11/21/2019
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`NALOXONE HYDROCHLORIDE
`
`NALOXONE HYDROCHLORIDE
`
`Injection, USP
`Fliptop Vial, Opioid Antagonist
`Protect from light.
`Rx only
`
`DESCRIPTION
`’
`Naloxone Hydrochloride Injection, USP is a sterile, nonpyrogenic solution of naloxone hydrochloride in water for injection. Each milliliter (mL)
`contains 0.4 mg naloxone hydrochloride and sodium chloride to adjust tonicity in water for injection. May contain hydrochloric acid for pH
`adjustment; pH 4.0 (3.0 to 6.5).
`The single-dose solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended for use only as a
`single-dose injection. When smaller doses are required, the unused portion should be discarded.
`The multiple-dose solution contains, in addition, 1.8 mg/mL methylparaben and 0.2 mg/mL propylparaben added as preservatives.
`Naloxone Hydrochloride Injection, USP may be administered intravenously, intramuscularly, or subcutaneously.
`Naloxone, an opioid antagonist, is a synthetic congener of oxymorphone. It differs from oxymorphone in that the methyl group on the nitrogen atom
`is replaced by an allyl group.
`Naloxone Hydrochloride, USP is chemically designated 17-Allyl-4,5a-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (C19H21NO4 • HCl), a
`white to slightly off-white powder soluble in water, in dilute acids, and in strong alkali; slightly soluble in alcohol; practically insoluble in ether and
`chloroform. It has a molecular weight of 363.84. It has the following structural formula:
`
`*HCI
`
`CLINICAL PHARMACOLOGY
`Complete or Partial Reversal of Opioid Depression
`Naloxone prevents or reverses the effects of opioids including respiratory depression, sedation and hypotension. Also, Naloxone can reverse the
`psychotomimetic and dysphoric effects of agonist-antagonists, such as pentazocine.
`Naloxone is an essentially pure opioid antagonist, i.e., it does not possess the "agonistic" or morphine-like properties characteristic of other opioid
`antagonists. When administered in usual doses and in the absence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially no
`pharmacologic activity.
`Naloxone has not been shown to produce tolerance or cause physical or psychological dependence. In the presence of physical dependence on
`opioids, naloxone will produce withdrawal symptoms. However, in the presence of opioid dependence, opiate withdrawal symptoms may appear
`within minutes of naloxone administration and will subside in about 2 hours. The severity and duration of the withdrawal syndrome are related to the
`dose of naloxone and to the degree and type of opioid dependence.
`While the mechanism of action of naloxone is not fully understood, in vitro evidence suggests that naloxone antagonizes opioid effects by competing
`for the mu, kappa, and sigma opiate receptor sites in the CNS, with the greatest affinity for the mu receptor.
`When naloxone hydrochloride is administered intravenously, the onset of action is generally apparent within two minutes; the onset of action is
`slightly less rapid when it is administered subcutaneously or intramuscularly. The duration of action is dependent upon the dose and route of
`administration of naloxone hydrochloride. Intramuscular administration produces a more prolonged effect than intravenous administration. Since the
`duration of action of naloxone may be shorter than that of some opiates, the effects of the opiate may return as the effects of naloxone dissipates. The
`requirement for repeat doses of naloxone, however, will also be dependent upon the amount, type and route of administration of the opioid being
`antagonized.
`Adjunctive Use in Septic Shock
`Naloxone has been shown in some cases of septic shock to produce a rise in blood pressure that may last up to several hours; however this pressor
`response has not been demonstrated to improve patient survival. In some studies, treatment with naloxone in the setting of septic shock has been
`associated with adverse effects, including agitation, nausea and vomiting, pulmonary edema, hypotension, cardiac arrhythmias, and seizures. The
`decision to use naloxone in septic shock should be exercised with caution, particularly in patients who may have underlying pain or have previously
`received opioid therapy and may have developed opioid tolerance.
`Because of the limited number of patients who have been treated, optimal dosage and treatment regimens have not been established.
`
`https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=8535cc84-ad4a-4d67-8480-fb5a2e3406f8&type=display
`
`1/11
`
`Opiant Exhibit 2045
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 1
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`

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`Opiant Exhibit 2045
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 2
`
`

`

`Opiant Exhibit 2045
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 3
`
`

`

`Opiant Exhibit 2045
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 4
`
`

`

`Opiant Exhibit 2045
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 5
`
`

`

`Opiant Exhibit 2045
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 6
`
`

`

`Opiant Exhibit 2045
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 7
`
`

`

`Opiant Exhibit 2045
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 8
`
`

`

`Opiant Exhibit 2045
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 9
`
`

`

`Opiant Exhibit 2045
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 10
`
`

`

`Opiant Exhibit 2045
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 11
`
`