopreservative.Itismarketedin10mLvials.OnceAlfaxan®hasbeenopened,vialcontentsshouldbedrawnintosterilesyringes;eachsyringeshouldbepreparedforsinglepatientuseonly.Unusedproductshouldbediscardedwithin6hours.[10]

Alfaxan®isregisteredfortheinductionand/ormaintenanceofanesthesiaindogsandcats.Itcanbeusedtomaintainanesthesiabyintermittentintravenousboluses.

Use of Alfaxan®: tolerance studies

Alfaxan®doesnotcausetissueirritationafterperi-vascular,subcutaneousorintramuscularinjection.[11]

Acutetolerancetoover-dosagewithAlfaxan®hasbeendemonstratedupto5 timestherecommendeddoseof5mg/kgincatsandupto10 timestherecommendeddoseof2mg/kgindogs.[12,13]

RepeatedoverdosingofAlfaxan®at5 timestherecommendedrateindogsand5 timestherecommendedrateincats,at48hourintervalson3occasionsover7days,causednoclinicalpathology.[14,15]

Alfaxan®canbeusedtosupplyanesthesiainjuvenilepatients-puppiesfrom12weeksofage[16]andkittensfrom4weeksofage.[17]

Alfaxan®hasbeenproventobereliableandeffectiveasananestheticinductionagentincanineCaesareansection.[18]

Alfaxan®hasbeenproventobeareliableandeffectiveanestheticinductionagentinsighthounds.[19]

Alfaxan®: the essential factsActive ingredient and mode of action

Alfaxan® Intravenous Injectable Anestheticisananestheticinductionagentregisteredforuseindogsandcats,basedontheneurosteroid,alfaxalone.Thismoleculeissimilarinstructuretoprogesterone.Itworksatthesametrans-membraneGABAAreceptorasother(non-dissociative)anestheticinductiondrugs.

Pharmacokinetics/pharmacodynamics

TheactiveingredientofAlfaxan®,alfaxaloneisrapidlyeliminatedfromthebodyafterasingledose,beingcompletelyclearedwithinafewhours.[3]

AfteradministrationofAlfaxan®thedurationofunconsciousnesswillvaryduetoarangeoffactors.Asageneralguide,atrecommendeddosesandwithoutpremedication,catswillremainanesthetizedforapproximately25minutesanddogsforapproximately10minutes.[12,13]Concomitantuseofsedativeandanalgesicmedicationscanbeexpectedtodecreasethedose

requirementsforAlfaxan®andalterthedurationoftheresultinganesthesia.

Cardiorespiratory profile

Patientsinducedwith Alfaxan®inaccordancewiththelabelgenerallymaintainclinicallyacceptablebloodpressureparameters,breathespontaneouslyandmaintainclinicallyacceptablerespiratoryrate.[21,22]

Alfaxancancausedosedependantalterationsincardio-respiratoryfunctions.

Features and Benefits of Alfaxan®

Alfaxan®isaclear,aqueous,pHneutraliso-osmolarsolution.Thereforeitcausesnotissuedamageifinadvertentlygivenperi-vascularly.[11]

Alfaxan®containscyclodextrinasthesolubilizingagent.Thereforeitsuseisfreeofallergic-typehistaminicreactions.Itcanbeusedinbothcatsanddogs.[20]

Alfaxan®isaneurosteroidmoleculesimilartoendogenoussteroids.Thereforetherearewelldevelopedmetabolicprocessestoeliminatesuchmoleculesandtheactiveingredientisrapidlycleared,givinglittleornopost-anesthetichangover,evenafteritsuseinmaintenanceanesthesia.

WithAlfaxan®thereisnoinductionexcitementfromsub-anestheticdoses.[21,22]Thereforetheinjectioncanbegivenslowlytoeffectwhichmeansthepatientchoosesthetotaldoserequired,reducingtheriskofrespiratorydepressionandallowingasmoother,morerapidtransitiontomaintenancewithagaseousagent.

