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`[TED STATES OFMIERICA
`
`UNITED STATES DEPARTMENT OF COMMERCE
`
`United States Patent and Trademark Office
`
`October 25, 2018
`
`THIS IS TO CERTIFY THAT ANNEXED HERETO IS A TRUE COPY FROM
`THE RECORDS OF THIS OFFICE OF:
`
`U.S. PATENT: 9,468, 747
`
`ISSUE DATE: October 18, 201' 6
`
`
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`
`
`By Authority ofthe
`
`Under Secretary of Commerce for Intellectual Property
`and Director of the United States Patent and Trademark Office
`
`,¢'/4’f’
`P. R. GRANT
`
`Certifying Officer
`
`Nalox 1 001
`
`NalOX-l Pharmaceuticals, LLC
`
`Page 1 Of 39
`
`

`

`10000000000 IMHNMM
`U3009468747Bz
`
`US 9,468,747 B2
`(10) Patent No:
`(12) Unite States Patent
`
`
`
`(45) Date of Fat-nt:1.Cry:.2! e1 *Get. 18, 2016
`
`(S4) NASAL DRUG PRODUCTS AND METHODS
`OF THEIR U E
`5
`('11) Applicant: Lightlake Therapeutics, Inc._. New
`York. NY (US)
`
`(72)
`
`,
`Inventors: Roger Crystal. Santa Monica, CA
`[115); Michael Brenner Weiss, New
`York, NY (US)
`
`{'13} Assignee:
`
`_
`{ " ) Notice:
`
`()plant Pharmaceuticals, Inc., Santa
`.
`Monica, CA (US)
`.
`_
`_
`_
`.
`Subject to an).r disclaimer, the term 01 this
`patent is extended or adjusted under 35
`U'S'C' 1540’) by 0 day?"
`This patent is subject to a terminal dis-
`claimer
`
`'
`
`(21) APP‘- N04 1419509797
`(22) Filed:
`Nov. 24, 2015
`
`(65)
`
`Prior Publication Data
`
`iglgrglfiool A]
`1 i” ESSOI‘J A]
`20165000821? AI
`
`6-‘2015 Wyse et 21.
`9-"2015 Crystal eta].
`112016 Crystal et al.
`
`.
`\
`FOREIGN PATENT DOCUMENTS
`15'5'9'
`23005
`16111115; Bl
`3:30.03
`wo 3203758 Al
`11.11982
`W0 9830211 A]
`711993
`W0 1.106275? A]
`11132000
`WU “074652 M 1212000
`W0 053447 A1
`8.’200l
`wo 0132931 A1
`1112001
`wo 0211778 A]
`272002
`WO 1131134520 A2
`10321103
`21:8 22300233335; 3 1:33:
`wo 20060§9973 22
`012005
`W0 2001033073 M
`712007
`WO 2009040595 A]
`2:"2009
`WO 2012026963 AZ
`32012
`WO 2131315631? A2
`1152012
`wo 2013128447 Al
`972013
`W0 20l4016653 AI
`1521114
`“'0 2015095644 Al
`(152015
`WO 2015136373 Al
`9-"2015
`W0 2D|6007729 A]
`|-"2016
`
`CN'
`EP
`wo
`W0
`W0
`“'0
`W0
`wo
`wo
`W0
`:3
`wo
`W0
`“'0
`W0
`W0
`wo
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`W0
`W0
`W0
`
`!
`‘
`.
`
`US 201610184294 A1
`
`'
`
`(200601)
`(2006-01 )
`(2006.01)
`(2006.01)
`(2006.01)
`
`Jun. 3|). 2016
`_
`Related “‘5' Application Data
`(63) Continuation of application No. 141942.344, filed on
`Nov. 16. 2015. which is =1 continuation-impart of
`applirfptrolr':I No. 1416553412, filed on Mar. 10, 2015,
`now at.
`0' 9’211‘2
`'
`Provisional a
`lieation No. (11953379. filed on Mar.
`14 2014
`PP
`)
`"
`Int. Cl.
`AH‘” 31/”
`A 61"" 5/110
`AMP 13/00
`AISLE 31/56
`.‘161‘K 43/02
