Narcan

Agents for Opioid Toxicity or Overdose

The duration of action of some opioids may exceed that of naloxone. When used as an opioid antagonist, monitor patients carefully and repeat doses as necessary.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
The solution should be clear; do not administer if the solution is discolored, cloudy, or contains solid particles.

IV Push
Administer undiluted by IV push; if necessary, may also dilute in Sterile Water for Injection.
In neonates, may administer via the umbilical vein.
 
Continuous IV Infusion
Dilute in 5% Dextrose Injection or 0.9% Sodium Chloride Injection to a concentration of 4 to 8 mcg/mL.
ASHP Recommended Standard Concentrations for Pediatric Continuous Infusions: 16 mcg/mL, 40 mcg/mL, or 400 mcg/mL.
Do not mix naloxone with preparations that contain bisulfite, metabisulfite, long-chain or high molecular weight anions, or any solutions with an alkaline pH. Do not add any drug or chemical agent to naloxone unless the effect of the substance on the chemical and physical stability of the naloxone solution has been established.
Rate of administration should be titrated to the patient's response.
Storage: Diluted injection is stable for 24 hours; discard any unused solution.

NOTE: Absorption after intramuscular administration of naloxone may be erratic or delayed. In cases of emergency, intravenous administration is preferred if an intravenous route is immediately available.
 
Intramuscular Injection with Standard Syringe
Inject deeply into a large muscle mass (e.g., anterolateral thigh or deltoid [children, adolescents, and adults only]). Aspirate prior to injection to avoid injection into a blood vessel.
 
Intramuscular Injection with Auto-injector (Zimhi)
Preparation of Caregivers and Family
Because treatment of suspected opioid overdose must be performed by someone other than the patient, caregivers and people in close contact with the recipient should be informed of the presence of Zimhi and its instructions for use before the need for the medication arises.
Prior to a medical emergency (during storage), periodically visually inspect Zimhi through the viewing window on the device. If the solution is discolored yellow or brown color, cloudy, or contains particles, replace Zimhi with a new one.
Zimhi is intended to be administered by individuals 12 years of age or older. Younger individuals or those with limited hand strength may find the device difficult to use.
Those who administer Zimhi should be aware that the use of naloxone in patients who are opioid dependent may cause an acute abstinence syndrome. In neonates, opioid withdrawal can be life-threatening and must be treated immediately.
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. Higher than usual doses of naloxone may be needed.
Administration
Remove the needle cap to expose needle; do not attempt to re-cap the needle with the needle cap once it has been removed.
Administer intramuscularly, as quickly as possible, into the anterolateral aspect of the thigh, through clothing if necessary. Ensure the needle is embedded completely before pushing the plunger. Push the plunger firmly all the way down until it clicks and hold in place for 2 seconds.
For neonates and infants: The caregiver should pinch the middle of the outer thigh muscle prior to and during drug administration. Carefully observe the administration site for evidence of residual needle parts and/or signs of infection.
Immediately after the injection, using one hand with fingers behind the needle, slide the safety guard over the needle. Do not use two hands to activate the safety guard. Put the used syringe into the blue case and close the case.
After use, the Zimhi needle is exposed until the safety guard is deployed. A needlestick injury could occur during use in emergency situations. In the event that an accidental needlestick occurs, seek immediate medical attention. Potential exposure to blood-borne pathogens including HIV, HBV, and HCV requires immediate evaluation by a medical professional. Stress to patients and caregivers the importance of familiarizing themselves with the safety guard and its deployment.
It is normal for most of the medicine to remain in the syringe after the dose has been injected. The correct dose has been injected if the plunger has been pushed all the way down and the solution window is at least partially blocked.
After the initial injection, seek immediate medical attention. Keep the patient under continued surveillance because the duration of action of most opioids is longer than that of naloxone. Repeat doses every 2 to 3 minutes as needed to achieve desired response until emergency medical assistance arrives.
Do NOT attempt to reuse Zimhi; each device contains a single dose of naloxone. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency assistance.
Storage: Store in outer case at room temperature. Replace the product before its expiration date.
 
Intramuscular Injection with 10 mg/0.4 mL Auto-injector
NOTE: This formulation is indicated for use by military personnel and chemical incident responders.
Read the Instructions for Use at the time of receiving a single-dose, pre-filled 10 mg/0.4 mL auto-injector.
Periodically inspect the solution through the viewing window for particulate matter. Request a replacement auto-injector if the solution is cloudy or contains particles, or if the glass container is damaged.
The auto-injector can be self- or buddy-administered.
Administer as soon as possible after known or suspected opioid exposure, as prolonged respiratory depression may result in damage to the CNS or death.
For prophylaxis of respiratory or CNS depression, administer the injection immediately prior to entering an area believed to be contaminated with high-potency opioids.
Once the red safety guard is removed, the auto-injector must be used immediately or disposed of properly. DO NOT attempt to replace the red safety guard once it has been removed.
Inject intramuscularly or subcutaneously into the anterolateral aspect of the thigh as follows:
The auto-injector can be used through clothing or MOPP4 PPE. Ensure the injection site is free of other materials (e.g., equipment or other obstructions), except for clothing.
Pull the auto-injector from the outer case.
Firmly pull off the red safety guard. DO NOT touch the black base of the auto-injector, which is where the needle comes out.
Place the black end against the anterolateral aspect of the thigh, through clothing, if needed.
Press firmly until you hear a click and hiss sound, and then hold in place for 5 seconds.
Upon actuation, the auto-injector inserts the needle intramuscularly or subcutaneously, delivers the naloxone solution, and retracts the needle into the device. The needle is not visible before, during, or after the injection.
After the injection, the black base of the auto-injector locks in place and the red indicator appears in the drug viewing window. Each auto-injector is for single use only; DO NOT attempt to reuse.