Alfaxan®hasminimaldose-dependanteffectsoncardiovascularfunction.[12,13]Thereforebloodpressureisgenerallywellmaintainedandprovidesacceptabletissueperfusion,importantinsustainingnormaltissue/organfunction.

Alfaxan®administeredasrecommendedcausesminimaldose-dependentrespiratorydepression.[21,22]Thereforepatientsoftenbreathenormally,assistinginsmoothtransitiontogaseousmaintenance.Apneaandrespiratorydepressioncanoccurafteralfaxaloneadministration.

Alfaxan®providesgoodmusclerelaxation.[12,13]Thereforethereisnoneedforadjunctivemusclerelaxants.

Alfaxan®hasanextremelywidesafetymargin,proveninacutetolerance[12,13]aswellrepeatedover-dosage[14,15]trials.Thereforeclinicstaffcanbecomfortableintheknowledgethatover-dosagecangenerallybemanagedwithsupportivecareofrespiratoryandcardiovascularfunction.

Alfaxan®hasbeenprovenreliableinyounganimals.[16,17]Thereforeitcanbegiventokittensasyoungas4weeksandpuppiesasyoungas12weeksofage.

Alfaxan®hasbeenevaluatedasasafeandeffectiveinductionagentinbitchespriortocaesareansection.[18]Thereforethereisnoneedforaspecificdrugforsuchcases,ifAlfaxan®becomestheclinic’sroutineinductionagent.

Alfaxan®hasbeenprovencompatiblewiththemajorgroupsofpremedicationagents.[19,21-34]Thereforetheintroductionof Alfaxan®totheclinicdoesnotalterthepremedicationprotocolswhichhavebeenusedtodate.

Alfaxan®isarapid,shortactinginductionagentwithawidesafetymargin.[12,13]Thereforeitisnotastressfulexperienceintroducingthedrugintotheclinicandexperiencecanbequicklygainedwithconfidence,byallmembersofstaff.

FollowingasingledoseofAlfaxan®,alfaxalone,theactiveingredient,israpidlymetabolizedintheliverandeliminatedinthebileandurine,withthedrugbeingcompletelyclearedfromthebodywithinafewhours.[3]Thereforethepatientreturnstonormalbehaviorsoonerandcangohomewithitsownersattheshortestpracticabletimeafteranesthesia.

Alfaxalonebindstoasiteonthereceptorresultingintheopeningofthechloridepore,allowingentryofchlorideions.[1,2]Thiscauseshyperpolarizationoftheneuroneandinhibitionofimpulsetransmissionwhichgivesthemoleculeitsanestheticproperties.

Alfaxalone is short-acting and is rapidly cleared from the circulation[3] and Alfaxan® is suitable for use as an induction, and/or maintenance, anesthetic agent.

The development history of Alfaxan®

Intheearlypartofthetwentiethcenturytherewasagrowingrecognitionofthepotentialofcertainendogenoushormonestoactasagentsofsedation.Systematicresearch,beginninginthe1940s,producedanumberofcandidatecompoundsamongwhichalfaxaloneshowedmostpromiseintermsofsafetyandefficacy.[4,5,6]

Initialattemptsatdevelopmentandmarketingofananestheticbasedonthealfaxalonemoleculewerenotsuccessfulastheactiveingredientisnotsolubleinaqueoussolutionandwasconsequentlyformulatedinsuspensionwithacastoroilderivative,Cremophor.Thiscompoundproducedundesirablesideeffectswhichmanifestedasallergic-typereactions.[7]Thetwoproductscontainingalfaxalonewhichwerethenavailable,AlthesininhumananesthesiaandSaffaninveterinaryanesthesia,werewithdrawnfromthemarket.

However,workcontinuedtodevelopaformulationthatdidnotcausetheaboveeffects.[8,9]Finallyinthelate1990salfaxalonewasformulatedincyclodextrin,acomplexsugarthatallowedsolubilizationinaqueoussolutionwithouttheeffectsseenwiththeearlierproducts.