`(52) U.S. Cl.
`(.‘PC'
`
`Se
`
`ti
`'fi
`fCl
`[‘1 1d
`“55‘ 93 on
`‘ e
`'3
`are
`None
`.
`_
`.
`See application file for complete search history.
`References Cited
`
`61]
`
`)
`
`{
`
`(51)
`
`(58)
`
`[56)
`
`“run/00 (2013.00; A6117 47/02
`(2013 01)
`'
`'
`
`h
`
`OTHER PUBLICATIONS
`L'.S. Appl. No. [43942.344‘ filed Nov. 16. 2015. Crystal ct a].
`Walley. A ‘1’ ct a]. ‘Opioid overdose rates and implementation of
`overdose “ducal”? “‘1 1‘3“” 1.1101013? dismbuulon “1 “wacm'
`1:5'3Tfafig’rd “me “”95 ”315'5‘5‘ BM] 346.1"1‘1‘4.{Pubhshed
`Walley A Y er 211.. "Opioid memos: p
`tion with imam“
`naloxone among people wno take methadone,” .1 Subst Abuse Treat
`44= 3 34M? (Epub Sen I2 20121
`Weber 1 M ct 21. “Can nebulimd 0210x011: be used Rafel) and
`efl‘ecuvcly by emergency medical services for suspected opioid
`ggiiriooe?’ Prehasp Emcrg (are 16:-9. 289—92 t’Epuh 13130.22
`Merlin M A et 21., “[ntranasal mloxone deliver).r is an alternative to
`intravenous naloxone foropioid overdoses," Am J 15111ng Med 28:3,
`290—303 (Bpuh Ian. 28. 2010).
`Kerr D et 21.. “Randomized controlled trial comparing the efl'ec-
`ti\'en<:ss and safety of iannasal and inLrarnuscular nnloxone for the:
`treatment of suspected heroin overdose." Addiction 104:12. 206?-
`“(F-1“" N0“ 96°09)-
`.
`.
`.
`Robertson T M,
`[mt-20213211 naloxone IS a_ viable alternative to
`Intravenous naloxone lor prehospttal narcotic overdose." Prchosp
`Emerg Care 13:4. 512—15 (Published Oct. 2009).
`.
`C
`ed
`( 0nt|nu
`)
`
`Jeflrev T Palenjk
`Primary Examiner
`(74) Attorney. Agent, or Firm — Dennis A. Bennett;
`Cynthia Halltawa}.r
`
`(5?)
`
`ABSTRACT
`
`Drug products adapted for nasal delivery. comprising a
`pro-primed device filled with a pharmaceutical composition
`comprising an opioid receptor antagonist. are provided.
`Methods of treating opioid overdose or its symptoms with
`the inventive [1mg products are also provided.
`
`45 Claims, 7 Drawing Sheets
`
`U.S. PATENT DOCUMENTS
`4,181.726 A
`131980 Bernstein
`4.464.318 A
`$31934 Hussein
`5,866,154 A
`21999 Ballal 21.11.
`9.192.510 32‘ ”£015 \Vyse .................. AfilK9-‘0'U4J
`200330017300 Al
`45211113 Wermeling
`20061-’0120967 AI
`6-‘2006 Namhuri el al.
`2009.5110l7102 AI
`1-2009 Srinchcornb er a1.
`20103018495 .-‘\I
`512010 Wennelingetal.
`20107'0l68147 Al
`712010 Chaplet) at a].
`201(1-"0331354 A]
`1232010 Wermeling
`201150045112 A]
`252011 Chaplet) 01:1].
`2012113270895. Al
`lU.-'2012 Wenneling
`3111330023825 A1
`1.52013 Edwards et 21.
`
`Copy provided by USPTO from 111:: PIRS Image Database on 10—23~201 3
`
`NaloxlOOl
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`Nalox—l Pharmaceuticals, LLC
`
`Page 2 of 39
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`

