`
`These highlights do not include all the information needed to use NARCAN NASAL SPRAY safely and effectively.
`information for NARCAN e NASAL SPRAY.
`
`See full prescribing
`
`NARCAN e (naloxone hydrochloride) nasal spray
`Initial U.S. Approval: 1971
`
`-----RECENT MAJOR CHANGES----
`Dosage and Administration, Dosing in Adults and
`Pediatric Patients (2.2)
`
`01/2017
`
`-----INDICATIONS AND USAGE-----
`NARCAN Nasal Spray is an opioid antagonist indicated for the
`emergency treatment of known or suspected opioid overdose, as
`manifested by respiratory and/or central nervous system
`depression. (1)
`
`NARCAN Nasal Spray is intended for immediate administration
`as emergency therapy in settings where opioids may be present.
`(1)
`
`NARCAN Nasal Spray is not a substitute for emergency medical
`care. (1)
`----DOSAGE AND ADMINISTRATION--
`• NARCAN Nasal Spray is for intranasal use only. (2.1)
`• Seek emergency medical care immediately after use. (2.1)
`• Administration of asingle spray of NARCAN Nasal Spray
`intranasally into one nostril. (2.2)
`• Administer additional doses of NARCAN Nasal Spray, using
`a new nasal spray with each dose, if the patient does not
`respond or responds and then relapses into respiratory
`depression, additional doses of NARCAN Nasal Spray may be
`given every 2 to 3 minutes until emergencymeclical
`assistancearrives. (2.2)
`• Additional supportive and/or resuscitative measures may be
`helpful while awaiting emergency medical assistance. (2.2)
`
`---DOSAGE FORMS AND STRENGTHS----
`Nasal spray: 2 mg and 4 mg of naloxone hydrochloride in
`0.1 mL. (3)
`
`—CONTRAINDICATIONS------
`Hypersensitivity to naloxone hydrochloride. (4)
`
`-----WARNINGS AND PRECAUTIONS-----
`• Risk of Recurrent Respiratory and CNS Depression: Due to the
`duration of action of naloxone relative to the opioid, keep patient
`under continued surveillance and administer repeat doses of
`naloxone using a new nasal spray with each dose, as necessary,
`while awaiting emergency medical assistance. (5.1)
`• Risk of Limited Efficacy with Partial Agonists or Mixed
`Anonists/Antagonists: Reversal of respiratory depression caused
`by partial agonists or mixed agonists/antagonists, such as
`buprenorphine and pentazocine, may be incomplete. Larger or
`repeat doses may be required. (5.2)
`• Precipitation of Severe Opioid Withdrawal: Use in patients who
`are opioid dependent may precipitate opioid withdrawal. In
`neonates , opioid withdrawal may be life-threatening if not
`recognized and properly treated. Monitor for the development of
`opioid withdrawal. (5.3)
`• Risk of Cardiovascular (CV) Effects: Abrupt postoperative
`reversal of opioid depression may result in adverse CV effects.
`These events have primarily occurred in patients who had pre-
`existing CV disorders or received other drugs that may have
`similar adverse CV effects. Monitor these patients closely in an
`appropriate healthcare setting after use of naloxone
`hydrochloride. (5.3)
`
`-----ADVERSE REACTIONS------
`The following adverse reactions were observed in a NARCAN
`Nasal Spray clinical study: increased blood pressure,
`musculoskeletal pain, headache, nasal dryness, nasal edema, nasal
`congestion, and nasal inflammation. (6)
`
`To report SUSPECTED ADVERSE REACTIONS, contact
`Adapt Pharma, Inc. at 1-8444NARCAN (1-844-462-7226) or
`FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA-approved patient labeling.
`
`Revised: 01/2017
`
`Reference ID: 4045900
`
`APT00018727
`
`Opiant Exhibit 2097
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 1
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.2 Phannacodynamics
`
`12.3 Phannacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, IvIutagenesis, Impairment of Fertility
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`16.1 How Supplied
`
`16.2 Storage and Handling
`
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing
`information are not listed.