ThisformulationisnowmarketedacrosstheglobeasAlfaxan®.ItiscurrentlyregisteredandmarketedinAustralia,NewZealand,SouthAfrica,France,theUK,

theRepublicofIreland,Germany,theNetherlands,Spain,Canada,BelgiumandThailand.Alfaxan®isnowalsoavailableintheU.S.

Alfaxan®isa1%(10mg/mL)clear,colourless,aqueous,pHneutral,iso-osmolarsolutionofalfaxaloneincyclodextrinandsterilewater.Itcontainsnopreservative.Itismarketedin10mLvials.OnceAlfaxan®hasbeenopened,vialcontentsshouldbedrawnintosterilesyringes;eachsyringeshouldbepreparedforsinglepatientuseonly.Unusedproductshouldbediscardedwithin6hours.[10]

Alfaxan®isregisteredfortheinductionand/ormaintenanceofanesthesiaindogsandcats.Itcanbeusedtomaintainanesthesiabyintermittentintravenousboluses.

Use of Alfaxan®: tolerance studies

Alfaxan®doesnotcausetissueirritationafterperi-vascular,subcutaneousorintramuscularinjection.[11]

Acutetolerancetoover-dosagewithAlfaxan®hasbeendemonstratedupto5 timestherecommendeddoseof5mg/kgincatsandupto10 timestherecommendeddoseof2mg/kgindogs.[12,13]

RepeatedoverdosingofAlfaxan®at5 timestherecommendedrateindogsand5 timestherecommendedrateincats,at48hourintervalson3occasionsover7days,causednoclinicalpathology.[14,15]

Alfaxan®canbeusedtosupplyanesthesiainjuvenilepatients-puppiesfrom12weeksofage[16]andkittensfrom4weeksofage.[17]

Alfaxan®hasbeenproventobereliableandeffectiveasananestheticinductionagentincanineCaesareansection.[18]

Alfaxan®hasbeenproventobeareliableandeffectiveanestheticinductionagentinsighthounds.[19]

Alfaxan®: the essential factsActive ingredient and mode of action

Alfaxan® Intravenous Injectable Anestheticisananestheticinductionagentregisteredforuseindogsandcats,basedontheneurosteroid,alfaxalone.Thismoleculeissimilarinstructuretoprogesterone.Itworksatthesametrans-membraneGABAAreceptorasother(non-dissociative)anestheticinductiondrugs.

Pharmacokinetics/pharmacodynamics

TheactiveingredientofAlfaxan®,alfaxaloneisrapidlyeliminatedfromthebodyafterasingledose,beingcompletelyclearedwithinafewhours.[3]

AfteradministrationofAlfaxan®thedurationofunconsciousnesswillvaryduetoarangeoffactors.Asageneralguide,atrecommendeddosesandwithoutpremedication,catswillremainanesthetizedforapproximately25minutesanddogsforapproximately10minutes.[12,13]Concomitantuseofsedativeandanalgesicmedicationscanbeexpectedtodecreasethedose

requirementsforAlfaxan®andalterthedurationoftheresultinganesthesia.

Cardiorespiratory profile

Patientsinducedwith Alfaxan®inaccordancewiththelabelgenerallymaintainclinicallyacceptablebloodpressureparameters,breathespontaneouslyandmaintainclinicallyacceptablerespiratoryrate.[21,22]

Alfaxancancausedosedependantalterationsincardio-respiratoryfunctions.

Features and Benefits of Alfaxan®

Alfaxan®isaclear,aqueous,pHneutraliso-osmolarsolution.Thereforeitcausesnotissuedamageifinadvertentlygivenperi-vascularly.[11]

Alfaxan®containscyclodextrinasthesolubilizingagent.Thereforeitsuseisfreeofallergic-typehistaminicreactions.Itcanbeusedinbothcatsanddogs.[20]

Alfaxan®isaneurosteroidmoleculesimilartoendogenoussteroids.Thereforetherearewelldevelopedmetabolicprocessestoeliminatesuchmoleculesandtheactiveingredientisrapidlycleared,givinglittleornopost-anesthetichangover,evenafteritsuseinmaintenanceanesthesia.

