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Naloxone: Drug information

Naloxone: Drug information
(For additional information see "Naloxone: Patient drug information" and see "Naloxone: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Evzio [DSC];
  • Kloxxado;
  • LifEMS Naloxone;
  • Narcan;
  • Zimhi
Brand Names: Canada
  • Narcan;
  • S.O.S. Naloxone Hydrochloride
Pharmacologic Category
  • Antidote;
  • Opioid Antagonist
Dosing: Adult

Note: Evzio auto-injector (all strengths) has been discontinued in the United States for >1 year.

Note: Available routes of administration include IV (preferred), IM, SUBQ, and intranasal; other available routes (off-label) include inhalation via nebulization (adults only), and intraosseous (IO). Endotracheal administration is the least desirable and is supported by only anecdotal evidence (case report) (AHA [Neumar 2010]):

Opioid use disorder, naloxone challenge:

IM: 0.4 to 0.8 mg (Bisaga 2018; WFSBP [Soyka 2011]).

IV: 0.2 mg single dose. After 30 seconds, if withdrawal symptoms are present stop the challenge and treat symptomatically; may repeat challenge in 24 hours. If no withdrawal symptoms and vital signs are stable inject 0.6 mg and observe for 20 minutes. After 20 minutes if withdrawal symptoms are present stop the challenge and treat symptomatically; may repeat challenge in 24 hours. If no withdrawal symptoms are present may initiate naltrexone (SAMHSA 2020).

SUBQ: 0.8 mg single dose. After 20 minutes, if withdrawal symptoms are present stop the challenge and treat symptomatically; may repeat challenge in 24 hours. If no withdrawal symptoms and vital signs are stable may initiate naltrexone (SAMHSA 2020).

Opioid overdose:

Note: For the initial treatment of an opioid-associated life-threatening emergency, the American Heart Association recommends, after initiation of CPR, the use of intranasal or IM naloxone with a repeat dose as needed. If there is an initial patient response (ie, purposeful movement, regular breathing, moan or other response) but the patient then stops responding, begin CPR and repeat naloxone dose. If no initial response, continue CPR and use AED as appropriate (AHA [Panchal 2020]).

IV, IM, SUBQ: Initial: 0.4 to 2 mg; may need to repeat doses every 2 to 3 minutes. A lower initial dose (0.1 to 0.2 mg) should be considered for patients with opioid dependence to avoid acute withdrawal or if there are concerns regarding concurrent stimulant overdose (Mokhlesi 2003). After reversal, may need to readminister dose(s) at a later interval (ie, 20 to 60 minutes) depending on type/duration of opioid. If no response is observed after 10 mg total, consider other causes of respiratory depression. Note: May be given endotracheally (off-label route) as 2 to 2.5 times the initial IV dose (ie, 0.8 to 5 mg) (AHA [Neumar 2010]).

IM, SUBQ:

Evzio: 2 mg (contents of 1 auto-injector) as a single dose; may repeat every 2 to 3 minutes until emergency medical assistance becomes available.

Zimhi: 5 mg (contents of 1 prefilled syringe) as a single dose; may repeat every 2 to 3 minutes until emergency medical assistance becomes available.

Continuous infusion (off-label dosing): IV: Note: For use with exposures to long-acting opioids (eg, methadone), sustained release product, and symptomatic body packers after initial naloxone response. Calculate dosage/hour based on effective intermittent dose used and duration of adequate response seen (Tenenbein 1984) or use two-thirds (2/3) of the initial effective naloxone bolus on an hourly basis (typically 0.25 to 6.25 mg/hour); one-half (1/2) of the initial bolus dose should be readministered 15 minutes after initiation of the continuous infusion to prevent a drop in naloxone levels; adjust infusion rate as needed to assure adequate ventilation and prevent withdrawal symptoms (Goldfrank 1986).

Inhalation via nebulization (off-label route): 2 mg; may repeat. Switch to IV or IM administration when possible (Weber 2012). Note: This administration method is not included in the AHA recommendations for initial management of opioid-associated life-threatening emergency (AHA [Lavonas 2015]).