`
`1 INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Important Administration Instructions
`
`2.2 Dosing in Adults and Pediatric Patients
`
`2.3 Dosing Modifications due to Partial Agonists or Mixed
`Agonist/Antagonists
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Risk of Recurrent Respiratory and Central Nervous
`System Depression
`
`5.2 Risk of Limited Efficacy with Partial Agonists or
`Mixed Agonist/Antagonists
`
`5.3 Precipitation of Severe Opioid Withdrawal
`
`6 ADVERSE REACTIONS
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.2 Lactation
`
`8.4 Pediatric use
`
`8.5 Geriatric Use
`
`Reference ID: 4045900
`
`APT00018728
`
`Opiant Exhibit 2097
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 2
`
`
`
`FULL PRESCRIBING INFORMATION
`1 INDICATIONS AND USAGE
`
`NARCAN Nasal Spray is indicated for the emergency treatment of known or suspected opioid
`overdose, as manifested by respiratory and/or central nervous system depression.
`
`NARCAN Nasal Spray is intended for immediate administration as emergency therapy in settings
`where opioids may be present.
`
`NARCAN Nasal Spray is not a substitute for emergency medical care.
`
`Limitations of Use:
`
`Restrict prescription of NARCAN Nasal Spray 2 mg to opioid-dependent patients expected to be at risk
`for severe opioid withdrawal in situations where there is a low risk for accidental or intentional opioid
`exposure by household contacts.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1
`
`Important Administration Instructions
`
`NARCAN Nasal Spray is for intranasal use only.
`
`No additional device assembly is required.
`
`Because treatment of suspected opioid overdose must be performed by someone other than the
`patient, instruct the prescription recipient to inform those around them about the presence of
`NARCAN Nasal Spray and the Instructions for Use.
`
`Instruct the patient or caregiver to read the Instructions for Use at the time they receive a
`prescription for NARCAN Nasal Spray. Emphasize the following instructions to the patient or
`caregiver:
`
`• Administer NARCAN Nasal Spray as quickly as possible because prolonged respiratory
`depression may result in damage to the central nervous system or death. Since the duration of
`action of most opioids exceeds that of naloxone hydrochloride and the suspected opioid
`overdose may occur outside of supervised medical settings, seek immediate emergency
`medical assistance, keep the patient under continued surveillance until emergency personnel
`arrive, and administer repeated doses of NARCAN Nasal Spray, as necessary. Always seek
`emergency medical assistance in the event of a suspected, potentially life-threatening opioid
`emergency after administration of the first dose of NARCAN Nasal Spray.
`
`• Additional doses of NARCAN Nasal Spray may be required until emergency medical
`assistance becomes available.
`
`• Do not attempt to reuse NARCAN Nasal Spray. Each NARCAN Nasal Spray contains a
`single dose of naloxone and cannot be reused.
`
`• Re-administer NARCAN Nasal Spray, using a new nasal spray, every 2 to 3 minutes if the
`patient does not respond or responds and then relapses into respiratory depression.
`
`Reference ID: 4045900
`
`APT00018729
`
`Opiant Exhibit 2097
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 3
`
`
`
`• Administer NARCAN Nasal Spray in alternate nostrils with each dose.
`
`• Administer NARCAN Nasal Spray according to the printed instructions on the device label
`and the Instructions for Use.
`
`• Place the patient in the supine position. Prior to administration, be sure the device nozzle is
`inserted in either nostril of the patient, and provide support to the back of the neck to allow
`the head to tilt back. Do not prime or test the device prior to administration.
`
`• To administer the dose press firmly on the device plunger.
`
`• Remove the device nozzle from the nostril after use.
`
`• Turn patient on their side as shown in the Instructions for Use and call for emergency
`medical assistance immediately after administration of the first dose of NARCAN Nasal
`Spray.
`
`2.2
`
`Dosing in Adults and Pediatric Patients
`
`Initial Dosing
`
`The recommended initial dose of NARCAN Nasal Spray in adults and pediatric patients is one
`spray delivered by intranasal administration into one nostril.
`
`Repeat Dosing
`
`Seek emergency medical assistance as soon as possible after administering the first dose of
`NARCAN Nasal Spray.