NOTE: Subcutaneous administration of naloxone may be erratic or delayed. In cases of emergency, intravenous administration is preferred if an intravenous route is immediately available.
Subcutaneous Injection with Standard Syringe
Inject undiluted solution subcutaneously taking care not to inject intradermally.
 
Subcutaneous Injection with Auto-injector (Zimhi)
Preparation of Caregivers and Family
Because treatment of suspected opioid overdose must be performed by someone other than the patient, caregivers and people in close contact with the recipient should be informed of the presence of Zimhi and its instructions for use before the need for the medication arises.
Prior to a medical emergency (during storage), periodically visually inspect Zimhi through the viewing window on the device. If the solution is discolored yellow or brown color, cloudy, or contains particles, replace Zimhi with a new one.
Zimhi is intended to be administered by individuals 12 years of age or older. Younger individuals or those with limited hand strength may find the device difficult to use.
Those who administer Zimhi should be aware that the use of naloxone in patients who are opioid dependent may cause an acute abstinence syndrome. In neonates, opioid withdrawal can be life-threatening and must be treated immediately.
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. Higher than usual doses of naloxone may be needed.
Administration
Remove the needle cap to expose needle; do not attempt to re-cap the needle with the needle cap once it has been removed.
Administer subcutaneously, as quickly as possible, into the anterolateral aspect of the thigh, through clothing if necessary. Ensure the needle is embedded completely before pushing the plunger. Push the plunger firmly all the way down until it clicks and hold in place for 2 seconds.
For neonates and infants: The caregiver should pinch the middle of the outer thigh muscle prior to and during drug administration. Carefully observe the administration site for evidence of residual needle parts and/or signs of infection.
Immediately after the injection, using one hand with fingers behind the needle, slide the safety guard over the needle. Do not use two hands to activate the safety guard. Put the used syringe into the blue case and close the case.
After use, the Zimhi needle is exposed until the safety guard is deployed. A needlestick injury could occur during use in emergency situations. In the event that an accidental needlestick occurs, seek immediate medical attention. Potential exposure to blood-borne pathogens including HIV, HBV, and HCV requires immediate evaluation by a medical professional. Stress to patients and caregivers the importance of familiarizing themselves with the safety guard and its deployment.
It is normal for most of the medicine to remain in the syringe after the dose has been injected. The correct dose has been injected if the plunger has been pushed all the way down and the solution window is at least partially blocked.
After the initial injection, seek immediate medical attention. Keep the patient under continued surveillance because the duration of action of most opioids is longer than that of naloxone. Repeat doses every 2 to 3 minutes as needed to achieve desired response until emergency medical assistance arrives.
Do NOT attempt to reuse Zimhi; each device contains a single dose of naloxone. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency assistance.
Storage: Store in outer case at room temperature. Replace the product before its expiration date.
 
Subcutaneous Injection with 10 mg/0.4 mL Auto-injector
NOTE: This formulation is indicated for use by military personnel and chemical incident responders.
Read the Instructions for Use at the time of receiving a single-dose, pre-filled 10 mg/0.4 mL auto-injector.
Periodically inspect the solution through the viewing window for particulate matter. Request a replacement auto-injector if the solution is cloudy or contains particles, or if the glass container is damaged.
The auto-injector can be self- or buddy-administered.
Administer as soon as possible after known or suspected opioid exposure, as prolonged respiratory depression may result in damage to the CNS or death.
For prophylaxis of respiratory or CNS depression, administer the injection immediately prior to entering an area believed to be contaminated with high-potency opioids.
Once the red safety guard is removed, the auto-injector must be used immediately or disposed of properly. DO NOT attempt to replace the red safety guard once it has been removed.
Inject intramuscularly or subcutaneously into the anterolateral aspect of the thigh as follows:
The auto-injector can be used through clothing or MOPP4 PPE. Ensure the injection site is free of other materials (e.g., equipment or other obstructions), except for clothing.
Pull the auto-injector from the outer case.
Firmly pull off the red safety guard. DO NOT touch the black base of the auto-injector, which is where the needle comes out.
Place the black end against the anterolateral aspect of the thigh, through clothing, if needed.
Press firmly until you hear a click and hiss sound, and then hold in place for 5 seconds.
Upon actuation, the auto-injector inserts the needle intramuscularly or subcutaneously, delivers the naloxone solution, and retracts the needle into the device. The needle is not visible before, during, or after the injection.
After the injection, the black base of the auto-injector locks in place and the red indicator appears in the drug viewing window. Each auto-injector is for single use only; DO NOT attempt to reuse.

Intraosseous Administration
NOTE: Naloxone is not FDA-approved for intraosseous administration.
During cardiopulmonary resuscitation, the same dosage may be given via the intraosseous route when IV access is unsuccessful or not feasible.[43713] [60636]

NOTE: Naloxone is not FDA-approved for oral inhalation administration.
Dilute 2 mg in 3 mL of 0.9% Sodium Chloride Injection.
Administer through a standard face mask.