WithAlfaxan®thereisnoinductionexcitementfromsub-anestheticdoses.[21,22]Thereforetheinjectioncanbegivenslowlytoeffectwhichmeansthepatientchoosesthetotaldoserequired,reducingtheriskofrespiratorydepressionandallowingasmoother,morerapidtransitiontomaintenancewithagaseousagent.

Alfaxan®hasminimaldose-dependanteffectsoncardiovascularfunction.[12,13]Thereforebloodpressureisgenerallywellmaintainedandprovidesacceptabletissueperfusion,importantinsustainingnormaltissue/organfunction.

Alfaxan®administeredasrecommendedcausesminimaldose-dependentrespiratorydepression.[21,22]Thereforepatientsoftenbreathenormally,assistinginsmoothtransitiontogaseousmaintenance.Apneaandrespiratorydepressioncanoccurafteralfaxaloneadministration.

Alfaxan®providesgoodmusclerelaxation.[12,13]Thereforethereisnoneedforadjunctivemusclerelaxants.

Alfaxan®hasanextremelywidesafetymargin,proveninacutetolerance[12,13]aswellrepeatedover-dosage[14,15]trials.Thereforeclinicstaffcanbecomfortableintheknowledgethatover-dosagecangenerallybemanagedwithsupportivecareofrespiratoryandcardiovascularfunction.

Alfaxan®hasbeenprovenreliableinyounganimals.[16,17]Thereforeitcanbegiventokittensasyoungas4weeksandpuppiesasyoungas12weeksofage.

Alfaxan®hasbeenevaluatedasasafeandeffectiveinductionagentinbitchespriortocaesareansection.[18]Thereforethereisnoneedforaspecificdrugforsuchcases,ifAlfaxan®becomestheclinic’sroutineinductionagent.

Alfaxan®hasbeenprovencompatiblewiththemajorgroupsofpremedicationagents.[19,21-34]Thereforetheintroductionof Alfaxan®totheclinicdoesnotalterthepremedicationprotocolswhichhavebeenusedtodate.

Alfaxan®isarapid,shortactinginductionagentwithawidesafetymargin.[12,13]Thereforeitisnotastressfulexperienceintroducingthedrugintotheclinicandexperiencecanbequicklygainedwithconfidence,byallmembersofstaff.

FollowingasingledoseofAlfaxan®,alfaxalone,theactiveingredient,israpidlymetabolizedintheliverandeliminatedinthebileandurine,withthedrugbeingcompletelyclearedfromthebodywithinafewhours.[3]Thereforethepatientreturnstonormalbehaviorsoonerandcangohomewithitsownersattheshortestpracticabletimeafteranesthesia.

Contact your Midwest Veterinary Supply Rep for more information.Lakeville, MN Sun Prairie, WI Des Moines, IA Fort Wayne, IN Valley Forge, PA Owings Mills, MD Dallas, TX1-800-328-2975 1-800-362-9226 1-800-643-9378 1-800-447-7496 1-800-583-8020 1-800-583-8020 1-877-507-6531

What is Alfaxan® ?

References1. JuroxandRicera,Aninvitrostudyevaluatingthebindingofalfaxaloneto

variousnuclearreceptors(RiceraStudyNo.AA94464).RecordsinHouse,2010.

2. JuroxandRicera,Aninvitrostudyevaluatingthebindingofalfaxalonetovarious abuse receptors (Ricera Study No. AA94047). Records in House,2010.

3. Child,K.J.,etal.,MetabolismandexcretionofCT1341intherat.InSteroidAnaesthesia,1972.RoyalCollegeofPhysicians,London.

4. Selye, H., Anaesthetic effects of steroid hormones. Proceedings of theSocietyforExperimentalBiology,1941.46:p.116.

5. Phillips, G.H., Structure-activity relationships in steroid anaesthetics. J.SteroidBiochem.,1975.6(5):p.607-613.

6. ChildK.J.,etal.,ThepharmacologicalpropertiesinanimalsofCT1341–anewsteroidanaestheticagent.Br.J.Anaesth.,1971.43(1):p.2-13.