`

`US 9,468,?47 B2
`Page 2
`
`(56)
`
`Rafe routes Cited
`
`OTHER PUBLICATIONS
`Doe-Shaking M et al.. “Saved by the nose; bystander-administered
`intranasai naloxone hde‘lJclIloridc for opioid overdose." Am J
`Public HeaIlh 99:5. 783-91 (published May 2009).
`Heard C et a1.. "intranasal fiumazenil and naloxone to reverse
`ove -sedation in a child undergoing dental reslorations.” Paodiatr
`Anaesth 19:8 ?9$-99 (published Aug. 2009).
`Dowling J et a].. “Population phannacokinetics ol‘ intravenous.
`intramuscular. and intranasal naloxone in human volunteers.” Ther
`Drug Monit 30:4 490-96 (published Aug. 2008).
`Ashton H el a1.. "Rest evidence topic report. Intranasal naloxone in
`suspected opioid overdose.“ Emerg Med 1 23:3. 221-23 (published
`Mar. 2006).
`Barton E D et a1.. "Eflicacy ofintranasal anoxone as a noedleless
`alternative for treatment of opioid overdose in the prehospital
`setting." J Emerg Mod 29:3. 265-?1 [published Oct. 2005).
`Kelly A M et a[., “Randomised trial of inn-anneal vcrzus intramus-
`cular naloxonc in prehospital treatment for suspected opioid over-
`dose.” Med J Rust [82:I 24-27 (published Jan. 3. 2005).
`Kelly A M et a1. “[ntranasal naloxone for litc threatening opioid
`toxicity," Ernerg .Vled J 19:4. 375 (published Jul. 2002).
`Barton Ii D et al.. “Intranasal administration of naloxone by
`paramedics." Prehosp Emerg Care 6:1, 54-58 (published Jan. 2002).
`Loin-1e1- N et al.. "Nasal administration of naloxone is as ofi’ective as
`the intravenous route in opiate addicts." Int J Addict 29:6. 819-21:r
`(published Apr. 1994).
`
`Loirner N et al., "Nasal administration of naloxone for detection of
`opiate dependence,” J Psychiatr Res 26:1. 39-43 (published Jan.
`1992).
`Bailey A M et 31.. "Naluxone for opioid overdose prevention:
`pharmacists'
`role in community-based practice settings." Ann.
`Pharmacother 48:5. 601—05 (published May 2014).
`Wermeling D P ct a1., "Aresponsc to the opioid overdose epidemic:
`ualoxone nasal spray.” Drug Delivery Trans]. Res. 3:1. 63—?4
`(published Feb. [.2013].
`Wenncling I) P et 31.. “Opioid harm reduction strategies: focus on
`expanded access to innanasal naloxone." Pharmacotherapy 30:?.
`627—31. 2010.
`Apta: I lnirDose and Bi1)ose product information sheet. available at
`uww.aptar.com’docSe'piianna-prescriptionfuds‘bds-datasheetpdf,
`publication date unknown. last accessed Mar. 26. 2015.
`International Search Report and Written Opinion for Application
`No. IBrzoismoosMi; Sep. 2. 2015.
`II pgs.
`Notice of Allowance. us. App]. No. 14.-"659.472. Oct. 9, 2015, 9
`[‘33-
`Corrected Notice Allowance, T.i.S. Appl. No. 143659.472. Nov.
`2015. 9 pgs.
`LES. Appl. No. 151483.441. filed Jun. 14, 2016. Keegan F. at a].
`Krielet P, ct a1.. thnacokinclic Properties and Human L'se Char-
`acteristics of an FDA Approved lntranasal Naloxone Product for the
`Treatment of Opioid Overdose. J Clin Phannacol. 2016. pp. 1-11.
`International Search Report and Written Opinion for W02016.’
`007729. Dec. 4. 2015, 16 pages.
`
`‘ cited by examiner
`
`
`
`Cop}.r provided by USPTO from the PIRS image Database on 10-23-2018
`
`NaloxlOOl
`
`Naiox—l Pharmaceuticals, LLC
`
`Page 3 0f 39
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`

`

`US. Patent
`
`0a. 13, 2016
`
`Sheet 1 of?
`
`US 9,468,747 B2
`
`7‘0 ‘-
`g
`6‘0 ‘
`I? 5.0 «
`z
`E
`'63
`E.GIC
`OI
`2(E
`z
`
`FIG. 1
`
`”W04 mg 3M
`“IE-*2 mg RN
`M°5~372o2m4 mg IN
`
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`ii
`
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`
`0.5
`
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`:5
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`2.9
`
`2.5
`
`3.3
`
`fime Post Administration {hr}
`
`:
`
`‘
`
`Copy pruvidcd by USPTO from {he HRS Image Databas: m1 10-23-2018
`
`NaloxlOOl
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`Nalox-l Pharmaceuticals, LLC
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`Page 4 0f 39
`
`

`

`US. Patent
`
`Oct. 18, 2016
`
`Sheet 2 of 7
`
`US 9,468,747 B2
`
`FIG. 2
`
`meg mg IM
`
`”W2 mg IN
`
`W444 mg IN
`
`{mg/mi.) i
`
`Naioxone
`
`i
`
`-
`
`~
`
`”WWW.”
`
`”WM-
`mm ,
`
`-
`
`:
`
`g
`2;
`
`0.0
`
`2.0
`
`3.9
`6.0
`4.0
`Time Post Administration (hr)
`
`10.0
`
`12.0
`
`Copy provided by USPTO from [he PIRS Image Dawbaac on "3—23-20] 8
`
`Naloxl 001
`
`Nalox- '1 Pharmaceuticals, LLC
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`Page 5 of 39
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`

`

`U.S. Patent
`
`Oct. 18, 2016
`
`Sheet 3 of 7
`
`US 9,468,747 B2
`
`10
`
`3A
`
`FIG. 3
`
`8
`
`6
`
`
`
`
`
` NaloxonePlasmaConcentration{ngimL}
`
`4— 2 x 40 mgme
`-- 2 x 20 mgirnL
`1— 1 x40 1119me
`+ 1 x 20 mglmL
`+ 0.4 mg IM
`
`Hours Posidose
`
`1 0
`
`12
`
`1o
`
`_
`
`33
`
`+ 2 x 20 mglmL
`
`
`
`
`
`
` oNaloxonePlasmaConcentration{nglmL}
`
`
`
`0.01 4- 2 x 40 mgme
`
`
`+ 1 x 20 mgz‘mL
`
`+ 04 mg EM
`.0001
`
`0.001
`
`—*— 1 x 4D mglrnL
`
`
`
`Hours Postdose
`
`Cnpy provided by USPTD From the PIRS Imagc Databas: on 10-23—20] 8
`
`NaloxlOOl
`
`Nalox-l Phannaceuticals, LLC
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`Page 6 01°39
`
`