Intranasal Administration
Preparation of Caregivers and Family
Alert others about the presence of naloxone nasal spray, as administration must be performed by someone other than the patient. Family members, caregivers, or other people who may have to use naloxone in an opioid emergency should know the signs and symptoms of opioid overdose, where the nasal spray is stored, and how to administer the drug before an opioid emergency occurs. Once obtained, become familiar with how to use the nasal spray by reading the instructions.
Those who administer naloxone should be aware that its use in patients who are opioid dependent may precipitate opioid withdrawal. In neonates, opioid withdrawal can be life-threatening and must be treated immediately.
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. Higher doses or repeated administrations of naloxone may be needed.
Administration
Administer naloxone nasal spray as quickly as possible if a patient is unresponsive and an opioid overdose is suspected, even when in doubt. Prolonged respiratory depression may result in central nervous system damage or death.
Hold the device with your thumb on the bottom of the plunger and your first and middle fingers on either side of the nozzle.
Place the patient in the supine position. Assure that the device nozzle is inserted into 1 of the patient's nostrils and provide support to the back of the neck to allow the head to tilt back. Both of your fingers on either side of the nozzle should be against the bottom of the patient's nose. DO NOT prime or test the device prior to administration.
Press firmly on the device plunger to administer the dose.
Remove the device nozzle from the nostril.
Turn the patient on their side (recovery position) and seek immediate medical assistance after the first dose of naloxone has been administered. Additional supportive and resuscitative measures may be helpful while awaiting emergency medical assistance. Keep the patient under continued surveillance until emergency personnel arrive and administer repeated naloxone doses as necessary.
Do NOT attempt to reuse the naloxone nasal spray device; each device contains a single dose.
Using a new nasal spray device, re-administer naloxone every 2 to 3 minutes if the patient does not respond or responds and then relapses into respiratory depression. The requirement for repeat doses depends on the amount, type, and route of administration of the opioid being antagonized.
Administer the nasal spray in alternate nostrils with each dose.
After use, put the device back into its box and dispose of properly.
Replace the product before its expiration date.[60315]
 
Endotracheal Administration
NOTE: Naloxone is not FDA-approved for endotracheal (ET) administration.
Consider ET administration only when other access is not available. ET administration is the least-preferred administration due to its association with unpredictable (but generally low) drug concentrations and lower rates of return of spontaneous circulation (ROSC) and survival.
If CPR is in progress, stop chest compressions briefly and administer the medication.
Adults: Dilute the dose in 5 to 10 mL of saline or sterile water.
Pediatrics: Follow drug administration with a saline flush (5 mL or more) and 5 consecutive positive-pressure ventilations.

bradycardia / Rapid / Incidence not known
pulmonary edema / Early / Incidence not known
seizures / Delayed / Incidence not known
ventricular tachycardia / Early / Incidence not known
cardiac arrest / Early / Incidence not known
ventricular fibrillation / Early / Incidence not known
neonatal abstinence syndrome / Early / Incidence not known

sinus tachycardia / Rapid / Incidence not known
hypertension / Early / Incidence not known
depression / Delayed / Incidence not known
loss of consciousness / Rapid / Incidence not known
hypotension / Rapid / Incidence not known
dyspnea / Early / Incidence not known
hypoxia / Early / Incidence not known
hallucinations / Early / Incidence not known
hot flashes / Early / Incidence not known
confusion / Early / Incidence not known
respiratory depression / Rapid / Incidence not known
withdrawal / Early / Incidence not known
constipation / Delayed / Incidence not known

back pain / Delayed / Incidence not known
hyperhidrosis / Delayed / Incidence not known
vomiting / Early / Incidence not known
miosis / Early / Incidence not known
nausea / Early / Incidence not known
malaise / Early / Incidence not known
agitation / Early / Incidence not known
tremor / Early / Incidence not known
anxiety / Delayed / Incidence not known
injection site reaction / Rapid / Incidence not known
paresthesias / Delayed / Incidence not known
flushing / Rapid / Incidence not known
dizziness / Early / Incidence not known
sneezing / Early / Incidence not known
irritability / Delayed / Incidence not known
yawning / Early / Incidence not known
shivering / Rapid / Incidence not known
fever / Early / Incidence not known
weakness / Early / Incidence not known
abdominal pain / Early / Incidence not known
restlessness / Early / Incidence not known
diarrhea / Early / Incidence not known
rhinorrhea / Early / Incidence not known
myalgia / Early / Incidence not known
asthenia / Delayed / Incidence not known
nasal congestion / Early / Incidence not known
rhinalgia / Early / Incidence not known
nasal dryness / Early / Incidence not known
headache / Early / Incidence not known
musculoskeletal pain / Early / Incidence not known
dental pain / Delayed / Incidence not known
syncope / Early / Incidence not known
nasal irritation / Early / Incidence not known

Kloxxado, Narcan, ZIMHI

Rx

Opioid antagonist; derivative of oxymorphone
Used for reversal of opioid-induced respiratory and CNS depression
Auto-injector and nasal formulations available to treat or prevent an overdose outside of healthcare setting

0.4 to 2 mg IV, IM, or subcutaneously every 2 to 3 minutes as needed up to a total dose of 10 mg. Some literature suggests up to a total dose of 15 mg. For patients in cardiac arrest, in the absence of a proven benefit from naloxone, standard resuscitative measures take priority over naloxone administration. Do not delay activating emergency response systems while awaiting the patient's response to naloxone.