`
`The requirement for repeat doses of NARCAN Nasal Spray depends upon the amount, type, and
`route of administration of the opioid being antagonized.
`
`Administer NARCAN Nasal Spray in alternate nostrils with each dose.
`
`If the patient responds to NARCAN Nasal Spray and relapses back into respiratory depression
`before emergency assistance arrives, administer an additional dose of NARCAN Nasal Spray
`using a new NARCAN Nasal Spray and continue surveillance of the patient.
`
`If the desired response is not obtained after 2 or 3 minutes, administer an additional dose of
`NARCAN Nasal Spray using a new NARCAN Nasal Spray. If there is still no response and
`additional doses are available, administer additional doses of NARCAN Nasal Spray every 2 to
`3 minutes using a new NARCAN Nasal Spray with each dose until emergency medical
`assistance arrives.
`
`Additional supportive and/or resuscitative measures may be helpful while awaiting emergency
`medical assistance
`
`2.3
`
`Dosing Modifications due to Partial Agonists or Mixed Agonist/Antagonists
`
`Reversal of respiratory depression by partial agonists or mixed agonist/antagonists, such as
`buprenorphine and pentazocine, may be incomplete and require higher doses of naloxone
`
`Reference ID: 4045900
`
`APT00018730
`
`Opiant Exhibit 2097
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 4
`
`
`
`hydrochloride or repeated administration of NARCAN Nasal Spray using a new nasal spray [see
`Warnings and Precautions (5.2)].
`
`3 DOSAGE FORMS AND STRENGTHS
`
`NARCAN Nasal Spray is supplied as a single-dose intranasal spray containing 2 mg or 4 mg of
`naloxone hydrochloride in 0.1 mL.
`
`4 CONTRAINDICATIONS
`
`NARCAN Nasal Spray is contraindicated in patients known to be hypersensitive to naloxone
`hydrochloride or to any of the other ingredients.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1
`
`Risk of Recurrent Respiratory and Central Nervous System Depression
`
`The duration of action of most opioids may exceed that of NARCAN Nasal Spray resulting in a
`return of respiratory and/or central nervous system depression after an initial improvement in
`symptoms. Therefore, it is necessary to seek emergency medical assistance immediately after
`administration of the first dose of NARCAN Nasal Spray and to keep the patient under continued
`surveillance. Administer additional doses of NARCAN Nasal Spray if the patient is not
`adequately responding or responds and then relapses back into respiratory depression, as
`necessary [see Dosage and Administration (2.2)]. Additional supportive and/or resuscitative
`measures may be helpful while awaiting emergency medical assistance.
`
`5.2
`
`Risk of Limited Efficacy with Partial Agonists or Mixed Agonist/Antagonists
`
`Reversal of respiratory depression by partial agonists or mixed agonist/antagonists such as
`buprenorphine and pentazocine, may be incomplete. Larger or repeat doses of naloxone
`hydrochloride may be required to antagonize buprenomhine because the latter has a long
`duration of action due to its slow rate of binding and subsequent slow dissociation from the
`opioid receptor [see Dosage and Administration (2.3)]. Buprenorphine antagonism is
`characterized by a gradual onset of the reversal effects and a decreased duration of action of the
`normally prolonged respiratory depression.
`
`5.3
`
`Precipitation of Severe Opioid Withdrawal
`
`The use of NARCAN Nasal Spray in patients who are opioid-dependent may precipitate opioid
`withdrawal characterized by the following signs and symptoms: body aches, diarrhea,
`tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting,
`nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness,
`and increased blood pressure. In neonates, opioid withdrawal may be life-threatening if not
`recognized and properly treated and may include the following signs and symptoms:
`convulsions, excessive crying, and hyperactive reflexes. Monitor the patient for the development
`of the signs and symptoms of opioid withdrawal.
`
`There are limited data to inform if the 2 mg dose of NARCAN Nasal Spray will avoid
`precipitation of severe opioid withdrawal in the setting of opioid dependence. However, the 2
`
`Reference ID: 4045900
`
`APT00018731
`
`Opiant Exhibit 2097
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 5
`
`
`
`mg dose may not provide an adequate and timely reversal in persons who may be exposed to an
`overdose of a potent or very high dose of opioids.