Intranasal: Note: Onset of action is slightly delayed compared to IM or IV routes (Kelly 2005; Robertson 2009):

4 or 8 mg (contents of 1 nasal spray) as a single dose in one nostril; may repeat every 2 to 3 minutes in alternating nostrils until medical assistance becomes available or 2 mg (1 mg per nostril) using injectable solution (delivered with a mucosal atomization device); may repeat in 3 to 5 minutes if respiratory depression persists (AHA [Panchal 2020]; AHA [Vanden Hoek 2010]; Kelly 2005; Robertson 2009; Walley 2013; manufacturer’s labeling).

Reversal of respiratory depression with therapeutic opioid doses: IV: Initial: 0.02 to 0.2 mg; titrate to avoid profound withdrawal, seizures, arrhythmias, or severe pain (APS 2008; Doyon 2010; AHA [Lavonas 2015]). Note: May be given endotracheally (off-label route) as 2 to 2.5 times the initial recommended IV dose (ie, 0.04 to 0.5 mg) (AHA [Neumar 2010]).

Continuous infusion (off-label dosing): IV: Note: For use with exposures to long-acting opioids (eg, methadone) or sustained release products. Calculate dosage/hour based on effective intermittent dose used and duration of adequate response seen (Tenenbein 1984) or use two-thirds (2/3) of the initial effective naloxone bolus on an hourly basis (typically 0.2 to 0.6 mg/hour); one-half (1/2) of the initial bolus dose should be readministered 15 minutes after initiation of the continuous infusion to prevent a drop in naloxone levels; adjust infusion rate as needed to assure adequate ventilation and prevent withdrawal symptoms (Goldfrank 1986).

Opioid-dependent patients being treated for cancer pain (off-label dosing): IV: Note: May dilute 1 mL of a naloxone 0.4 mg/mL formulation with 9 mL of NS or SWFI for a total volume of 10 mL to achieve a 0.04 mg/mL (40 mcg/mL) concentration.

0.02 mg (20 mcg) IV push; administer every 2 minutes until improvement in symptoms (APS guidelines, v.6.2008) or

0.04 to 0.08 mg (40 to 80 mcg) slow IV push; administer every 30 to 60 seconds until improvement in symptoms; if no response is observed after total naloxone dose 1 mg, consider other causes of respiratory depression. If respiratory depression is due to long-acting opioids, may consider administering naloxone as a continuous infusion starting at 66% of the total bolus dose (or 0.2 mg per hour) to reverse the opioid toxicity (Howlett 2016).

Postoperative reversal: IV: 0.1 to 0.2 mg every 2 to 3 minutes until desired response (adequate ventilation and alertness without significant pain). Note: Repeat doses may be needed within 1 to 2 hour intervals depending on type, dose, and timing of the last dose of opioid administered.

Opioid-induced pruritus (off-label use): IV infusion: 0.25 mcg/kg/hour (Gan 1997). Doses up to ~3 mcg/kg/hour have been employed (Kendrick 1996). However, doses >2 mcg/kg/hour are more likely to lead to reversal of analgesia and are not recommended (Kjellberg 2001; Miller 2011). Note: Monitor pain control; verify that the naloxone is not reversing analgesia.

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Pediatric

(For additional information see "Naloxone: Pediatric drug information")

Opioid intoxication/overdose (full reversal):

IV (preferred), Intraosseous: Note: May be administered IM, SUBQ, or E.T., but onset of action may be delayed, especially if patient has poor perfusion; E.T. preferred if IV/Intraosseous route not available; doses may need to be repeated (PALS [Kleinman 2010]).

Infants and Children <5 years or ≤20 kg: IV, Intraosseous: 0.1 mg/kg/dose; repeat every 2 to 3 minutes if needed; monitor closely; may need to repeat doses (eg, every 20 to 60 minutes) if duration of action of opioid is longer than naloxone.

Children ≥5 years or >20 kg and Adolescents: IV, Intraosseous: 2 mg/dose; if no response, repeat every 2 to 3 minutes; monitor closely; may need to repeat doses (eg, every 20 to 60 minutes) if duration of action of opioid is longer than naloxone.

E.T.: Infants, Children, and Adolescents: Optimal endotracheal dose unknown; current expert recommendations are 2 to 3 times the IV dose (PALS [Kleinman 2010]).

IM, SUBQ: Note: IM or SUBQ absorption may be delayed or erratic.