`

`US. Patent
`
`Oct. 18, 2016
`
`Sheet 4 al' 7
`
`US 9,468,747 B2
`
`FIG. 4
`
`10mE
`
`
`
`
`
`:30'}
`
`
`
`
`
`
`
`{Hm-r-
` .Iv—r—r.
`
`
`
`
`00
`0.510
`1.5
`2.0
`2.5
`3.0
`35
`40
`Hours Postdose
`
`
`
`
`
`4A
`
`4" 2 x 40 mg/mL
`+ 2 x 20 mg/mL
`+ 1 x 40 mgme
`+ 1 x 20 mg/mL
`+ 0.4 mg IM
`
`‘
`8-
`
`
`
`NaloxonePlasmaConcentration(nge‘mL) N
`
`107
`3 -:
`EU)
`E,
`E
`
`.g
`g 1C
`
`8C
`
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`*- 2 x40 mgimL
`o 1
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`E ‘
`+ 1x40 mglmL
`g
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`5
`+ 0.4 mng
`1
`g
`
`0.01W!WIWPIWIWIW>II|
`0.0
`0.5
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`3.5
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`Hours Postdose
`
`Copy provided by USPTO from the PIRS Image Database on III—234018
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`Naloxl 001
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`Nalox-l Pharmaceuticals, LLC
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`Page 7 0f 39
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`

`

`US. Patent
`
`Oct. 13, 2016
`
`Sheet 5 of 7
`
`US 9,468,747 B2
`
`FIG.5
`0.4 mg IM
`
`A c:
`
`01 13'
`
`i i
`
`:
`
`F3 on
`
`.0 on
`
` NaioxonePlasmaConcentration(nglmL)
`
`
`
`
`
`NaloxonePlasmaConcentration(nglmL)AM
`
`
`
`573.p.
`
`F3 n:
`
`53 o
`
`A.
`
`DJ
`
`C)
`
`One Spray 20 mglmL
`
`SB
`
`+ Female
`
`4— Maia
`
`C)
`
`N
`
`A
`
`03
`Hour
`
`03
`
`10
`
`12
`
`Copy provided by lJSP'iI'O from the PIRS Image Database on |0-23-20] E
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`Nalox '1 00 '1
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`Page 8 0f 39
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`

`

`U.S. Patent
`
`Oct. 18, 2016
`
`Sheet 6 of 7
`
`US 9,468,747 B2
`
`i
`
`FIG.6
`
`Two Sprays 20 mgme
`
`03
`
`6A
`
`O}
`
`O
`
`
`
`NaloxonePlasmaConoentration(ngme)N4:»
`
`
`
`
`
`
`
`NafoxonePlasmaConcentration(ngme)
`
`
`Hour
`
`One Spray 40 mgr'mL
`
`
`
`Copy provided by USPI'U from [he PIRS Image Database on l0-23-2018
`
`NaloxlOOl
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`Page 9 of 39
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`

`

`U.S. Patent
`
`Oct. 13, 2016
`
`Sheet 7 of 7
`
`US 9,468,747 32
`
`FIG. 7
`
`Two Sprays 40 mglmL
`
`
`
`
`
`NaloxonePlasmaConcentration(nglmL)
`
`
`
`
`
`Copy provided by Li'SPTO from Ihc PIRS Image Database on 1023-2018
`
`Naloxl 001
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`Page '10 of 39
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`