2 mg IV or IO; may require repeated doses to prevent recurrent apnea.[43713] The FDA-approved dose is 0.01 mg/kg/dose IV, IM, or subcutaneously every 2 to 3 minutes until the desired response is obtained.[52015]

0.1 mg/kg/dose IV or IO; may require repeated doses to prevent recurrent apnea. FDA-approved labeling recommends 0.01 mg/kg/dose IV, IM, or subcutaneously every 2 to 3 minutes until the desired response is obtained.

0.1 mg/kg/dose IV or IM; may require repeated doses to prevent recurrent apnea. FDA-approved labeling recommends 0.01 mg/kg/dose IV, IM, or subcutaneously every 2 to 3 minutes until the desired response is obtained.

5 mg IM or subcutaneously every 2 to 3 minutes as needed; each device contains a single dose. Seek immediate medical attention after administration of the first dose.

5 mg IM or subcutaneously every 2 to 3 minutes as needed; each device contains a single dose. Seek immediate medical attention after administration of the first dose.

5 mg IM or subcutaneously every 2 to 3 minutes as needed; each device contains a single dose. Seek immediate medical attention after administration of the first dose.

NOTE: Indicated for use by military personnel and chemical incident responders.

10 mg IM or subcutaneously as emergency treatment in situations where it is suspected that high-potency opioids, such as fentanyl analogs, are being used as a chemical weapon. Seek immediate medical attention after administration of the first dose, while continuing to monitor the exposed person. Additional doses may be administered if the exposed person relapses into respiratory or CNS depression before medical assistance becomes available. If no improvement is observed, consider if the respiratory depression is due to a non-opioid etiology. Each device contains a single dose and can only be used 1 time.

10 mg IM or subcutaneously as emergency treatment in situations where it is suspected that high-potency opioids, such as fentanyl analogs, are being used as a chemical weapon. Seek immediate medical attention after administration of the first dose, while continuing to monitor the exposed person. Additional doses may be administered if the exposed person relapses into respiratory or CNS depression before medical assistance becomes available. If no improvement is observed, consider if the respiratory depression is due to a non-opioid etiology. Each device contains a single dose and can only be used 1 time.

3, 4, or 8 mg (1 spray) intranasally every 2 to 3 minutes in alternating nostrils as needed. Each device contains a single dose. Seek immediate medical assistance after administration of the first dose. Monitor the patient closely until emergency medical personnel arrive and for at least 24 hours after administration. If the patient responds to treatment and subsequently relapses back into respiratory depression before medical assistance arrives, administer an additional dose in the opposite nostril.

3, 4, or 8 mg (1 spray) intranasally every 2 to 3 minutes in alternating nostrils as needed. Each device contains a single dose. Seek immediate medical assistance after administration of the first dose. Monitor the patient closely until emergency medical personnel arrive and for at least 24 hours after administration. If the patient responds to treatment and subsequently relapses back into respiratory depression before medical assistance arrives, administer an additional dose in the opposite nostril.

3, 4, or 8 mg (1 spray) intranasally every 2 to 3 minutes in alternating nostrils as needed. Each device contains a single dose. Seek immediate medical assistance after administration of the first dose. Monitor the patient closely until emergency medical personnel arrive and for at least 24 hours after administration. If the patient responds to treatment and subsequently relapses back into respiratory depression before medical assistance arrives, administer an additional dose in the opposite nostril.

NOTE: Consider ET administration only when other access is not available. ET administration is the least-preferred administration due to its association with unpredictable (but generally low) drug concentrations and lower rates of survival.

0.8 to 5 mg via ET tube.

4 to 6 mg/dose via ET tube.[43713]

0.2 to 0.3 mg/kg/dose via ET tube.[43713]

2 mg via oral inhalation. May repeat if needed; in an observational study, median time to a second dose (IV/intranasal/nebulized) was 33 minutes (range 15 to 300 minutes). Nebulized naloxone was well-tolerated and resulted in a reduction in the need for supplemental oxygen as well as improving median Glasgow Coma Scale (GCS) and Richmond Agitation Sedation Scale (RASS) scores in patients with known or suspected opioid intoxication.

2 to 4 mg IV bolus, followed by 4 mg/hour continuous IV infusion or 3.66 to 5 mcg/kg IV bolus, followed by 2.5 to 3.66 mcg/kg/hour continuous IV infusion. Alternatively, two-thirds of the initial IV bolus dose (mg) that resulted in reversal of symptoms per hour continuous IV infusion (e.g., if 0.8 mg IV effectively reversed symptoms, then use 0.5 mg/hour continuous IV infusion, initially). Titrate dose as needed to patient response.

