12/14/2019
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`opiate_overdose_overview
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`Therapeutic Intranasal
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`Intranasal Naloxone Overview
`Topic summary:
`
`Opiate overdose is now among the leading causes of death in young adults in
`the western world. It is also still a scourge to the IVDU population. However,
`Naloxone - an effective and very safe antidote is available but must be
`administered in a timely fashion. Traditionally this antidote is injected either
`into a muscle or intravenously. This delivery method is effective, but due to
`issue surrounding needle safety, is not ideal or adequate for adoption by the lay
`public where effective treatment methods can have the most value. Fortunately,
`nasal naloxone can reverse the majority of opiate overdoses and is now proven
`to be safe and highly effective in the hands of the lay public. This overview
`section provides a quick look at the topic and provides dosing and protocols.
`Digging deeper behind this page is an extensive review the literature with
`supporting references (Click here to skip the overview below and to go directly
`to the deeper discussion).
`
`News Flash 2015: FDA Approved nasal naloxone
`for prescription and probably OTC use in the USA
`
`Adapt Pharma company announced formal FDA approval of a 4 mg/0.1 ml
`single dose, single nostril formulation of naloxone - NARCAN Nasal spray. They
`also acquired the trademark brand name "Narcan." Sales are expected to begin
`in the USA early in 2016. They have special pricing for first responders and
`community based treatment programs of $37.50 per preloaded device.
`
`Editorial comment: Even though I invented the MAD nasal, began the research
`on nasal naloxone in the 1990s and have used this therapy for 18 years (so
`have a bit of a historical bent towards the original method of delivery), it seems
`pretty apparent to me that this new product is probably a better method for
`delivery of nasal naloxone than the way we have posted here on this website
`since 2008. The new formulation is more appropriately concentrated, it has a
`pre-attached atomizer and because of the recent price increased in generic
`naloxone (single supplier cranked the price last year) this new formulation is
`not only better formulated, its also less expensive (in 2016). If they continue
`pricing it properly they should replace all generic "home made" kit formulations,
`if not - as of late 2017 - the research data does not show any better results
`than less concentrated generic formulations so the end user will need to decide
`which formulation to choose based on budget and convenience issues. I hope
`the company keeps this life saving drug at a reasonable price.
`
`intranasal.net/OpiateOverdose/Opiate_overdose_overview.htm
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`1/3
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`Opiant Exhibit 2149
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 1
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`12/14/2019
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`opiate_overdose_overview
`Key Concepts regarding delivery of any nasal medication to
`the systemic circulation and brain
`
`
`
`Use the right dose!
`
`Nasal medication doses are NOT equivalent to IV dosing. Using an IV
`dose will usually fail. (Read about bioavailability in the Overview page)
`Intranasal naloxone has not been studied in any dose other than 2 mg. A
`lower dose might work - but until confirmed with research it should not
`be recommended except in a research setting.
`
`Minimize volume, maximize concentration of the drug
`
`Use the most concentrated (potent) available formulation
`eg: Use naloxone 2 mg/2 ml, not 0.4 mg/ml
`Do NOT dilute the drug
`
`Large volumes are lost into the pharynx or out the nostril.
`
`Maximize total absorptive surface area
`
`Use BOTH nostrils for volumes over 0.3 ml. This doubles the absorptive
`surface area and reduces runoff.
`ABOUT half per nostril is clinically adequate - do not worry about being
`exact.
`
`Use a delivery system that maximizes mucosal surface area coverage
`and minimizes loss to the environment and runoff
`
`Droppers work in research using cooperative patients who hold still for
`many minutes. They tend to be less effective in clinical trials.
`Atomization (not nebulization over minutes) allows immediate delivery of
`all the drug directly to the mucosa in a broad area of coverage with little
`loss to the environment. This improves clinical effect and does not
`require a cooperative patient.
`
`Be thoughtful about anatomic issues and head positioning to enhance
`delivery
`
`If possible place the Occiput/crown of the head down (neck extended in
`recumbent position) delivers more drug higher onto the turbinate's to
`enhance absorption and nose-brain transport.
`Blood and mucous should be suctioned if possible to enhance mucosal
`coverage.
`Use of vasoconstrictors might reduce drug absorption (cocaine,
`epinephrine, oxymetazoline, phenyephrine)
`
`Key Concepts related to this specific application
`
`Dosing: Naloxone come is two concentrations (2 mg/2 ml and 0.4 mg/ml).
`Research confirms that either concentration will work, but the 2 mg/ml is lower
`volume so less with run out of the nose. The only dose studied in every paper
`to date (as of March 2014) is 2 mg. A lower dose MIGHT work, but until
`confirmed in research, it should not be recommended.
`
`Awakening: Some medics are concerned that 2 mg will cause violent arousal.
`Too date the studies that have investigated this suggest IN naloxone leads to
`less violent awakening compared to injectable naloxone. This is likely due to
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`intranasal.net/OpiateOverdose/Opiate_overdose_overview.htm
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`2/3
`
`Opiant Exhibit 2149
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 2
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`

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`12/14/2019
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`opiate_overdose_overview
`bioavailability and absorption kinetics (see overview page here). The nasal drug
`is not completely absorbed (they do NOT get 2 mg in their brain) and it is
`absorbed over 15 minutes (they slowly wake up). It may be true that a lower
`dose will work and cause less arousal. However, it should be studied, and only
`in patients in whom you can easily bag-mask and maintain oxygen delivery for
`a prolonged time while you wait to find out. Ideally this would be done in
`volunteer study with controlled opiate sedation and controlled dosing of
`naloxone.
`
`Dosing information
`
`Naloxone 2 mg/2 ml: Deliver 2 mg, half up each nostril and support
`ventilation for a few minutes as the drug begins to work.
`
`Protocol for intranasal naloxone (click here)
`
`Commonly used generic intranasal medications - single page dosing summary
`(click here)
`
`In Depth literature review, discussion, bibliography (Click
`here)
`
`
`
`Home | Overview | Off-label | Anatomy | Delivery | Protocols | Teaching | Bibliography | Links
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`intranasal.net/OpiateOverdose/Opiate_overdose_overview.htm
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`3/3
`
`Opiant Exhibit 2149
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 3
`
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