`

`]
`NASAL DRUG PRODUCTS AND METHODS
`OF THEIR USE
`
`US 9,468,747 BZ
`
`S
`
`10
`
`15
`
`2|]
`
`
`
`This application is a continuation ofUS. application Ser.
`No, 14.942344, filed Nov. 16, 2015, which is a continua-
`tion-in-part of US. application Ser. No. 1436595172, filed
`Mar. 16, 2015, which claims the benefit ofU.S. Provisional
`Application No. 61r‘953,3?9, filed Mar. 14, 2014, the dis-
`closure of which is hereby incorporated by reference as if
`written herein in its entirety.
`Provided are drug products adapted for nasal delivery
`comprising a pro-primed device and a pharmaceutical com—
`position comprising an opioid receptor antagonist, pharma-
`ceutical compositions comprising an opioid receptor antago-
`nist, and methods of use thereof.
`Opioid receptors are G protein—coupled receptors (GP-
`CR5) that are activated both by endogenous opioid peptides
`and by clinically important alkaloid analgesic drugs such as
`morphine. 'Ihere are three principal types of opioid recep-
`tors:
`the o—opioid receptor, the rr—opioid receptor. and the
`u-opioid receptor. Opioids depress respiration, which is
`controlled principally through medullary respiratory centers
`with peripheral
`input
`from chemoreccptors and other
`sources. Opioids produce inhibition at the clternoreceptors
`via p-opioid receptors and in the medulla via IC— and o-opioid
`receptors. While there are a number of neurotransmitters
`mediating the conLrol of respiration, glutamate and Tamin-
`obrrtyric acid (GABA) are the major excitatory and inhibi-
`tory neurotransmitters, respectively. This explains the poten-
`tial for interaction of opioids with henzodiachines and
`alcohol: both benzodiazepines and alcohol facilitate the
`inhibitory efl'ect of GABA at the GABM receptor. while
`alcohol also decreases the excitatory eflect of glutamate at
`NMDA receptors. Oxycodone and other opioid painkillers,
`as well as heroin and methadone are all implicated in fatal
`overdose. Heroin has three metabolites with opioid activity.
`Variation in the formation of these metabolites due to
`genetic factors and the use of other drugs could explain
`differential sensitivity to overdose. Metabolites of metha-
`done contribute little to its action. However, variation in rate
`of metabolism due to genetic factors and other drugs used
`can modify methadone concentration and hence overdose
`risk. The degree of tolerance also determines risk. Tolerance
`to respiratory depression is less than complete, and may be
`slower than tolerance to euphoric and other effects. One
`consequence ofthis may be a relatively high risk of overdose
`among experienced opioid users. While agonist administra-
`tion modifies receptor function, changes (usually in the
`opposite direction) also result from use of antagonists, for
`example, supersensitivity to opioids following a period of
`administration of antagonists such as naltrexone.
`In the United States mortality rates closely correlate with
`opioid sales.
`in 2003, approximately 36,450 people died
`from drug overdoses. At
`least 14,800 of these deaths
`involved prescription opioid analgesics. Moreover, accord-
`ing to the Substance Abuse and Mental Health Services
`Administration, the numberi'rate of Americans l2 years of
`age and older who currently abuse pain relievers has
`increased by 20 percent between 2002 and 2009. in New
`York City, between 1990 and 2006. the fatality rate from
`prescription opioids increased seven-fold, from 0.39 per
`100,000 persons to 2.7. Drugs classed as prescription opi-
`oids in this study include both typical analgesics, such as
`()xyContin® (oxycodone HC]
`controlled-release) and
`methadone (used in the treatment of dependence on other
`opioids such as heroin and also prescribed for pain). but the
`increase in the rate ofdrug overdose over the 16 years of the
`
`2
`study was driven entirely by overdoses ol'typieal analgesics.
`Over the same time period. methadone overdoses remained
`stable, and overdoses from heroin declined. Whites were
`more likely than blacks and Latinos to over-dose on these
`analgesics, and deaths mostly occurred in neighborhoods
`with loWer rates of poverty, suggesting dill'ercntial access to
`doctors who can write painkiller prescriptions may be a
`driVing force behind the racial disparity. ((Ierda et al. “Pre-
`scription opioid mortality trends in New limit City, 1990-
`2006: Examining the emergence ofan rpt‘demic." Drug and
`Alcohol Dependence Volume 132, Issues 1-2,
`1 Sep. 2013.
`53-62.)
`Naloxonc is an opioid receptor antagonist that is approved
`for use by injection for the reversal of opioid overdose and
`for adjunct use in the treatment of septic shock.
`It
`is
`currently being used mainly in emergency departments and
`in ambulances by trained medical professionals. There have
`been eflorts to expand its use by providing the drug to some
`patients with take—home opioid prescriptions and those who
`inject illicit drugs, potentially facilitating earlier administra-
`tion of the drug. The UN Commission on Narcotics Drugs
`”encourages all Member States to include efiective elements
`for the prevention and treatment of drug overdose, in par-
`ticular opioid overdose,
`in national dnrg policies. where
`. appropriate, and to share best practices and information on
`the prevention and treatment ot‘drng overdose, in particular
`opioid overdose,
`including the use of opioid receptor
`antagonists such as naloxone.”
`U.S. Pat. No. 4,464,37I'8 describes a method for eliciting