Auto-injector: Evzio: Infants, Children, and Adolescents: IM, SUBQ: 0.4 mg or 2 mg (contents of 1 auto-injector) as a single dose; may repeat every 2 to 3 minutes if needed until emergency medical assistance becomes available.

Parenteral formulation (AAP [Shenoi 2020]): Infants, Children, and Adolescents: IM, SUBQ: 0.1 mg/kg/dose; maximum dose: 2 mg/dose; repeat every 2 to 3 minutes if needed; monitor closely; may need to repeat doses (eg, every 20 to 60 minutes) if duration of action of opioid is longer than naloxone.

Intranasal: Note: Onset of action is slightly delayed compared to IM or IV routes (Barton 2005; Kelly 2005).

Intranasal formulations (eg, Kloxxado, Narcan Nasal Spray): Infants, Children, and Adolescents: Intranasal: 4 mg or 8 mg (contents of 1 nasal spray) as a single dose; may repeat every 2 to 3 minutes in alternating nostrils if needed until medical assistance becomes available (manufacturer's labeling).

Parenteral formulation (1 mg/mL injection) for intranasal administration: Adolescents ≥13 years: Intranasal: 2 mg (1 mg per nostril) (Barton 2005; Kelly 2005). Note: Naloxone 0.4 mg/mL parenteral formulation has been evaluated and may be used for opioid overdose; however, due to the volume needed to administer the dose it is not ideal for nasal administration; should be used if intranasal administration is needed and a more concentrated naloxone is not readily available (Dowling 2008; Kerr 2008; Robinson 2014; Wolfe 2004).

Continuous IV infusion: Limited data available: Infants, Children, and Adolescents: 24 to 40 mcg/kg/hour has been reported (Gourlay 1983; Lewis 1984; Tenenbein 1984). Doses as low as 2.5 mcg/kg/hour have been reported in adults and a dose of 160 mcg/kg/hour was reported in one neonate (Tenenbein 1984). If continuous infusion is required, calculate the initial dosage/hour based on the effective intermittent dose used and duration of adequate response seen (Tenenbein 1984) or use two-thirds (2/3) of the initial effective naloxone bolus given as the hourly infusion (Perry 1996); titrate dose; Note: The infusion should be discontinued by reducing the infusion rate in decrements of 25%; closely monitor the patient (eg, pulse oximetry and respiratory rate) after each adjustment and after discontinuation of the infusion for recurrence of opioid-induced respiratory depression (Perry 1996).

Reversal of respiratory depression from therapeutic opioid dosing: Infants, Children, and Adolescents: IV, Intraosseous, IM, SUBQ: 0.001 to 0.005 mg/kg/dose; titrate to effect (PALS [Kleinman 2010]); AAP recommends a wider dosage range of 0.001 to 0.02 mg/kg/dose and may increase if necessary up to 0.1 mg/kg/dose (full reversal dose); maximum dose: 2 mg/dose; may repeat dose every 2 minutes as needed based on response; monitor patient closely; symptoms may recur if duration of action of opioid is longer than naloxone; repeat doses (eg, every 20 to 60 minutes) may be required (AAP [Shenoi 2020]).

Opioid-induced pruritus: Limited data available:

Prevention: Children ≥6 years and Adolescents ≤17 years: Continuous IV infusion: 0.25 mcg/kg/hour was used in a double-blind, prospective, randomized, placebo-controlled study (n=20) which showed lower incidence and severity of opioid-induced side effects (ie, pruritus, nausea) without a loss of pain control (Maxwell 2005).

Treatment: Children ≥3 years and Adolescents: Continuous IV infusion: Initial: 2 mcg/kg/hour; if pruritus continues, may titrate by 0.5 mcg/kg/hour every few hours; dosing based on a retrospective study (n=30, age range: 3 to 20 years) with a reported mean (±SD) dose of 2.3 ± 0.68 mcg/kg/hour; monitor closely; doses ≥3 mcg/kg/hour may increase risk for loss of pain control and patients may require an increase in opioid dose (Vrchoticky 2000).