7. Krantz, J.C. et al., XXVI. Pharmacodynamic studies of polyoxyalkylenederivativesofhexitolanhydridepartialfattyacidesters.J.Pharmacol.Exp.Ther.,1948.93(2):p.188-195.

8. Brewster, M.E. et al., Development of a non-surfactant formulationfor alfaxalone through the use of chemically-modified cyclodextrins.J.Parenter.Sci.Technol.,1989.43(6):p.262-5.

9. Brewster,M.E.,etal.,Anintravenoustoxicitystudyof2-hydroxypropyl--cyclodextrin,ausefuldrugsolubilizer,inratsandmonkeys.Int.J.Pharm.,1990.59:p.232-243.

10. NADA141-342Alfaxan®zIntravenousinjectableanestheticforuseincatsanddogs.

11. Heit,M.C.,etal.,SafetyandefficacyofAlfaxan®CDRTUadministeredoncetocatssubcutaneouslyat10mg/kg.InACVIM,2004.

12. Muir, W., et al., Cardiorespiratory and anesthetic effects of clinical andsupraclinical doses of alfaxalone in dogs. Veterinary Anaesthesia andAnalgesia,2008.35(6):p.451-462.

13. Muir, W., et al., The cardiorespiratory and anesthetic effects of clinicalandsupraclinicaldosesofalfaxaloneincats.VeterinaryAnaesthesiaandAnalgesia,2009.36(1):p.42-54.

14. Whittem,T.andPasloske,P.,RD9604.03–H005.Eightdaytargetanimalsafetystudyof intravenousAlfaxan®CDRTUindogsadministeredeveryotherday.2004,JuroxPty.Ltd.

15. Pasloske, K. and Whittem, T., JX9604.07-H004. A target animal safetystudyincatsafteradministrationofAlfaxan®CDRTUassingle,repeatedinjectionsondays0,2and5atdosesof5,15or25mg/kg.2004,0nfileatJuroxPtyLtd.

16. NADA141-342:Dogfieldstudy(JX9604.03-C009)p.22.17. NADA141-342:Catfieldstudy(JX9604.07-C006)p.11.18. Metcalfe,S.,etal.,Amulti-centreclinicaltrialevaluatingtheefficacyand

safety of Alfaxan® administered to bitches for induction of anaesthesiaprior tocaesareansection. In33rdWorldsmallAnimalCongress.2008.Dublin,Ireland:WSAVA/FECAVA.

19. Pasloske, K., et al., Plasma pharmacokinetics of alfaxalone in bothpremedicated and un-premedicated Greyhound dogs after single,intravenous administration of Alfaxan at a clinical dose. Journal ofVeterinaryPharmacologyandTherapeutics,2009.32:p.510-513.

20. Mesens, J.L., et al., Pharmaceutical applications of 2-hydroxypropyl--cyclodextrin. In New trends in cyclodextrins and derivatives. (Editor: D.Duchene).1991:Paris.P.369-407.

21. Pasloske, K., et al., A multicentre clinical trial evaluating the efficacyand safety of Alfaxan®-CD RTU administered to dogs for inductionand maintenance of anaesthesia. In British Small Animal VeterinaryAssociationCongress.2005.Birmingham,UK.

22. Pasloske, K., et al., A multicentre clinical trial evaluating the efficacyand safety of Alfaxan®-CD RTU administered to cats for inductionand maintenance of anaesthesia. In British Small Animal VeterinaryAssociationCongress.2007.Birmingham,UK.

23. Ambros, B., et al., Comparison of the anesthetic efficacy andcardiopulmonary effects of continuous rate infusions of alfaxalone in2-hydroxypropyl--cyclodextrin and propofol in dogs. Am. J. vet. Res.,2008.69(11):p.1391-8.

24. Heit,M.C.,etal.,CardiovascularandrespiratorysafetyofAlfaxan®CDRTUin cats premedicated with acepromazine, medetomidine, midazolam orbutorphanol.InACVIM.2004.

