`
`
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use NARCAN NASAL SPRAY safely and effectively. See full prescribing
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`information for NARCAN® NASAL SPRAY.
`
`
`
`
`NARCAN® (naloxone hydrochloride) nasal spray
`
`
`
`
`
`
` Initial U.S. Approval: 1971
`
`
`
`
`
` -----------------------RECENT MAJOR CHANGES--------------------­
`
`
`Dosage and Administration, Dosing in Adults and
`
`Pediatric Patients (2.2)
`
`
`
`-----------------------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 a single 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 emergency medical
`
`
`
`
`
`
` assistance arrives. (2.2)
`
`
`
`• Additional supportive and/or resuscitative measures may be
`
`
`
`
`
` helpful while awaiting emergency medical assistance. (2.2)
`
`
`
`
`01/2017
`
`
`
`
`
`
`
`
` ----------------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
`
`
`
`Agonists/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 1-844-4NARCAN (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
`
`Opiant Exhibit 2016
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00690
`Page 1
`
`

`

`
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
` INDICATIONS AND USAGE
`
`1
`
`
`2
`
` DOSAGE AND ADMINISTRATION
`
`
`
`
` Important Administration Instructions
`2.1
`
`
`
`
` 2.2 Dosing in Adults and Pediatric Patients
`
`
` 2.3 Dosing Modifications due to Partial Agonists or Mixed
`
`
`
` Agonist/Antagonists
`
` DOSAGE FORMS AND STRENGTHS
`
`
`
`3
`
` CONTRAINDICATIONS
`
`
`4
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 11 DESCRIPTION
`
` 12 CLINICAL PHARMACOLOGY
`
`
` 12.1 Mechanism of Action
`
`
`
`
` 12.2 Pharmacodynamics
`
`
` 12.3 Pharmacokinetics
`
`
` 13 NONCLINICAL TOXICOLOGY
`
`
`
`
`
` 13.1 Carcinogenesis, Mutagenesis, 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 5.3 Precipitation of Severe Opioid Withdrawal
`
` ADVERSE REACTIONS
`
`
`
` USE IN SPECIFIC POPULATIONS
`
`
` 8.1 Pregnancy
`
`
`
` 8.2 Lactation
`
`
`
` 8.4 Pediatric use
`
`
` 8.5 Geriatric Use
`
`
`
`
`
`6
`
`
` 8
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4045900
`
`Opiant Exhibit 2016
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00690
`Page 2
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
` INDICATIONS AND USAGE
`
`1
`
`
` 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
`
`Opiant Exhibit 2016
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00690
`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
`
`Opiant Exhibit 2016
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00690
`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 buprenorphine 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
`
`Opiant Exhibit 2016
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00690
`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
`
`Opiant Exhibit 2016
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00690
`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
`
`
` Pregnancy
` 8.1
`
`
` 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)]. 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
`
`Opiant Exhibit 2016
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00690
`Page 7
`
`

`

`
` Lactation
` 8.2
`
`
` 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.
`
`
`Pediatric Use
`8.4
`
`
`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
`
`Opiant Exhibit 2016
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00690
`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-Allyl-4,5α-epoxy-3,14­
`
`
` dihydroxymorphinan-6-one hydrochloride with the following structure:
`
`
`
`
`C19H21NO4• HCl
`
`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
`
`Opiant Exhibit 2016
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00690
`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.
`
`
`
`
`
` Mean Pharmacokinetic Parameters (CV%) for Naloxone Following NARCAN
`
`
`
`
`
` (Naloxone HCl) Nasal Spray and Intramuscular Injection of Naloxone HCl to
`
` Healthy Subjects
` 2 mg– One Nasal
`
`
` Spray in one
`
` nostril
`
` 20 mg/ml
`
` (N=29)
` 0.33 (0.25, 1.00)
`
`
`
`
` 2.91 (35)
`
` 4.60 (27)
`
` 4.66 (27)
`
`
` 1.85 (33)
`
`
` 4 mg – Two Nasal
`
`
`Sprays, one in
`
`each nostril
`
`20 mg/ml
`
`(N=29)
` 0.33 (0.17, 0.57)
`
`
` 6.30 (34)
`
` 9.64 (24)
`
`
` 9.74 (24)
`
`
` 2.19 (33)
`
`
`
`
`
`
`
`
`4 mg – One Nasal
`
`Spray in one
`
`nostril
`
`40 mg/ml
`
`(N=29)
` 0.50 (0.17, 1.00)
`
`
`
` 4.83 (43)
`
` 7.87 (37)
`
` 7.95 (37)
`
` 2.08 (30)
` 44.2 (31)††
`
`
`
`
`
`
`
`
`8 mg –Two Nasal
`Sprays, one in each
`
`nostril
`
`40 mg/ml
`
`(N=29)
` 0.33 (0.17, 1.00)
`
`
`
` 9.70 (36)
`
` 15.3 (23)
`
` 15.5 (23)
`
` 2.10 (32)
`
`
`
`0.4 mg
`
`Intramuscular
`
`Injection
`
`(N=29)
`
`
`
`
` 0.38 (0.08, 2.05)
`
` 0.88 (31)
`
` 1.75 (23)
`
`
` 1.79 (23)
`
` 1.24 (26)
`
`
`
`
`
`
`43.1 (24)
`
`
`100
`
`
`
` Table 1
`
`
`
` Parameter
`
`
`
`tmax (h)†
`
`
`
` Cmax (ng/mL)
`
` AUCt (hr.ng/mL)
`
`
` AUC0-inf (h*ng/mL)
`
` t½ (h)
` Dose normalized Relative BA
`
` (%) vs. IM
`
`
`
`
`
`
` 51.7 (22)
`
`
`
`
`
`
`
` 54.0 (23)
`
`† tmax reported as median (minimum, maximum)
`
`
`
`†† N=28 for Relative BA.
`
`
`
`
`
`
`
`
`Reference ID: 4045900
`
`Opiant Exhibit 2016
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00690
`Page 10
`
`

`

` Mean ± SD Plasma Concentration of Naloxone, (a) 0-6 h and (b) 0-1h Following
`
`
`
` Intranasal Administration and Intramuscular Injection
`
` (a)
`
`2 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
`
`4 mg - one spray (0.1 mL of 40 mg/mL) in one nostril
`
`8 mg - one spray (0.1 mL of 40 mg/mL) in each nostril
`
`0.4 mg IM injection
`
`
`
`
`
`
`
`
`
` Figure 1
`
`14
`
`12
`
`10
`
`8
`
`6
`
`4
`
`2
`
`0
`
`Naloxone Plasma Concentration (ng/mL)
`
`
`
`
`
`0
`
`1
`
`2
`
`
`
`6
`
`
`
`4
`
`5
`
`3
`
` Hours Postdose
`
` (b)
`
` 2 mg - one spray (0.1 mL of 20 mg/mL) in one nostril
`
`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
`
`8 mg - one spray (0.1 mL of 40 mg/mL) in each nostril
`
`0.4 mg IM injection
`
`10
`
`8
`
`6
`
`4
`
`2
`
`
`
`Naloxone Plasma Concentration (ng/mL)
`
`0
`
`0
`
`0.25
`
`0.5
` Hours Postdose
`
`
`0.75
`
`1
`
`
`
`
`
`
`
` The median naloxone tmax 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
`
`Opiant Exhibit 2016
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00690
`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