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Older Adult

Refer to adult dosing.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Liquid, Nasal, as hydrochloride:

Kloxxado: 8 mg/0.1 mL (2 ea) [contains alcohol, usp, edetate (edta) disodium dihydrate, propylene glycol]

Narcan: 4 mg/0.1 mL (2 ea) [contains benzalkonium chloride, edetate (edta) disodium]

Generic: 4 mg/0.1 mL (1 ea, 2 ea)

Prefilled Syringe Kit, Injection, as hydrochloride:

LifEMS Naloxone: 2 mg/2 mL (1 ea)

Solution, Injection, as hydrochloride:

Generic: 0.4 mg/mL (1 mL); 4 mg/10 mL (10 mL)

Solution, Injection, as hydrochloride [preservative free]:

Generic: 0.4 mg/mL (1 mL)

Solution Auto-injector, Injection, as hydrochloride:

Evzio: 0.4 mg/0.4 mL (0.4 mL [DSC]); 2 mg/0.4 mL (0.4 mL [DSC])

Solution Auto-injector, Injection, as hydrochloride [preservative free]:

Generic: 2 mg/0.4 mL (0.4 mL [DSC])

Solution Cartridge, Injection, as hydrochloride:

Generic: 0.4 mg/mL (1 mL)

Solution Prefilled Syringe, Injection, as hydrochloride [preservative free]:

Zimhi: 5 mg/0.5 mL (0.5 mL) [latex free]

Generic: 2 mg/2 mL (2 mL)

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Liquid, Nasal, as hydrochloride:

Narcan: 4 mg/0.1 mL (0.1 mL) [contains benzalkonium chloride, edetate (edta) disodium]

Solution, Injection, as hydrochloride:

Generic: 0.4 mg/mL (1 mL, 10 mL); 1 mg/mL (2 mL)

Product Availability

Evzio auto-injector (all strengths) has been discontinued in the United States for >1 year.

Kloxxado (naloxone 8 mg/0.1 mL) nasal spray: FDA approved April 2021; availability anticipated in the second half of 2021.

Zimhi 5 mg/0.5 mL prefilled syringe: FDA approved October 2021; availability anticipated in the first quarter of 2022.

Administration: Adult

IV push: Administer over 30 seconds as undiluted preparation or administer as diluted preparation for lower doses (eg, 0.02 to 0.04 mg) slow IV push by diluting 1 mL of a naloxone 0.4 mg/mL formulation with 9 mL of NS or SWFI for a total volume of 10 mL to achieve a concentration of 0.04 mg/mL (APS 2008; manufacturer's labeling).

IV continuous infusion: Dilute to 4 mcg/mL in D5W or NS.

IM, SUBQ: May administer IM or SUBQ if unable to obtain IV access.

Auto-injector: For IM or SUBQ use only. Intended for buddy administration; the person administering the medication should follow the printed instructions on the device or the electronic voice instructions coming from the speaker on the device. If the voice instruction system does not operate properly, the device will still deliver the intended dose of naloxone when properly administered. Administer IM or SUBQ into the anterolateral aspect of the thigh; may be injected through clothing. When being administered to infants <1 year of age, the thigh muscle should be pinched during administration. Following proper administration, a red indicator appears in the viewing window; the needle is not visible before, during, or after the injection. Patients who received naloxone in the out-of-hospital setting should seek immediate emergency medical assistance after the first dose due to the likelihood that respiratory and/or CNS depression will return. Repeat doses may be required until emergency medical assistance becomes available; a new device must be used as each device contains a single dose of naloxone.

Prefilled syringe (Zimhi): For IM or SUBQ use only. Periodically inspect solution through the viewing window during storage; replace with new device if solution is discolored yellow to brown, cloudy, or contains particles. Intended for buddy administration (by individuals ≥12 years of age); the person administering the medication should follow the printed instructions for use and the printed instructions on the device label. Place patient in supine position; administer IM or SUBQ into the anterolateral aspect of the thigh with the needle facing downwards; may be injected through clothing. When being administered to infants <1 year of age, the thigh muscle should be pinched during administration. Ensure the needle is embedded completely before injecting. After injection, slide the safety guard over the needle using one hand and return to blue case. Place patient in the lateral recumbent position (recovery position). Patients who received naloxone in the out-of-hospital setting should seek immediate emergency medical assistance after the first dose due to the likelihood that respiratory and/or CNS depression will return. Repeat doses may be required until emergency medical assistance becomes available. Used syringes should be given to health care provider for inspection and proper disposal.