Limited data available. If repeated intermittent doses are required, it has been suggested to calculate the initial infusion rate based on the effective intermittent dose used; use two-thirds up to the full intermittent IV bolus dose (mg) that resulted in reversal of symptoms per hour continuous IV infusion (e.g., if 0.02 mg/kg IV effectively reversed symptoms, then use 0.013 to 0.02 mg/kg/hour continuous IV infusion, initially). Titrate dose as needed to patient response.[56976] [56977] 0.002 to 0.16 mg/kg/hour continuous IV or IO infusion has been suggested; however, most reports in neonates, infants, and young children have utilized a rate of 0.024 to 0.044 mg/kg/hour continuous IV infusion.[54288] [56977] [56978] [56979] [64934] A single case in a 17-year-old male reports 0.8 mg/hour continuous IV infusion; weight was not reported, but it appears the infusion rate was based on 0.4 mg IV (adult dose) every 30 minutes.[56980] The decision to wean should take into account the half-life of the ingested substance, the amount ingested, and conditions that may predispose the patient to slow opioid metabolism.[56976] [56977] When appropriate, decrease dose by 25% increments and carefully monitor the patient for recurrence of opioid-induced respiratory depression.[56976]

Limited data available. If repeated intermittent doses are required, it has been suggested to calculate the initial infusion rate based on the effective intermittent dose used; use two-thirds up to the full intermittent IV bolus dose (mg) that resulted in reversal of symptoms per hour continuous IV infusion (e.g., if 0.02 mg/kg IV effectively reversed symptoms, then use 0.013 to 0.02 mg/kg/hour continuous IV infusion, initially). Titrate dose as needed to patient response.[56976] [56977] 0.002 to 0.16 mg/kg/hour continuous IV or IO infusion has been suggested; however, most reports in neonates have utilized a rate of 0.024 to 0.044 mg/kg/hour continuous IV infusion.[54288] [56977] [56978] [56979] [64934] The decision to wean should take into account the half-life of the ingested substance, the amount ingested, and conditions that may predispose the patient to slow opioid metabolism.[56976] [56977] When appropriate, decrease dose by 25% increments and carefully monitor the patient for recurrence of opioid-induced respiratory depression.[56976]

0.1 to 0.2 mg IV at 2 to 3 minute intervals until the desired response is obtained. Additional doses may be necessary at 1 to 2 hour intervals depending on patient response, as well as the dosage and duration of action of the opiate agonist.

0.001 to 0.005 mg/kg/dose IV.[43713] FDA-approved labeling recommends an initial dose of 0.005 to 0.01 mg IV at 2 to 3 minute intervals until the desired degree of reversal is obtained. Additional doses may be necessary at 1 to 2 hour intervals.[52015]

0.0037 mg/kg/hour continuous IV infusion. If necessary, higher doses may be used.

NOTE: Naloxone is not recommended as part of the initial resuscitation of neonates with respiratory depression in the delivery room.[44520]

0.1 mg/kg/dose IV or IM was recommended in previous guidelines; however, the efficacy of this dose has not been established in the neonatal population, and naloxone is not recommended for routine use during neonatal resuscitation.[44520] [52071] FDA-approved labeling recommends 0.01 mg/kg/dose IV, IM, or subcutaneously every 2 to 3 minutes until the desired response is obtained.[52015]

10 mg IM or subcutaneously administered immediately before entering the contaminated area. Additional doses may be necessary if exposure to high-potency opioids is prolonged. Each device contains a single dose and can only be used 1 time.

In a double-blind, placebo-controlled, crossover trial, naloxone significantly decreased pruritus associated with cholestatic liver disease. Pruritus was assessed by patients' perception of pruritus, visual analog scales, and monitoring of scratching activity. In this study, naloxone was administered as an initial IV bolus of 0.4 mg in 1 mL of normal saline followed by a 4 hour IV infusion of 0.2 mcg/kg/minute in dextrose 5%/0.45% NaCl.

0.2 mg naloxone IV may be helpful during continuous infusion morphine.

Limited data available. A dose range of 1 to 3 mcg/kg/hour by continuous IV infusion has been reported during continuous opioid infusions (Max: 5 mcg/kg/hour). Doses of 3 mcg/kg/hour or greater were associated with higher opioid dosage requirements.

Limited data are available. A dose range of 0.25 to 1 mcg/kg/hour by continuous IV infusion has been used during continuous opioid infusions. In one double-blind, prospective, randomized, placebo-controlled study (n = 46), children and adolescents received 0.25 mcg/kg/hour by continuous IV infusion. Patients who received this dose experienced a decreased incidence and severity of opioid-induced side effects (i.e., pruritus, nausea); pain control was not affected. In another study in sickle cell patients (n = 16), patients receiving 1 mcg/kg/hour experienced less pruritus compared to patients receiving 0.25 mcg/kg/hour; pain control was also not affected.

Initially, 0.4—0.8 mg IV bolus (may also give 0.8 mg IM, subcutaneously, or via tracheal route). Up to 6—10 mg IV may be required for suspected opiate overdose (especially propoxyphene or China White overdose), if there is no response the diagnosis should be questioned.

Give 0.16 mg IM. If no withdrawal symptoms are noted after 20—30 minutes, give a second dose of 0.24 mg IV. A negative test result is assumed if no withdrawal symptoms were apparent within 30 minutes following the second dose.

Following appropriate screening of the patient, 0.8 mg of naloxone should be drawn into a sterile syringe. Inject 0.2 mg. While the needle is still in the patient's vein, the patient should be observed for 30 seconds for evidence of withdrawal signs or symptoms. If there is no evidence of withdrawal, the remaining 0.6 mg IV should be given and the patient observed for an additional 20 minutes for signs and symptoms of withdrawal.

Following appropriate screening of the patient, inject 0.8 mg subcutaneously and observe the patient for 20 minutes for signs and symptoms of withdrawal.