`
`Abrupt postoperative reversal of opioid depression after using naloxone hydrochloride may
`result in nausea, vomiting, sweating, tremulousness, tachycardia, hypotension, hypertension,
`seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest. Death,
`coma, and encephalopathy have been reported as sequelae of these events. These events have
`primarily occurred in patients who had pre-existing cardiovascular disorders or received other
`drugs that may have similar adverse cardiovascular effects. Although a direct cause and effect
`relationship has not been established, after use of naloxone hydrochloride, monitor patients with
`pre-existing cardiac disease or patients who have received medications with potential adverse
`cardiovascular effects for hypotension, ventricular tachycardia or fibrillation, and pulmonary
`edema in an appropriate healthcare setting. It has been suggested that the pathogenesis of
`pulmonary edema associated with the use of naloxone hydrochloride is similar to neurogenic
`pulmonary edema, i.e., a centrally mediated massive catecholamine response leading to a
`dramatic shift of blood volume into the pulmonary vascular bed resulting in increased
`hydrostatic pressures.
`
`There may be clinical settings, particularly the postpartum period in neonates with known or
`suspected exposure to maternal opioid use, where it is preferable to avoid the abrupt precipitation
`of opioid withdrawal symptoms. In these settings, consider use of an alternative, naloxone-
`containing product that can be titrated to effect and, where applicable, dosed according to
`weight. [see Use in Specific Populations (8.4)] .
`
`6 ADVERSE REACTIONS
`
`The following serious adverse reactions are discussed elsewhere in the labeling:
`
`• Precipitation of Severe Opioid Withdrawal [see Warnings and Precautions (5.3)]
`
`Because clinical studies are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical
`studies of another drug and may not reflect the rates observed in practice.
`
`The following adverse reactions were observed in a NARCAN Nasal Spray clinical study.
`
`In a pharmacokinetic study of 30 healthy adult volunteers exposed to one spray of NARCAN
`Nasal Spray in one nostril or two sprays of NARCAN Nasal Spray, one in each nostril, the most
`common adverse reactions were: increased blood pressure, constipation, toothache, muscle
`spasms, musculoskeletal pain, headache, nasal dryness, nasal edema, nasal congestion, nasal
`inflammation, rhinalgia, and xeroderma.
`
`The following adverse reactions have been identified primarily during post-approval use of
`naloxone hydrochloride in the post-operative setting. Because these reactions are reported
`voluntarily from a population of uncertain size, it is not always possible to reliably estimate
`their frequency or establish a causal relationship to drug exposure: Hypotension, hypertension,
`ventricular tachycardia and fibrillation, dyspnea, pulmonary edema, and cardiac arrest. Death,
`coma, and encephalopathy have been reported as sequelae of these events. Excessive doses of
`
`Reference ID: 4045900
`
`APT00018732
`
`Opiant Exhibit 2097
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 6
`
`
`
`naloxone hydrochloride in post-operative patients have resulted in significant reversal of
`analgesia, and have caused agitation.
`
`Abrupt reversal of opioid effects in persons who were physically dependent on opioids has
`precipitated an acute withdrawal syndrome. Signs and symptoms have included: body aches,
`fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shivering or trembling,
`nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal cramps,
`increased blood pressure, tachycardia. In some patients, there may be aggressive behavior upon
`abrupt reversal of an opioid overdose. In the neonate, opioid withdrawal signs and symptoms
`also included convulsions, excessive crying, and hyperactive reflexes.
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1
`
`Pregnancy
`
`Risk Summary
`
`The limited available data on naloxone use in pregnant women are not sufficient to inform a drug-
`associated risk. However, there are clinical considerations [see Clinical Considerations] . In animal
`reproduction studies, no embryotoxic or teratogenic effects were observed in mice and rats treated with
`naloxone hydrochloride during the period of organogenesis at doses equivalent to 6-times and 12-times,
`respectively, a human dose of 8 mg/day (two NARCAN Nasal Sprays) based on body surface area
`comparison [see Data] .