Endotracheal (off-label route): There is only anecdotal support for this route of administration. May require a slightly higher dose than used in other routes. Dilute to 1 to 2 mL with normal saline; flush with 5 mL of saline and then administer 5 ventilations (AHA [Neumar 2010]).

Inhalation via nebulization (off-label route): Dilute 2 mg of naloxone with 3 mL of normal saline and administer via nebulizer face mask (Mycyk 2003; Weber 2012).

Intranasal:

Administer initial dose as soon as possible. Do not prime or test the device prior to administration. Administer in alternating nostrils with each dose. Place the patient in the supine position and provide support to the back of the neck to allow the head to tilt back. Following administration, turn the patient on their side. Each container contains a single intranasal spray, do not reuse; if repeat administration is necessary a new container must be used.

Alternate intranasal administration instructions using generic injectable solution: Administer total dose equally divided into each nostril using a mucosal atomization device (MAD) (AHA [Vanden Hoek 2010]; Kelly 2005; Robertson 2009). If a MAD is not available, the solution may be sprayed into the nares without a MAD; however, a significant amount of drug may be lost likely due to swallowing and subsequent first-pass metabolism (Dowling 2008; Robinson 2014).

Administration: Pediatric

Endotracheal: Dilute with NS prior to administration; follow with a flush ≥5 mL of NS and 5 consecutive positive-pressure ventilations (PALS [Kleinman 2010]).

Intranasal:

Intranasal formulation (eg, Kloxxado, Narcan Nasal Spray): Administer initial dose as soon as possible. Do not prime or test the device prior to administration. Administer additional doses (when required) in alternating nostrils. Place the patient in the supine position and provide support to the back of the neck to allow the head to tilt back. Following administration, turn the patient on their side (recovery position). Each container contains a single intranasal spray; do not reuse; if repeat administration is necessary, a new container must be used.

Parenteral formulation for intranasal use: Note: If a mucosal atomizer device (MAD) is not available, the solution may be sprayed into the nares without a MAD; however, a significant amount of drug may be lost likely due to swallowing and subsequent first-pass metabolism (Dowling 2008; Robinson 2014).

1 mg/mL formulation (preferred): Administer total dose equally divided into each nostril using a MAD (AHA [Vanden Hoek 2010]; Kelly 2005; Robertson 2009).

0.4 mg/mL formulation: Administer total dose in repeated increments of 0.1 mL per nostril over ~2 minutes using a MAD (Malmros Olsson 2021). Note: Due to the volume needed to administer the dose, 0.4 mg/mL is not ideal for nasal administration but may be used if more concentrated naloxone is not readily available (Dowling 2008; Kerr 2008; Malmros Olsson 2021; Robinson 2014; Wolfe 2004).

Parenteral:

IV push: Administer over 30 seconds as undiluted preparation. May also be diluted and administer slow IV push (APS 2008).

Continuous IV infusion: Dilute in NS or D5W prior to administering as continuous IV infusion.

IM, Intraosseous, SubQ: May administer IM, Intraosseous, or SubQ if unable to obtain IV access. Note: IM or SubQ administration in pediatric patients, hypotensive patients, or patients with peripheral vasoconstriction or hypoperfusion may result in erratic or delayed absorption.

Auto-injector: Evzio: For IM or SubQ use only. Intended for buddy administration; the person administering the medication should follow the printed instructions on the device or the electronic voice instructions coming from the speaker on the device. If the voice instruction system does not operate properly, the device will still deliver the intended dose of naloxone when properly administered. Administer IM or SubQ into the anterolateral aspect of the thigh; may be injected through clothing. When being administered to infants <1 year of age, the thigh muscle should be pinched during administration. Following proper administration, a red indicator appears in the viewing window; the needle is not visible before, during, or after the injection. Do not replace red safety guard for any reason. Patients who received naloxone in the out-of-hospital setting should seek immediate emergency medical assistance after the first dose due to the likelihood that respiratory and/or central nervous system depression will return. Repeat doses may be required until emergency medical assistance becomes available; a new device must be used as each device contains a single dose of naloxone.