This use of naloxone is described in the manufacturer's product literature and clinical literature, however, the optimal dosage or duration of therapy has not been established. The literature describes reports of a naloxone pressor effect early in the course of treatment of septic shock with naloxone 0.4 mg IV over 3—5 minutes, repeated for 3—5 doses, depending on the response. Bolus infusions ranging from 0.03—0.2 mg/kg IV over 5 minutes have also been used. If a response was seen, treatment was continued using continuous infusions ranging 0.03—0.3 mg/kg/hour IV for 1—24 hours or more, depending on clinical response.

0.2 mg IV may be helpful.

0.2 mg IV may be helpful.

Naloxone has been studied in the management of opiate agonist-induced constipation. Doses of 1—12 mg PO 3 times daily have been used. In 1 series of 17 patients, oral naloxone was started at a dose of 3 mg PO 3 times daily and was increased up to 12 mg PO 3 times daily (by increasing dosage in 3-mg increments on consecutive days, if a bowel movement did not occur with the previous dose). Laxative use decreased in 9 patients and stooling increased in 14 patients. Serious withdrawal effects were seen in 4 patients, but resolved quickly; 3 of these patients were continued on reduced dosages of naloxone.

Naloxone has been studied in the management of constipation-predominant IBS, but more data are needed to assess efficacy. In 1 randomized, controlled trial, patients (n = 28) received naloxone 10 mg PO twice daily or placebo for 8 weeks. Six of 14 (42%) patients receiving naloxone reported symptomatic relief (decreased symptoms like bloating, pain, straining) vs. 3 of 11 (27%) patients receiving placebo. The trial lacked sufficient power to achieve statistical significance.

†Indicates off-label use

Use with caution; naloxone is metabolized by the liver. The safety and efficacy of naloxone in patients with hepatic disease have not been established in well-controlled clinical trials.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Atazanavir; Cobicistat: (Moderate) The plasma concentrations of buprenorphine and naloxone may be elevated when administered concurrently with cobicistat. When initiating buprenorphine; naloxone in patients currently on a regimen containing cobicistat and atazanavir or darunavir, use the lowest buprenorphine; naloxone starting dose and slowly titrate to desired effect. When initiating antiretroviral regimens containing cobicistat and atazanavir or darunavir to patients on buprenorphine; naloxone, an adjustment of buprenorphine; naloxone dose may be needed. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while buprenorphine is a CYP3A4 substrate.
Atropine; Difenoxin: (Major) Naloxone can antagonize the therapeutic efficacy of diphenoxylate in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including diphenoxylate.
Cobicistat: (Moderate) The plasma concentrations of buprenorphine and naloxone may be elevated when administered concurrently with cobicistat. When initiating buprenorphine; naloxone in patients currently on a regimen containing cobicistat and atazanavir or darunavir, use the lowest buprenorphine; naloxone starting dose and slowly titrate to desired effect. When initiating antiretroviral regimens containing cobicistat and atazanavir or darunavir to patients on buprenorphine; naloxone, an adjustment of buprenorphine; naloxone dose may be needed. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while buprenorphine is a CYP3A4 substrate.
Darunavir; Cobicistat: (Moderate) The plasma concentrations of buprenorphine and naloxone may be elevated when administered concurrently with cobicistat. When initiating buprenorphine; naloxone in patients currently on a regimen containing cobicistat and atazanavir or darunavir, use the lowest buprenorphine; naloxone starting dose and slowly titrate to desired effect. When initiating antiretroviral regimens containing cobicistat and atazanavir or darunavir to patients on buprenorphine; naloxone, an adjustment of buprenorphine; naloxone dose may be needed. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while buprenorphine is a CYP3A4 substrate.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) The plasma concentrations of buprenorphine and naloxone may be elevated when administered concurrently with cobicistat. When initiating buprenorphine; naloxone in patients currently on a regimen containing cobicistat and atazanavir or darunavir, use the lowest buprenorphine; naloxone starting dose and slowly titrate to desired effect. When initiating antiretroviral regimens containing cobicistat and atazanavir or darunavir to patients on buprenorphine; naloxone, an adjustment of buprenorphine; naloxone dose may be needed. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while buprenorphine is a CYP3A4 substrate.
Diphenoxylate; Atropine: (Major) Naloxone can antagonize the therapeutic efficacy of diphenoxylate in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including diphenoxylate.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) The plasma concentrations of buprenorphine and naloxone may be elevated when administered concurrently with cobicistat. When initiating buprenorphine; naloxone in patients currently on a regimen containing cobicistat and atazanavir or darunavir, use the lowest buprenorphine; naloxone starting dose and slowly titrate to desired effect. When initiating antiretroviral regimens containing cobicistat and atazanavir or darunavir to patients on buprenorphine; naloxone, an adjustment of buprenorphine; naloxone dose may be needed. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while buprenorphine is a CYP3A4 substrate.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) The plasma concentrations of buprenorphine and naloxone may be elevated when administered concurrently with cobicistat. When initiating buprenorphine; naloxone in patients currently on a regimen containing cobicistat and atazanavir or darunavir, use the lowest buprenorphine; naloxone starting dose and slowly titrate to desired effect. When initiating antiretroviral regimens containing cobicistat and atazanavir or darunavir to patients on buprenorphine; naloxone, an adjustment of buprenorphine; naloxone dose may be needed. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while buprenorphine is a CYP3A4 substrate.
Methylnaltrexone: (Major) Avoid concomitant use of methylnaltrexone with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
Naldemedine: (Major) Avoid concomitant use of naldemedine with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
Naloxegol: (Major) Avoid concomitant use of naloxegol with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.

