` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`208411Orig1s000
`
`
`LABELING
`
`
`
`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
`
`-----------------------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)
`• Administer a single spray of NARCAN Nasal Spray to adults
`or pediatric patients 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)
`
`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: 11/2015
`
`
`
`
`
`----------------DOSAGE FORMS AND STRENGTHS-----------------
`Nasal spray: 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
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3848912
`
`
`
`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.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`INDICATIONS AND USAGE
`1
`2
`DOSAGE AND ADMINISTRATION
`Important Administration Instructions
`2.1
`2.2 Dosing Information
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Duration of Effect
`5.2 Limited Efficacy with Partial Agonists or Mixed
`Agonist/Antagonists
`
`5.3 Precipitation of Severe Opioid Withdrawal
`ADVERSE REACTIONS
`USE IN SPECIFIC POPULATIONS
` Pregnancy
`8.1
`8.2 Lactation
`8.4 Pediatric use
`8.5 Geriatric Use
`
`6
`8
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3848912
`
`
`
`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.
`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.
`
`• 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.
`
`
`
`Reference ID: 3848912
`
`
`
`• 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, which delivers 4 mg of naloxone hydrochloride.
`
`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
`hydrochloride or repeated administration of NARCAN Nasal Spray using a new nasal spray [see
`Warnings and Precautions (5.2)].
`3
`DOSAGE FORMS AND STRENGTHS
`
`
`Reference ID: 3848912
`
`
`
`NARCAN Nasal Spray is supplied as a single 4 mg dose of naloxone hydrochloride in a 0.1 mL
`intranasal spray.
`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
`Risk of Recurrent Respiratory and Central Nervous System Depression
`5.1
`
`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.
`
`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
`
`
`Reference ID: 3848912
`
`
`
`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, musculoskeletal pain, headache,
`nasal dryness, nasal edema, nasal congestion, and nasal inflammation.
`
`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
`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 the neonate, opioid withdrawal signs and symptoms
`also included convulsions, excessive crying, and hyperactive reflexes.
`8
`USE IN SPECIFIC POPULATIONS
`
`
`
`Reference ID: 3848912
`
`
`
`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).
`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.
`
`Pediatric Use
`8.4
`The safety and effectiveness of NARCAN Nasal Spray has been established in pediatric patients
`for known or suspected opioid overdose, as manifested by respiratory and/or central nervous
`system depression. Use of naloxone hydrochloride in pediatric patients is supported by evidence
`from adequate and well-controlled studies of naloxone hydrochloride in adults with additional
`
`
`Reference ID: 3848912
`
`
`
`data from 15 clinical studies (controlled and uncontrolled) in which neonates and pediatric
`patients received parenteral naloxone hydrochloride in doses ranging from 0.005 mg/kg to
`0.01 mg/kg. Safety and effectiveness are also supported by use of other naloxone hydrochloride
`products in the post-marketing setting, as well as data available in the medical literature and
`clinical practice guidelines. NARCAN Nasal Spray may be administered to pediatric patients of
`all ages.
`
`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.
`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:
`
`
`
`Reference ID: 3848912
`
`
`
`
`
`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 single 4 mg dose of naloxone hydrochloride in a 0.1 mL
`intranasal spray.
`
`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 (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 (8 mg total dose,
`0.1 mL of 40 mg/mL naloxone hydrochloride solution in each nostril) was 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 HCl) Nasal Spray and Intramuscular Injection of Naloxone HCl to
`Healthy Subjects
`
`Parameter
`
`
`
`Reference ID: 3848912
`
`4 mg – One Nasal
`Spray in one
`nostril
`
`8 mg –Two Nasal
`Sprays, one in each
`nostril
`
`0.4 mg
`Intramuscular
`Injection
`
`
`
`
`
`(N=29)
`
`(N=29)
`
`(N=29)
`
`25555255
`
`5552225
`
`2552255
`
`
`
`25552555
`552552555
`
`25555255
`255255)
`55552555 n-
`
`T tun: reported as median (mininmm. maximum)
`" N=28 for Relative BA.