Use: Labeled Indications

Opioid overdose: For the complete or partial reversal of opioid depression (including respiratory depression) induced by natural and synthetic opioids (eg, propoxyphene, methadone, nalbuphine, butorphanol, pentazocine). Naloxone is also indicated for the diagnosis of suspected or known acute opioid overdosage.

Evzio (IM, SUBQ), intranasal, Zimhi (IM, SUBQ): For the emergency treatment of known or suspected opioid overdose as manifested by respiratory and/or CNS depression. Intended for immediate administration as emergency therapy in settings where opioids may be present. Not a substitute for emergency medical care.

Use: Off-Label: Adult

Opioid-induced pruritus; Opioid use disorder, naloxone challenge

Medication Safety Issues
Sound-alike/look-alike issues:

Naloxone may be confused with Lanoxin, nalbuphine, naltrexone

Narcan may be confused with Marcaine, Norcuron

Pediatric patients: High-risk medication:

KIDs List: Naloxone, when used in neonates for postpartum resuscitation, is identified on the Key Potentially Inappropriate Drugs in Pediatrics (KIDs) list; use should be avoided due to risk of seizure (strong recommendation; high quality of evidence) (PPA [Meyers 2020]).

International issues:

Narcan [multiple international markets] may be confused with Marcen brand name for ketazolam [Spain]

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

Frequency not defined:

Cardiovascular: Flushing (parenteral), hypertension, hypotension, presyncope (nasal), tachycardia, ventricular fibrillation, ventricular tachycardia

Dermatologic: Diaphoresis, piloerection, xeroderma (nasal)

Endocrine & metabolic: Hot flash (parenteral)

Gastrointestinal: Abdominal cramps, abdominal pain (nasal), constipation (nasal), diarrhea, nausea, toothache (nasal), vomiting

Hepatic: Increased serum bilirubin (parenteral)

Local: Erythema at injection site (parenteral), injection site reaction (parenteral)

Nervous system: Agitation, body pain, coma, confusion (parenteral), disorientation (parenteral), dizziness (parenteral), encephalopathy, excessive crying (neonates), hallucination (parenteral), headache (nasal), hyperreflexia (neonates), irritability, nervousness, outbursts of anger (parenteral), paresthesia (parenteral), restlessness, seizure (neonates), shivering, tonic-clonic epilepsy (parenteral), withdrawal syndrome, yawning

Neuromuscular & skeletal: Asthenia, muscle spasm (nasal), musculoskeletal pain (nasal), tremor

Respiratory: Dry nose (nasal), dyspnea, hypoxia (parenteral), nasal congestion (nasal), nasal discomfort (pain; nasal), nasal mucosa swelling (nasal), pulmonary edema, respiratory depression (parenteral), rhinitis (nasal), rhinorrhea, sneezing

Miscellaneous: Fever

Postmarketing: Nervous system: Drowsiness, loss of consciousness, unresponsive to stimuli

Contraindications

Hypersensitivity to naloxone or any component of the formulation

Warnings/Precautions

Concerns related to adverse effects:

• Acute opioid withdrawal: Administration of naloxone causes the release of catecholamines, which may precipitate acute withdrawal or unmask pain in those who regularly take opioids. Symptoms of acute withdrawal in opioid-dependent patients may include pain, tachycardia, hypertension, fever, sweating, abdominal cramps, diarrhea, nausea, vomiting, agitation, and irritability. In neonates born to mothers with opioid dependence, opioid withdrawal may be life-threatening and symptoms may include excessive crying, shrill cry, failure to feed, seizures, and hyperactive reflexes. In settings other than acute opioid overdose (eg, postoperative patients), carefully titrate the dose to reverse hypoventilation; do not fully awaken patient or reverse analgesic effect. The 2 mg nasal dose (off-label) is less likely to precipitate severe opioid withdrawal compared to the 4 mg dose; however, the 2 mg dose may not provide an adequate and timely reversal in patients who have been exposed to an overdose of a potent or very high dose of opioids.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiovascular disease or in patients receiving medications with potential adverse cardiovascular effects (eg, hypotension, pulmonary edema or arrhythmias); pulmonary edema and cardiovascular instability, including ventricular fibrillation, have been reported in association with abrupt reversal when using opioid antagonists.