25. Amengual, M., et al., An evaluation of anaesthetic induction in healthydogsusingrapidintravenousinjectionofpropofoloralfaxalone.VeterinaryAnaesthesiaandAnalgesia,2012:p.n/a.

26. Herbert, G.L., et al., Alfaxalone for total intravenous anaesthesia indogs undergoing ovariohysterectomy: a comparison of premedicationwith acepromazine or dexmedetomidine. Veterinary Anaesthesia andAnalgesia,2012:p.n/a.

27. Jansen, K.S. and Uilenreel, J.J., A comparison between alfaxalone andpropofol continuous rate infusions in a total intravenous anaesthesiaprotocolforcaninesurgicalpatients.2009,FacultyofVeterinaryMedicine–UniversityofUtrecht.

28. Jimenez, C.P., et al., Evaluation of the quality of recovery afteradministration of propofol or alfaxalone for induction of anaesthesiain dogs anaesthetized for magnetic resonance imaging. VeterinaryAnaesthesiaandAnalgesia,2012.39(2):p.151-159.

29. Maddern,K.,etal.,Alfaxaloneinductiondosefollowingadministrationofmedetomidine and butorphanol in the dog. Veterinary Anaesthesia andAnalgesia,2010.37(1):p.7-13.

30. Martinez Taboada, F. and Murison, P.J., Induction of anaesthesia withalfaxaloneorpropofolbefore isofluranemaintenance incats.VeterinaryRecord,2010.167(3):p.85-89.

31. Mathis,A.,etal.,Comparisonofqualityof recovery fromanaesthesia incats induced with propofol or alfaxalone. Veterinary Anaesthesia andAnalgesia,2012.39(3):p.282-290.

32. Murison,P.J.andMartinezTaboada,F.,Effectofpropofolandalfaxaloneonpainafterovariohysterectomyincats.VeterinaryRecord,2010.166(11):p.334-335.

33. Psatha,E.,etal.,Clinicalefficacyandcardiorespiratoryeffectsofalfaxalone,ordiazepam/fentanyl for induction of anaesthesia indogs that are apooranaestheticrisk.VeterinaryAnaesthesiaandAnalgesia,2011.38:p.24-36.

34. Zaki, S., et al., Clinical evaluation of Alfaxan-CD® as an intravenousanaestheticinyoungcats.AustralianVeterinaryJournal,2009.87(3):p.82-87.

TheFOIstatementforAlfaxan®(NADA#141-342)canbereviewedat:http://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/UCM326904.pdf

INDICATIONS:Alfaxan®is indicatedfortheinductionandmaintenanceofanesthesiaandforinductionofanesthesiafollowedbymaintenancewithaninhalantanesthetic,incatsanddogs.

Important Alfaxan® Risk Information: Warnings, Precautions and Contraindications:Whenusingalfaxalone,patientsshouldbecontinuouslymonitored,andfacilitiesforthemaintenanceofapatentairway,artificialventilation,andoxygensupplementationmustbeimmediatelyavailable.Alfaxan®doesnotcontainanantimicrobialpreservative.Donotuseifcontaminationissuspected.Strictaseptictechniquesmustbemaintainedbecausethevehicleiscapableofsupportingtherapidgrowthofmicroorganisms.Carefulmonitoringofthepatientisnecessaryduetopossibilityofrapidarousal.Alfaxan®iscontraindicatedincatsanddogswithaknownsensitivitytoalfaxaloneoritscomponents,orwhengeneralanesthesiaand/orsedationarecontraindicated.Adverse Reactions:Themostcommonsideeffectsofalfaxaloneincluderespiratoryandcardiovascularderangements,suchasapnea,hypotensionandhypertension.Appropriateanalgesiashouldbeprovidedforpainfulprocedures.

For more information contact:

Jurox Inc.

American Century Tower II, 4520 Main Street, Kansas City, MO 64111

Enquiries +1-844-ALFAXAN alfaxan@jurox.com

® Registered Trademark of Jurox Pty Limited.

Repeatable. Reliable. Relax.