Kloxxado/Naloxone Hydrochloride/Narcan Nasal Spray: 0.1mL, 4mg, 8mg
Naloxone Hydrochloride/Narcan Intravenous Inj Sol: 0.4mg, 1mL, 1mg
Naloxone Hydrochloride/Narcan/ZIMHI Intramuscular Inj Sol: 0.4mg, 0.5mL, 1mL, 1mg, 5mg
Naloxone Hydrochloride/Narcan/ZIMHI Subcutaneous Inj Sol: 0.4mg, 0.5mL, 1mg, 1mL, 5mg

2 mg per dose IV/IO/IM/subcutaneous (standard syringe); 5 mg per dose IM/subcutaneous (Zimhi auto-injector); 10 mg per dose IM/subcutaneous (10 mg/0.4 mL auto-injector); 1 spray (3, 4, or 8 mg) per dose intranasally; doses may be repeated to maintain opiate reversal.

2 mg per dose IV/IO/IM/subcutaneous (standard syringe); 5 mg per dose IM/subcutaneous (Zimhi auto-injector); 10 mg per dose IM/subcutaneous (10 mg/0.4 mL auto-injector); 1 spray (3, 4, or 8 mg) per dose intranasally; doses may be repeated to maintain opiate reversal.

2 mg per dose IV/IO/IM/subcutaneous (standard syringe); 5 mg per dose IM/subcutaneous (Zimhi auto-injector); 10 mg per dose IM/subcutaneous (10 mg/0.4 mL auto-injector); 1 spray (3, 4, or 8 mg) per dose intranasally; doses may be repeated to maintain opiate reversal.

12 years: 2 mg per dose IV/IO/IM/subcutaneous (standard syringe); 5 mg per dose IM/subcutaneous (Zimhi auto-injector); 10 mg per dose IM/subcutaneous (10 mg/0.4 mL auto-injector); 1 spray (3, 4, or 8 mg) per dose intranasally; doses may be repeated to maintain opiate reversal.
5 to 11 years and weighing more than 20 kg: 2 mg per dose IV/IO/IM/subcutaneous (standard syringe); 5 mg per dose IM/subcutaneous (Zimhi auto-injector); 1 spray (3, 4, or 8 mg) per dose intranasally; doses may be repeated to maintain opiate reversal.
1 to 4 years or weighing 20 kg or less: 0.1 mg/kg/dose IV/IO (standard syringe); 5 mg per dose IM/subcutaneous (Zimhi auto-injector); 1 spray (3, 4, or 8 mg) per dose intranasally; doses may be repeated to maintain opiate reversal.

0.1 mg/kg/dose IV/IO (standard syringe); 5 mg per dose IM/subcutaneous (Zimhi auto-injector); 1 spray (3, 4, or 8 mg) per dose intranasally; doses may be repeated to maintain opiate reversal.

0.1 mg/kg/dose IV/IM (standard syringe); 5 mg per dose IM/subcutaneous (Zimhi auto-injector); 1 spray (3, 4, or 8 mg) per dose intranasally; doses may be repeated to maintain opiate reversal.

Unlike the older narcotic antagonists levallorphan and nalorphine, which were subsequently removed from the market, naloxone is essentially a pure antagonist, with little or no agonistic activity. In patients who have not recently received opioid drugs, naloxone shows little or no pharmacological effects, even at high doses. Opiate receptors include mu, kappa, and delta, which have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (mu). Mu-receptors are responsible for analgesia, euphoria, respiratory depression, and miosis. Kappa-receptors are responsible for analgesia, dysphoria, some psychomimetic effects (e.g., disorientation and/or depersonalization), and sedation. Delta-receptors mediate analgesia, sedation, and possibly hormonal and neurotransmitter release. Naloxone is thought to antagonize mu- (highest affinity), kappa-, and delta-receptors, thus inhibiting both the toxic and clinical effects of opiates. This antagonism is competitive and short-lived, possibly necessitating repeat doses when long-acting opiates are involved. Naloxone itself produces no physical or psychological dependence and will not worsen respiratory depression if administered for non-opiate overdose.
 
Naloxone antagonizes both the toxic and clinical effects of opiates. Thus, not only are respiratory depression, hypotension, and sedation reversed, but analgesia as well. Clinicians should use discretion when considering administering naloxone to patients who are sedated from opiates but do not exhibit respiratory depression. Reversal of analgesia is undesirable in patients known to be in severe pain. Naloxone should not be used for drowsiness unless opiate-induced respiratory depression coexists.
 
Finally, because endorphins and enkephalins (endogenous substances with opiate-like activity) are known to exist in higher concentrations in certain disease states, naloxone has been considered a therapeutic agent for conditions other than opiate overdose. Various respiratory diseases have been associated with elevated circulating concentrations of endorphins, and naloxone has been studied in patients with COPD, obesity-hypoventilation syndrome, and high-altitude pulmonary edema.