`
`The estimated background risk of major birth defects and miscarriage for the indicated
`population is unknown. In the U.S. general population, the estimated background risk of major
`birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%,
`respectively.
`
`Clinical Considerations
`
`Fetal/Neonatal adverse reactions
`Naloxone hydrochloride crosses the placenta, and may precipitate withdrawal in the fetus, as
`well as in the opioid-dependent mother [see Warnings and Precautions (5.3,)J. The fetus should
`be evaluated for signs of distress after NARCAN Nasal Spray is used. Careful monitoring is
`needed until the fetus and mother are stabilized.
`
`Data
`
`Animal Data
`
`Naloxone hydrochloride was administered during organogenesis to mice and rats at
`subcutaneous doses up to 10 mg/kg/day (equivalent to 6-times and 12-times, respectively, a
`human dose of 8 mg (two NARCAN Nasal Sprays)) (based on body surface area comparison).
`These studies demonstrated no embryotoxic or teratogenic effects due to naloxone
`hydrochloride.
`
`Pregnant female rats were administered 2 or 10 mg/kg naloxone subcutaneously from Gestation
`Day 15 to Postnatal day 21. There were no adverse effects on the offspring (up to 12-times a
`human dose of 8 mg/day (two NARCAN Nasal Sprays) based on body surface area comparison).
`
`Reference ID: 4045900
`
`APT00018733
`
`Opiant Exhibit 2097
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 7
`
`
`
`8.2
`
`Lactation
`
`Risk Summary
`
`There is no information regarding the presence of naloxone in human milk, or the effects of
`naloxone on the breastfed infant or on milk production. Studies in nursing mothers have shown
`that naloxone does not affect prolactin or oxytocin hormone levels. Naloxone is minimally orally
`bioavailable.
`
`8.4
`
`Pediatric Use
`
`The safety and effectiveness of NARCAN Nasal Spray have been established in pediatric
`patients of all ages for known or suspected opioid overdose as manifested by respiratory and/or
`central nervous system depression. Use of naloxone hydrochloride in all pediatric patients is
`supported by adult bioequivalence studies coupled with evidence from the safe and effective use
`of other naloxone hydrochloride drug products. No pediatric studies were conducted for
`NARCAN Nasal Spray.
`
`Absorption of naloxone hydrochloride following intranasal administration in pediatric patients
`may be erratic or delayed. Even when the opiate-intoxicated pediatric patient responds
`appropriately to naloxone hydrochloride, he/she must be carefully monitored for at least
`24 hours, as a relapse may occur as naloxone hydrochloride is metabolized.
`
`In opioid-dependent pediatric patients, (including neonates), administration of naloxone
`hydrochloride may result in an abrupt and complete reversal of opioid effects, precipitating an
`acute opioid withdrawal syndrome. Neonatal opioid withdrawal syndrome, unlike opioid
`withdrawal syndrome in adults, may be life-threatening, if not recognized, and should be treated
`according to protocols developed by neonatology experts [see Warnings and Precautions (5.3)].
`
`In settings such as in neonates with known or suspected exposure to maternal opioid use, where
`it may be preferable to avoid the abrupt precipitation of opioid withdrawal symptoms, consider
`use of an alternate naloxone-containing product that can be dosed according to weight and
`titrated to effect.
`
`Also, in situations where the primary concern is for infants at risk for opioid overdose, consider
`whether the availability of alternate naloxone-containing products may be better suited than
`NARCAN Nasal Spray.
`
`8.5
`
`Geriatric Use
`
`Geriatric patients have a greater frequency of decreased hepatic, renal, or cardiac function and of
`concomitant disease or other drug therapy. Therefore, the systemic exposure of naloxone
`hydrochloride can be higher in these patients.
`
`Clinical studies of naloxone hydrochloride did not include sufficient numbers of subjects aged 65
`and over to determine whether they respond differently from younger subjects. Other reported
`clinical experience has not identified differences in responses between the elderly and younger
`patients.