• Seizures: Use caution in patients with history of seizures; avoid use in the treatment of meperidine-induced seizures.

Dosage form specific issues:

• Auto-injector: When administered to infants <1 year of age, monitor the injection site for residual needle parts and signs of infection.

Other warnings/precautions:

• Addiction involving opioid use: To prevent overdose deaths, there are initiatives to dispense naloxone for self- or buddy-administration to patients at risk of opioid overdose (eg, recipients of high-dose opioids, suspected or confirmed history of illicit opioid use) and individuals likely to be present in an overdose situation (eg, family members of illicit drug users) (Albert 2011; Bennett 2011). Clinical practice guidelines recommend patients being treated for opioid use disorder should be given prescriptions for naloxone. Patients and family members/significant others should be trained in the use of naloxone in overdose (ASAM 2020). Evzio and intranasal products are indicated for emergency treatment. Needleless administration via nebulization and the intranasal route using the injectable solution (with a mucosal atomization device) by first responders and bystanders has also been described (Doe-Simkins 2009; Weber 2012). Needleless administration provides an alternative route of administration in patients with venous scarring due to illicit drug use (eg, heroin). There is a low incidence of death following naloxone reversal of opioid toxicity in patients who refuse transport to a healthcare facility (Wampler 2011). Nevertheless, patients who received naloxone in the out-of-hospital setting should seek immediate emergency medical assistance after the first dose due to the likelihood that respiratory and/or central nervous system depression will return.

• Opioid overdose: Recurrence of respiratory and/or CNS depression is possible if the opioid involved is long-acting; continuously observe patients until there is no further risk of recurrent respiratory or CNS depression.

• Partial opioid agonist and mixed opioid agonist/antagonist overdose: Reversal of partial opioid agonists or mixed opioid agonist/antagonists (eg, buprenorphine, pentazocine) may be incomplete and larger or repeat doses of naloxone may be required.

• Postoperative reversal: Appropriate use: Excessive dosages should be avoided after use of opioids in surgery. Abrupt postoperative reversal may result in nausea, vomiting, sweating, tachycardia, hypertension, seizures, and other cardiovascular events (including pulmonary edema and arrhythmias).

Metabolism/Transport Effects

None known.

Drug Interactions

Methylnaltrexone: May enhance the adverse/toxic effect of Opioid Antagonists. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid combination

Naldemedine: Opioid Antagonists may enhance the adverse/toxic effect of Naldemedine. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid combination

Naloxegol: Opioid Antagonists may enhance the adverse/toxic effect of Naloxegol. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid combination

Pregnancy Considerations

Naloxone crosses the placenta.

Although naloxone may precipitate opioid withdrawal in the fetus in addition to the mother, treatment should not be withheld when needed in cases of maternal opioid overdose (ACOG 711 2017). When using the injection, starting at the low end of the dosing range is suggested to help avoid adverse fetal events but still provide treatment to the mother (Blandthorn 2018). Use of naloxone to test for opioid dependence during pregnancy is not recommended (ASAM 2020).

Naloxone is used off-label for the management of patients with opioid-induced pruritus, including women who received neuraxial opioids during labor and delivery (ACOG 209 2019; Kumar 2013; Miller 2011).

Breastfeeding Considerations

It is not known if naloxone is present in breast milk; however, systemic absorption following oral administration is minimal.

According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.

Monitoring Parameters

Respiratory rate, heart rate, blood pressure, temperature, level of consciousness, ABGs or pulse oximetry

Mechanism of Action

Pure opioid antagonist that competes and displaces opioids at opioid receptor sites

Pharmacokinetics

Onset of action: Endotracheal, IM, SUBQ: 2 to 5 minutes; Inhalation via nebulization: ~5 minutes (Mycyk 2003); Intranasal: ~8 to 13 minutes (Kelly 2005; Robertson 2009); IV: ~2 minutes.

Duration: ~30 to 120 minutes depending on route of administration; IV has a shorter duration of action than IM administration; since naloxone's action is shorter than that of most opioids, repeated doses are usually needed.

Absorption: Intranasal, IM, SUBQ: Pediatric patients: May be erratic or delayed.