`an analgesic or narcotic antagonist response in a warm-
`blooded animal, which comprises administering intranasally
`(IN) to said animal to elicit a narcotic antagonist response,
`a narcotic antagonist effective amount of naloxone. W0
`82.103768 discloses a composition that contains 1 mg of
`naloxone hydrochloride per 0.] ml of solution adapted for
`nasal administration used in the treatment of narcotic
`induced respiratory depression (overdose) at a dosage
`approximately the same as that employed for intravenous
`(IV), intramuscular (IM) or subcutaneous (SQ) administra-
`tion. W0 W62??? teaches pharmaceutical compositions for
`IN or oral (PO) administration which comprise an opioid
`antagonist. such as naloxone for application by spray in the
`reversal of opioid depression for treatment of patients suf-
`fering from opioid over—dosage, wherein the spray applica-
`tor is capable of delivering single or mtdtiple doses and
`suitable dosage units are in the range of 0.2 to 5 mg.
`The use of nasal naloxone is not without controversy. For
`instance, Loirner et al. (International Journal of Addictions,
`29(6), 819—321 [994) reported that the nasal administration
`of naloxone is as etfective as the intravenous route in opiate
`addicts, however. Bowling et al. ('lher Drug Mortit, Vol 30.
`No 4, August 2008) reported that naloxouc administered
`intranasally displays a relative bioavailability of 4% only
`and concluded that the IN absorption is rapid but does not
`maintain measurable concentrations for more than an hour.
`One early study of 196 consecutive patients with sus—
`pected opioid overdose conducted in an urban out—of-hos-
`pita] setting, had shown the mean interval from emergency
`medical services (HMS) arrival to a respiratory rate of 210
`breathslmin was 93:42 min with administration of ualorr-
`one 0.4 mg 1V. versus 9.62-1.58 min with administration of
`naloxone 0.8 mg SQ. The authors concluded that the slower
`rate of absorption via the SQ route was offset by the delay
`irt establishing an IV line. (Wanger et al., Intravenous vs
`subcutaneous aar’al‘orrefor out-ofhospimf management of
`presumed opioid tnerdose. Acad limerg Med. 1998 April:
`5(4):293-9).
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`The Denver Health Partunedic system subsequently
`investigated the cfiicacy and safety of atomized intranasal
`naloxone for the treatment of suspected opiate overdose
`(Barton, ct 31., Efficacy ofr'rrrmrwsa! rrar’oxorte as a needle—
`less alternative for treatment of opioid over-dose in the
`prekospr'mr’ setting. J Emerg Med, 2005. 29(3): p. 265-?1).
`All adult patients encountered in the prehospilal setting as
`suspected opiate overdose.
`found down. or with altered
`mental status who met the criteria for nalortone admirnsna-
`tion were included in the study. IN naloxone (2 mg) was
`administered immediately upon patient contact and before
`IV insertion and administration of 1V naloxone (2 mg).
`Patients \verc then treated by EMS protocol. The main
`outcome measures were: time of IN naloxone administra~
`lion, time of IV naloxone administration, titne ofappropriate
`patient response as reported by paramedics. Ninety-five
`patients received IN naloxone and were included in the
`study. A total of 52 patients responded to naloxone by either
`IN or IV, with 43 (33%) reSponding to [N naloxone alone.
`Seven patients (16%) in this grotlp required further doses of
`1V naloxone. The median times from arrival at patient side
`to awakening and from administration of the IN naloxone to
`patient awakening were 8.0 minutes and 3.0 minutes respec-
`tively.
`'lhe Drug Overdose Prevention and Education (DOPE)
`Project was the first naloxone prescription pong-am (NPP)
`established in partnership with a county health department
`(San Francisco Department of Public Health), and is one of
`the longest running NPPs in the USA. From September 2003
`to lkcembct‘ 2009, 1,942 individuals were trained and
`prescribed naloxone through the DOPE Project, of whom
`24% returned to receive a naloxonc refill, and 11% reported
`using naloxonc during an overdose event. Of 399 overdose
`events where naloxone was used, participants reported that
`39% were reversed. In addition, 83% of participants who
`reported overdose reversal attributed the reversal to their
`adminisn‘ation of naloxone, and fewer than 1% reported
`serious adverse effects. Findings from the DOPE Project add
`to a growing body ofrescarch that suggests that intravenous
`drug users (10115) at high risk of witnessing overdose events
`are Willing to be trained on overdose response strategies and
`use take-home naloxone during overdose events to prevent
`deaths (Enttx'n. et a1., Overdose prevention and nalcxorre
`prescription for opioid users in San Francisco. J Urban
`Health. 2010 December; 87(6):931-41).
`Another reported study reviewed EMS and hospital
`records before and after implementation of a protocol for
`administration of intranasal naloxorre by the Central Cali-
`fornia EMS Agency in order to compare the prchospital time
`intervals from patient contact and medication administration :
`to clinical response for IN versus intravenous IV naloxone
`in patients with suspected narcotic overdose. The protocol
`for the treatment of opioid overdose with intranasal nalox-
`one Was as follows: "intranasal (IN)—Adn1inister 2 mg
`intranasally (] mg per nostril} using mucosal atomizer
`device (MAD'M)
`ii' suspected narcotic intoxication and