`
`Reference ID: 4045900
`
`APT00018734
`
`Opiant Exhibit 2097
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 8
`
`
`
`11 DESCRIPTION
`
`NARCAN (naloxone hydrochloride) Nasal Spray is a pre-filled, single dose intranasal spray.
`Chemically, naloxone hydrochloride is the hydrochloride salt of 17-Ally1-4,5a-epoxy-3,14-
`dihydroxymoiphinan-6-one hydrochloride with the following structure:
`
`• HCI
`
`HO
`
`C19H21N04. HC1
`M.W. 363.84
`
`Naloxone hydrochloride, an opioid antagonist, occurs as a white to slightly off-white powder,
`and is soluble in water, in dilute acids, and in strong alkali; slightly soluble in alcohol; practically
`insoluble in ether and in chloroform.
`
`Each NARCAN Nasal Spray contains a 2 mg or 4 mg single dose of naloxone hydrochloride in a
`0.1 mL (100 microliter) aqueous solution.
`
`Inactive ingredients include benzalkonium chloride (preservative), disodium
`ethylenediaminetetraacetate (stabilizer), sodium chloride, hydrochloric acid to adjust pH, and
`purified water. The pH range is 3.5 to 5.5.
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`Naloxone hydrochloride is an opioid antagonist that antagonizes opioid effects by competing for
`the same receptor sites.
`
`Naloxone hydrochloride reverses the effects of opioids, including respiratory depression,
`sedation, and hypotension. It can also reverse the psychotomimetic and dysphoric effects of
`agonist-antagonists such as pentazocine.
`
`12.2 Pharmacodynamics
`
`When naloxone hydrochloride is administered intravenously, the onset of action is generally
`apparent within two minutes. The time to onset of action is shorter for intravenous compared to
`subcutaneous or intramuscular routes of administration. The duration of action is dependent upon
`the dose and route of administration of naloxone hydrochloride.
`
`12.3 Pharmacokinetics
`
`In a pharmacokinetic study in 30 healthy adult subjects, the relative bioavailability (BA) of one
`nasal spray in one nostril, consisting of a 2 mg total dose (0.1 mL of 20 mg/mL naloxone
`hydrochloride solution) and a 4 mg total dose (0.1 mL of 40 mg/mL naloxone hydrochloride
`solution), and two nasal sprays administered as one nasal spray in each nostril, consisting of a 4
`
`Reference ID: 4045900
`
`APT00018735
`
`Opiant Exhibit 2097
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 9
`
`
`
`mg total dose (0.1 mL of 20 mg/mL naloxone hydrochloride solution in each nostril) and an 8
`mg total dose ( 0.1 mL of 40 mg/mL naloxone hydrochloride solution in each nostril), were
`compared to a single dose of 0.4 mg naloxone hydrochloride intramuscular injection. For
`intranasal administration, the subjects were instructed not to breathe through the nose during
`administration of the nasal spray, and remained fully supine for approximately one hour post-
`dose. For intramuscular administration, naloxone was administered as a single injection in the
`gluteus maximus muscle. The pharmacokinetic parameters obtained in the study are shown in
`Table 1.
`
`Table 1
`
`Mean Pharmacokinetic Parameters (CV%) for Naloxone Following NARCAN
`(Naloxone HCI) Nasal Spray and Intramuscular Injection of Naloxone HCI to
`Healthy Subjects
`
`Parameter
`
`2 mg- One Nasal
`Spray in one
`nostril
`20 mg/ml
`(N=29)
`
`4 mg - Two Nasal
`Sprays, one in
`each nostril
`20 mg/ml
`(N=29)
`
`4 mg - One Nasal
`Spray in one
`nostril
`40 mg/ml
`(N=29)
`
`8 mg -Two Nasal
`Sprays, one in each
`nostril
`40 mg/ml
`01=29)
`
`0.4 mg
`Intramuscular
`Injection
`(N=29)
`
`0.33(0.25, 1.00)
`
`0.33(0.17,0.57)
`
`0.50(0.17, 1.00)
`
`0.33(0.17, 1.00)
`
`0.38(0.08,2.05)
`
`C.x (ng/mL)
`
`AUCt (hr.ng/mL)
`
`AUCo_i„f (h*ng/mL)
`
`t% (h)
`
`Dose normalized Relative BA
`(%) vs. IM
`
`2.91(35)
`
`4.60(27)
`
`4.66(27)
`
`1.85(33)
`
`51.7(22)
`
`6.30(34)
`
`9.64(24)
`
`9.74(24)
`
`2.19(33)
`
`54.0(23)
`
`4.83(43)
`
`7.87(37)
`
`7.95(37)
`
`2.08(30)
`
`9.70(36)
`
`15.3(23)
`
`15.5(23)
`
`2.10(32)
`
`0.88(31)
`
`1.75(23)
`
`1.79(23)
`
`1.24(26)
`
`44.2(31)"
`
`43.1(24)
`
`100
`
`reported as median (minimum, maximum)
`t t
`"N=28 for Relative BA.