`
`Figure 1
`
`Mean :L- SD Plasma Concentration of Naloxone, (a) 0—6 h and (b) 0—lh Following
`
`Intranasal Administration and Intramuscular Injection
`
`p—nA
`
`)—IN
`
`(3)
`
`+8mg - one spray (0.1 ml of40mg/mL)ineach nostril
`
`—0—4mg - one spray (0.1 ml of40mg/mL) in one nostril
`
`14
`
`.—N
`
`(b)
`
`0.25
`
`0.5
`Hours Postdose
`
`0.75
`
`—-—0_4mg IM injection
`
`anoxonePlasmaConcentration(ng/mL)
`
`
`
`oe 0
`
`.—O
`
`a A
`
`Hours Pnstdose
`
`
`
`anoxonePlasmaConcenmtlon(ng/mL)Ano
`
`a
`
`y—IO
`
`
`
`
`
`The median naloxone tm after intranasal administration of NARCAN Nasal Spray (one nasal
`
`spray in one nostril or two nasal sprays as one spray in each nostril) 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 (4 mg) or two doses (8 mg) of NARCAN
`
`Nasal Spray as compared to the 0.4 mg dose of naloxone hydrochloride administered by
`
`intramuscular injection was 46.7%, and 43.9%, respectively.
`
`Distribution
`
`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
`
`Reference ID: 3848912
`
`
`
`Following a single intranasal administration of NARCAN Nasal Spray (4 mg dose of naloxone
`hydrochloride), the mean plasma half-life of naloxone in healthy adults was approximately 2.08
`(30% CV) hours, 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
`Carton containing two blister packages each with a single NARCAN Nasal Spray (single 4 mg
`dose of naloxone hydrochloride intranasal spray).
`
`NARCAN Nasal Spray is not made with natural rubber latex.
`16.2 Storage and Handling
`
`
`
`Reference ID: 3848912
`
`
`
`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 4°C to
`40°C (39°F to 104°F). 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)].
`
`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
`
`
`Reference ID: 3848912
`
`
`
`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 may result in damage to the central nervous system or death. NARCAN Nasal
`Spray is not a substitute for emergency medical care [see Dosage and Administration
`(2.1)].
`
`• Lay the patient on their back and administer NARCAN Nasal Spray into one nostril while
`providing support to the back of the neck to allow the head to tilt back [see Dosage and
`Administration (2.1)].
`
`• Use each nasal spray only one time [see Dosage and Administration (2.1)].
`
`• 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. Additional supportive and/or resuscitative measures may be helpful while
`awaiting emergency medical assistance [see Dosage and Administration (2.1)].
`
`• Monitor patients and re-administer NARCAN Nasal Spray using a new NARCAN Nasal
`Spray every 2 to 3 minutes, if the patient is not responding or responds and then relapses
`back into respiratory depression. Administer NARCAN Nasal Spray in alternate nostrils
`with each dose [see Dosage and Administration (2.1)].
`
`• Replace NARCAN Nasal Spray before its expiration date.
`
`---------------------------------------------------------------------------------------------------------------
`
`NARCAN® is a registered trademark licensed by Adapt Pharma Operations Limited
`
`Distributed by Adapt Pharma, Inc., Radnor, PA 19087 USA.
`
`
`
`Reference ID: 3848912
`
`
`
`PATIENT INFORMATION
`NARCAN (nar´ kan)
`(naloxone hydrochloride)
`Nasal Spray
`
`You and your family members or caregivers should read this Patient Information leaflet before an opioid emergency
`happens. This information does not take the place of talking with your healthcare provider about your medical condition or
`your treatment.
`What is the most important information I should know about NARCAN Nasal Spray?
`NARCAN Nasal Spray is used to temporarily reverse the effects of opioid medicines. The medicine in NARCAN Nasal
`Spray has no effect in people who are not taking opioid medicines. Always carry NARCAN Nasal Spray with you in case
`of an opioid emergency.
`1. Use NARCAN Nasal Spray right away if you or your caregiver think signs or symptoms of an opioid emergency are
`present, even if you are not sure, because an opioid emergency can cause severe injury or death. Signs and
`symptoms of an opioid emergency may include:
`• unusual sleepiness and you are not able to awaken the person with a loud voice or by rubbing firmly on the
`middle of their chest (sternum)
`• breathing problems including slow or shallow breathing in someone difficult to awaken or who loo