`respiratory depression (rate 3 or less). This dose may be
`repeated in 5 minutes if respiratory depression persists.
`Respirations should be supported with a bag valve mask
`until respiratory rate is greater than 3. Intramuscular (1M)—
`Adminjster 1 mg if unable to administer intranasally (see
`special considerations}. May repeat once in 5 minutes.
`Intravenous ([V1—Administer 1 mg slow 1V push if no
`response to intranasal or IM administration alter 10 minutes.
`Pediatric dose—0.1 mgr'kg intranasally, if less than 10 kg
`and less than ] year old". Patients with suspected narcotic
`overdose treated in the prehospital setting over 1? months,
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`4
`between March 2003 and July 2004 were included. Para—
`medics documented dosc, route of administration. and posi-
`tive response times using an electronic record. Clinical
`response was defined as an increase in respiratory rate
`(breathstmin) or Glasgow Coma Scale score of at least 6.
`Main outcome variables included time fi'om medication to
`clinical response and time from patient contact to clinical
`response. Secondary variables included numbers of doses
`administered and reseue doses given by an alternate route.
`BetweIm-group comparisons were accomplished using
`Hosts and chi—square tests as appropriate. One hundred
`fifty-four patients met the inclusion criteria, including 104
`treated with IV and 50 treated with IN naloxonc. Clinical
`response was noted in 33 (66%) and 58 (56%) of the IN and
`1V groups. respectively (p-03). 'lhe mean time between
`naloxone administration and clinical response was longer for
`the IN group (12.9 vs. 8.] min, p=0.W). However, the mean
`times from patient contact to clinical response were not
`significantly difi‘erent between the IN and IV groups (20.3
`vs. 20.1f min, p—0.9). More patients in the IN group received
`two doses of nalosone (34% vs. 18%, p=0.05), and three
`patients in the IN group received a subsequent dose of 1V or
`IM naloxone. (Robertson et al., latrartasat natoxorre is a
`viable alternative to intravenous nar’oxone for prehospr'mr‘
`narcotic owrd‘ose. Prehosp Enterg Care. 2009 October—
`December',
`l3(4):512—5).
`in August 2006. the Boston Public Health Commission
`passed a public health regulation that authorized an opioid
`overdose prevention program that included intranasal nalox-
`one education and distribution of the spray to potential
`bystanders. Participants were instructed by trained stall" to
`deliver ] mL (1 mg) to each nostril of the overdose victim.
`After 15 months, the program had provided training and
`intranasal naloxone to 335 participants who reported ”M
`successful overdose reversals (Doe-Simkins et a1. Overdose
`prevention education with distribution ofr'mmnasat' Halo:—
`one is dr‘easiblepur‘mc health intervention to address opioid
`overdose. Am J Public Health. 2009: 99:733—791).
`Overdose education and nasal naloxone distribution
`(OENDJ programs are community-based interventions that
`educate people at risk for overdose and potential bystanders
`on how to prevent, recognize and respond to an overdose.
`They also equip these individuals with a tialoxone resoue kit.
`To evaluate the impact oIOENL) programs on rules ofopioid
`related death from overdose and acute care utilization in
`Massachusetts, an interrupted time series analysis of opioid
`related overdose death and acute care utilization rates from
`2002 to 2009 was performed comparing community—year
`strata with high and low rates ot'OEND implementation to
`those with no implementation. ‘lhe setting was nineteen
`Massachusetts communities (geographically distinct cities
`and towns) with at least live fatal opioid overdoses in each
`of the years 2004 to 2006. OEND was implemented among
`opioid users at risk For overdose, social service agency stall".
`family, and friends of opioid users. OEND programs
`equipped people at risk for overdose and bystanders with
`nasal naloxone rescue kits and trained them how to prevent.
`recognize, and respond to an overdose by engaging emer—
`gency medical services. providing rescue breathing, and
`delivering naloxone. Among these communities. ()END
`programs trained 2,912 potential bystanders who reported
`32? rescues. Both community—year strata with 1-100 enroll-
`ments per 100,000 population (adjusted rate ratio 0.73, 95%
`confidence interval 0.57" to 0.91) and community-ywrr strata
`with greater than 100 enrollments per 100,000 population
`(054, 0.39 to 0.76) had significantly reduced adjusted rate
`ratios compared with communities with no implementation.
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`Difierences in rates of acute care hospital utilization were
`not significant. Opioid overdose death rates were reduced in
`communities where OEN'D was implemented. This study
`provides observational evidence that by training potential
`bystanders to prevent, recognize, and respond to opioid
`overdoses, OEND is an efl'ective intervention (Walley et al .,
`Opioid overdose rates and implementation of overdose
`education and nasal calm-one distribution in Massachu—
`setts:
`interrupted time series await-sis. RM] 2013'. 346:
`fl'l-l).
`Naloxone prescription programs are also ofi‘ered by com—
`munity-based organisations in Los Angeles and Philadel-
`phia. Programs in both cities target 1|)Us. Studies which
`recruited 150 11)le across both sites for in-depth qualitative
`interviews compared two groups of 1DUs, those who ltad
`received naloxone prescriptions and those who had never