`
`Reference ID: 4045900
`
`APT00018736
`
`Opiant Exhibit 2097
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 10
`
`
`
`Figure 1
`
`Mean ± SD Plasma Concentration of Naloxone, (a) 0-6 hand (b) 0-1h Following
`Intranasal Administration and Intramuscular Injection
`
`14
`
`(a)
`mg - one spray (0.1 mL of 20 mg/mL) in one nostril
`4 mg - two spray (0.1 mL of 20 mg/mL) in each nostril
`mg - one spray (0.1 mL of 40 mg/mL) in one nostril
`mg - one spray (0.1 mL of 40 mg/mL) in each nostril
`—N-0.4 mg IM injection
`
`Hours Postdose
`(b)
`mg - one spray (0.1 mL of 20 mg/mL) in one nostril
`—N-4 mg - one spray (0.1 mL of 20 mg/mL) in each nostril
`—*-4 mg - one spray (0.1 mL of 40 mg/mL) in one nostril
`mg - one spray (0.1 mL of 40 mg/mL) in each nostril
`0.4 mg IM injection
`
`.
`
`0.25
`
`0.5
`Hours Postdose
`
`0.75
`
`1
`
`The median naloxone tn.after intranasal administration of NARCAN Nasal Spray (one nasal
`spray in one nostril (2 mg or 4 mg) or two nasal sprays as one spray in each nostril (4 mg or
`8 mg) was not significantly different compared to the 0.4 mg dose of naloxone hydrochloride
`intramuscular injection (Table 1).
`
`The dose normalized relative bioavailability of one dose (2 mg or 4 mg) or two doses (4 mg or
`8 mg) of NARCAN Nasal Spray as compared to the 0.4 mg dose of naloxone hydrochloride
`administered by intramuscular injection was 52%, 44%, 54%, and 43%, respectively.
`
`Distribution
`
`Reference ID: 4045900
`
`APT00018737
`
`Opiant Exhibit 2097
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 11
`
`
`
`Following parenteral administration, naloxone is distributed in the body and readily crosses the
`placenta. Plasma protein binding occurs but is relatively weak. Plasma albumin is the major
`binding constituent, but significant binding of naloxone also occurs to plasma constituents other
`than albumin. It is not known whether naloxone is excreted into human milk.
`
`Elimination
`
`Following a single intranasal administration of NARCAN Nasal Spray (2 mg or 4 mg dose of
`naloxone hydrochloride), the mean plasma half-life of naloxone in healthy adults was
`approximately 1.85 (33% CV) hours and 2.08 (30% CV) hours; respectively, which was longer
`than that observed after administrations of a 0.4 mg naloxone hydrochloride intramuscular
`injection, where the half-life was 1.24 hours (26% CV). In a neonatal study of naloxone
`hydrochloride injection, the mean (± SD) plasma half-life was observed to be 3.1 (± 0.5) hours.
`
`Metabolism
`
`Naloxone hydrochloride is metabolized in the liver, primarily by glucuronide conjugation, with
`naloxone-3-glucoronide as the major metabolite
`
`Excretion
`
`After an oral or intravenous dose, about 25-40% of naloxone is excreted as metabolites in urine
`within 6 hours, about 50% in 24 hours, and 60-70% in 72 hours.