Protein binding: Relatively weak (to albumin [major] and other plasma constituents).

Metabolism: Primarily hepatic via glucuronidation.

Bioavailability: 42% to 54% (nasal [Narcan] compared to 0.4 mg IM dose); 37% (nasal [Kloxxado] compared to 2 mg IV dose).

Half-life elimination: Neonates: Mean 3.1 ± 0.5 hours; Adults: IM, IV, or SUBQ: 0.5 to 1.5 hours; Intranasal: ~2 hours.

Time to peak: IM, Intranasal (Kloxxado), SUBQ: 15 minutes; Intranasal (Narcan): 19.8 to 30 minutes.

Excretion: Urine (as metabolites).

Pricing: US

Liquid (Kloxxado Nasal)

8MG/0.1ML (per each): $75.00

Liquid (Naloxone HCl Nasal)

4MG/0.1ML (per each): $70.32 - $71.25

Liquid (Narcan Nasal)

4MG/0.1ML (per each): $75.00

Solution (Naloxone HCl Injection)

0.4 mg/mL (per mL): $5.27 - $23.72

4 mg/10 mL (per mL): $14.19 - $14.95

Solution Cartridge (Naloxone HCl Injection)

0.4 mg/mL (per mL): $18.53

Solution Prefilled Syringe (Naloxone HCl Injection)

2 mg/2 mL (per mL): $18.81 - $19.80

Solution Prefilled Syringe (Zimhi Injection)

5 mg/0.5 mL (per 0.5 mL): $75.00

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Feng Du (CN);
  • Forvel (LV);
  • Grayxona (AR);
  • Jin Er Lun (CN);
  • Lefebre (MX);
  • Mapin (HK, MY);
  • Min-I-Jet Naloxone (GB);
  • N-Xone (LK);
  • Nalone (FR);
  • Nalox (IN);
  • Naloxon (BG, CH, IS);
  • Naloxone Hydrochlorid (GB);
  • Naloxonum Hydrochloricum (PL);
  • Naloxonum Prolongatum (PL);
  • Narcan (AE, AU, BF, BJ, BR, CI, CY, ET, FR, GB, GH, GM, GN, GR, IL, IQ, IR, IT, JO, KE, KR, LB, LR, LU, LY, MA, ML, MR, MU, MW, NE, NG, NZ, OM, PK, PL, QA, SA, SC, SD, SG, SL, SN, SY, TH, TN, TW, TZ, UG, VE, YE, ZA, ZM, ZW);
  • Narcanti (AT, DK, HN, PL, UY);
  • Narcotan (IN);
  • Narlox (PH);
  • Narxona (AR);
  • Naxan (PT);
  • Naxolan (PT);
  • Naxone (AE, CY, IL, IQ, IR, JO, LB, LY, OM, QA, SA, SY, YE);
  • Nex (LK);
  • Nexodal (DK, FI, HU, IE, LT, NL, NO, PT, SE, SI);
  • Nyxoid (AT, BE, CH, CZ, DE, DK, EE, FI, GB, HR, LV, NL, NO, PT, SE, SK);
  • Opaxon (BD);
  • Oxogina (VE);
  • Prenoxad (GB);
  • Resuerix (EG);
  • Xeropium (EG)


For country abbreviations used in Lexicomp (show table)

REFERENCES

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  22. Evzio 0.4 mg per 0.4 mL (naloxone hydrochloride) [prescribing information]. Richmond, VA: Kaleo; April 2014.
  23. Evzio 2 mg per 0.4 mL (naloxone hydrochloride) [prescribing information]. Richmond, VA: Kaleo; October 2016.
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  40. Kloxxado (naloxone) [prescribing information]. Columbus, OH: Hikma Specialty USA Inc; April 2021.
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  51. Naloxone hydrochloride [prescribing information] 0.4 mg/mL Carpuject syringe. Lake Forest, IL: Hospira Inc; May 2019.
  52. Naloxone hydrochloride [prescribing information] 0.4 mg/mL single-dose and multi-dose vials. Lake Forest, IL: Hospira Inc; August 2019.
  53. Naloxone hydrochloride [prescribing information] 2 mg/2 mL prefilled syringe. Princeton, NJ: Dr. Reddy's Laboratories Inc; September 2019.
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