`rcceiVed naioxone prescriptions. In both LA. and Philadel-
`phia. IDUs reported successfully administering naloxonc to
`reverse recently witnessed overdoses. Reversals often
`occurred in public places by both housed and homeless
`IDUs. Despite these successes, lDUs frequently did not have
`naloxone with them when they Witnesscd an overdose. 'l‘wo
`typical reasons reported were naloxonc was confiscated by
`police, and lDUs did not feel comfortable carrying naloitone
`in the event of being stopped by police. Similarly, some
`untrained lDUs reported discomfort with the idea of carry—
`ing naloxone on them as their reason for not gaining a
`prescription.
`A randomized trial comparing 2 mg neloxone delivered
`intranasally with a mucosa} atomizer to 2 mg intramuscular
`naloxone was reported by Kelly et al., in 2005 (Med J Aust.
`2005 Jan. 3: 182(1)124-7). The study involved 155 patients
`(7‘1 1M and 84 IN) requiring treatment for suspected opiate
`overdose and attended by paramedics of the Metropolitan
`Ambulance Service (MAS) and Rural Ambulance Victoria
`in Victoria, Australia. The 1M group had more rapid
`response than the 1N group, and were more likely to have
`more than 10 spontaneous respirations per minute within 8
`minutes (82% v. 613%; P=0.01?3). There was no statistically
`significant difl'erence between the 1M and IN groups for
`needing rescue naloxone (13% [IM group] v. 26% [IN
`group]; P= 0.05.53). The authors concluded that [N naloxone
`is reflective in treating opiate-induced respiratory depression.
`but is not as effective as 1M naloxonc.
`Kerret a1. (Addiction. 2009 December, 104(12);206’l—T4)
`disclosed treatment ofheroin overdose by intranasa] admin—
`istration of naloxone constituted in a vial as a preparation of
`2 mg in 1 mL. Participants received 1 mg (0.5 ml) in each
`nostril. The rate of response within 10 minutes was SCI-’83
`(72.3%) for 2 mg 1N nsloxone versus 6989 015%) for 2
`mg 1M naloxonc. The mean response times were 3.0 minutes
`and 71.9 minutes for [N and 1V naloxonc respectively.
`Supplementary naiortone was administered to fewer patients
`who received 1M naloxune (4.5%) than IN (18.1%).
`W020121563l'i‘ describes a study in which naloxone, 8
`mg and 16 mg, was administered as 400 p].- IN (2110 [IL per
`nostril). The administration was performed as follows: The
`pump of the nasal spray was primed by removing the cap
`and pressing downward. Tltis is repeated at least 6 times or
`until a line Spray appears; printing is done just prior to
`closing. The subject is in a standing or upright position and
`should gently blow the nose to clear the nostrils. The subject
`should tilt the head forward slightly and gently close one
`nostril by pressing the outside of the nose with a finger on
`the nostril to be closed. The device is inserted into the open
`nostril and it is sprayed 2 times into the nostril. The subject
`should gently breath inward through the nostril, the device
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`is removed, and the steps are repeated for the other nostril.
`The mean me values were reported to be 0.34 h (20.4 min)
`and 0.39 h (23.4 min) for the 8 and 16 mg doses respectively.
`Wcrmeling (Drug Deliv Transl Res. 2013 Febntary 1;
`3(1): 63—?4) teaches that the initial adult dose ofnaloxone in
`known or suspected narcotic overdose is 0.4 to 2 mg, which
`may be repeated to a total dose of 10 mg and that the current
`formulations ofnaloxone are approved for intravenous (IV)=
`intramuscular (1M) and subcutaneous (SC) administration,
`with IV being the recommended route. Wenneling also
`predicts that a 2 mg nasal solution dose of naloxone will
`likely have a Cm”, of 3—5 nngL and a rm“ of approximately
`20 minutes.
`
`Since the onset of action of nnloxone used in opioid
`overdose cases should be as fast as possible, naloxone is thus
`far mainly administered intravenously or intramuscularly by
`emergency health care personnel. Due to a high first pass
`metabolism, oral dosage forms comprising naloxone display
`a low bioavailability and thus seem to be not suitable for
`such purposes. The administration of naloxone via iniection
`into the blood stream or into the muscle requires first of all
`trained medical personnel (for intravenous injection) or a
`trained carer
`(for
`intramuscular
`injection). Secondly,
`depending on the constitution of the addict and the period of
`intravenous drug abuse, it can be particularly difficult to find
`acceSs into a vein of the addict’s body for administering
`naloxonc intravenously. Clearly, there is a risk of expOsurc
`to blood borne pathogens for the medical personnel or the
`trained carer since a large population of drug addicts sufi‘ers
`from blood borne pathogen induced diseases such as HIV,
`hepatitis B and C. and the like since accidental necdlestick
`is a serious safety concern. 385,000 needle-stick injuries
`have been estimated to have occurred in the year 2000 in the
`US alone (Wilburn, .N'eedl‘estr’rd and sharps injury preven-
`tion, OnlineJ lssues Nurs 2004, Sq). 30; 9(3):S).
`Nalottone has a relatively short half—life of compared to
`some longer—acting opioid formulations and so after a typi-
`cal therapeutic dose of naloxone is administered to an opioid
`overdose patient
`there is often the need to re—administer
`naloxone,
`in some cases even several
`times, and it
`is
`important to seek immediate medical attention.
`Furthermore, it has been suggested that in view of the
`growing Opioid ov