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Carcinogenesis
`
`Long-term animal studies to evaluate the carcinogenic potential of naloxone have not been
`completed.
`
`Mutagenesis
`
`Naloxone was weakly positive in the Ames mutagenicity and in the in vitro human lymphocyte
`chromosome aberration test but was negative in the in vitro Chinese hamster V79 cell HGPRT
`mutagenicity assay and in the in vivo rat bone marrow chromosome aberration study.
`
`Impairment of Fertility
`
`Male rats were treated with 2 or 10 mg/kg naloxone for 60 days prior to mating. Female rats
`treated for 14-days prior to mating and throughout gestation with the same doses of naloxone (up
`to 12-times a human dose of 8 mg/day (two NARCAN Nasal Sprays) based on body surface area
`comparison). There was no adverse effect on fertility.
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`16.1 How Supplied
`
`Reference ID: 4045900
`
`APT00018738
`
`Opiant Exhibit 2097
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 12
`
`
`
`NARCAN Nasal Spray 2 mg is supplied as a carton containing four blister packages (NDC
`69547-212-04) each with a single spray device and as a carton containing 24 blister packages
`(NDC 69547-212-24) each with a single spray device.
`
`NARCAN Nasal Spray 4 mg is supplied as Carton containing two blister packages (NDC
`69547-353-02) each with a single spray device.
`
`NARCAN Nasal Spray is not made with natural rubber latex.
`
`16.2 Storage and Handling
`
`Store NARCAN Nasal Spray in the blister and cartons provided.
`
`Store at controlled room temperature 59°F to 77°F (15°C to 25°C). Excursions permitted between 39°F
`to 104°F (4°C to 40°C). Do not freeze. Protect from light.
`
`17 PATIENT COUNSELING INFORMATION
`
`Advise the patient and family members or caregivers to read the FDA-approved patient labeling
`(Patient Information and Instructions for Use).
`
`Recognition of Opioid Overdose
`
`Inform patients and their family members or caregivers about how to recognize the signs and
`symptoms of an opioid overdose such as the following:
`
`• Extreme somnolence - inability to awaken a patient verbally or upon a firm sternal
`rub.
`
`• Respiratory depression - this can range from slow or shallow respiration to no
`respiration in a patient who is unarousable.
`
`• Other signs and symptoms that may accompany somnolence and respiratory
`depression include the following:
`
`• Miosis.
`
`• Bradycardia and/or hypotension.
`
`Risk of Recurrent Respiratory and Central Nervous System Depression
`
`Instruct patients and their family members or caregivers that, since the duration of action of most
`opioids may exceed that of NARCAN Nasal Spray, they must seek immediate emergency
`medical assistance after the first dose of NARCAN Nasal Spray and keep the patient under
`continued surveillance [see Dosage and Administration (2.2), Warnings and Precautions (5.3)1
`
`Reference ID: 4045900
`
`APT00018739
`
`Opiant Exhibit 2097
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00694
`Page 13
`
`
`
`Limited Efficacy for/with Partial Agonists or Mixed Agonist/Antagonists
`
`Instruct patients and their family members or caregivers that the reversal of respiratory
`depression caused by partial agonists or mixed agonist/antagonists, such as buprenorphine and
`pentazocine, may be incomplete and may require higher doses of naloxone hydrochloride or
`repeated administration of NARCAN Nasal Spray, using a new nasal spray each time [see
`Dosage and Administration (2.3), Warnings and Precautions (5.2)] .
`
`Precipitation of Severe Opioid Withdrawal
`
`Instruct patients and their family members or caregivers that the use of NARCAN Nasal Spray in
`patients who are opioid dependent may precipitate opioid withdrawal [see Warnings and
`Precautions (5.3), Adverse Reactions (6)].
`
`Administration Instructions
`
`Instruct patients and their family members or caregivers to:
`
`• Ensure NARCAN Nasal Spray is present whenever persons may be intentionally or
`accidentally exposed to an opioid overdose (i.e., opioid emergencies).
`
`• Administer NARCAN Nasal Spray as quickly as possible if a patient is unresponsive and
`an opioid overdose is suspected, even when in doubt, because prolonged respiratory
`depression