Naloxone is administered intravenously, intramuscularly, intraosseously, subcutaneously, or intranasally; absorption may be erratic or delayed with subcutaneous, intramuscular, or intranasal routes compared to after intravenous administration. In emergency situations, naloxone has also been administered via endotracheal tube; however, data are limited. Naloxone is rapidly distributed with weak protein binding. Plasma albumin is the major binding constituent, but significant binding of naloxone also occurs with other plasma constituents. Naloxone achieves a brain-to-serum ratio 12 to 15 times greater than morphine. Metabolism takes place rapidly in the liver, mainly by conjugation with glucuronic acid. The major metabolite is naloxone-3-glucuronide. Excretion of the metabolites in the urine indicates that approximately 50% of an intravenous dose is excreted within 24 hours, and 60 to 70% is excreted within 72 hours. The plasma half-life ranges from 0.5 to 2 hours in most populations. In neonates, an elimination half-life of approximately 3 hours has been observed with naloxone injection.
 
Affected cytochrome P450 isoenzymes: none

Onset of action occurs within 2 to 3 minutes after IV administration. Duration of action is estimated to be 45 to 90 minutes, but may be dependent on the dose of naloxone given and the duration of action of the opioid being reversed.

Onset of action occurs within 15 minutes after IM administration; however, absorption may be erratic or delayed with this route, particularly in pediatric patients. Duration of action is more prolonged with IM administration compared with IV administration. In a pharmacokinetic study comparing naloxone administered via auto-injector or standard syringe in healthy adults, a single 0.4 mg IM or subcutaneous dose administered from the auto-injector provided an equivalent AUC and 15% greater Cmax in comparison to the same dose administered via standard syringe. For the auto-injector, a mean Cmax of 1.24 (+/- 0.64) ng/mL was obtained in a median Tmax of 15 minutes (range: 5 to 72 minutes); corresponding values for the standard syringe were 1.07 (+/- 0.48) ng/mL and 20 minutes (range: 5 to 122 minutes), respectively. The mean half-lives in both groups were similar, 1.28 (+/- 0.48) and 1.36 (+/- 0.32) hours for the auto-injector and standard syringe, respectively. In a second study, a mean Cmax of 1.33 ng/mL (62.9% CV) was obtained in a median Tmax of 0.25 hours (range: 0.09 to 0.84 hours) for the 0.4 mg dose; corresponding values for the 2 mg dose were 7.91 ng/mL (45.8% CV) and 0.25 hours (range: 0.13 to 0.67 hours), respectively. The mean half-lives in both groups were similar, 1.58 hours (28.9% CV) and 1.53 hours (25% CV) for the 0.4 mg and 2 mg auto-injector doses, respectively. A third study compared the pharmacokinetic parameters of a single 10 mg IM or subcutaneous dose with a single 2 mg injection administered into the anterolateral aspect of the thigh. Slightly greater than 5-fold increases in Cmax and AUC were observed for the 10 mg dose compared to the 2 mg injection (42 ng/mL vs. 6.95 ng/mL and 51.1 ng/mL x hour vs. 9.22 ng/mL x hour, respectively). The median Tmax and mean half-life for the 10 mg dose were 15.6 minutes (range: 5.4 to 40.2 minutes) and 1.46 hours, respectively.

Onset of action occurs within 15 minutes after subcutaneous administration; however, absorption may be erratic or delayed with this route, particularly in pediatric patients. In a pharmacokinetic study comparing naloxone administered via auto-injector or standard syringe in healthy adults, a single 0.4 mg IM or subcutaneous dose administered from the auto-injector provided an equivalent AUC and 15% greater Cmax in comparison to the same dose administered via standard syringe. For the auto-injector, a mean Cmax of 1.24 (+/- 0.64) ng/mL was obtained in a median Tmax of 15 minutes (range: 5 to 72 minutes); corresponding values for the standard syringe were 1.07 (+/- 0.48) ng/mL and 20 minutes (range: 5 to 122 minutes), respectively. The mean half-lives in both groups were similar, 1.28 (+/- 0.48) and 1.36 (+/- 0.32) hours for the auto-injector and standard syringe, respectively. In a second study, a mean Cmax of 1.33 ng/mL (62.9% CV) was obtained in a median Tmax of 0.25 hours (range: 0.09 to 0.84 hours) for the 0.4 mg dose; corresponding values for the 2 mg dose were 7.91 ng/mL (45.8% CV) and 0.25 hours (range: 0.13 to 0.67 hours), respectively. The mean half-lives in both groups were similar, 1.58 hours (28.9% CV) and 1.53 hours (25% CV) for the 0.4 mg and 2 mg auto-injector doses, respectively. A third study compared the pharmacokinetic parameters of a single 10 mg IM or subcutaneous dose with a single 2 mg injection administered into the anterolateral aspect of the thigh. Slightly greater than 5-fold increases in Cmax and AUC were observed for the 10 mg dose compared to the 2 mg injection (42 ng/mL vs. 6.95 ng/mL and 51.1 ng/mL x hour vs. 9.22 ng/mL x hour, respectively). The median Tmax and mean half-life for the 10 mg dose were 15.6 minutes (range: 5.4 to 40.2 minutes) and 1.46 hours, respectively.

Intranasal Route
The pharmacokinetics of 4 mg intranasal naloxone were assessed in 30 healthy adult subjects, all of whom received 1 nasal spray in 1 nostril (4 mg total doses), 2 nasal sprays in alternate nostrils (8 mg total doses), and 0.4 mg naloxone as an intramuscular (IM) injection. For intranasal administration, participants were instructed not to breathe through nose during nasal spray administration and remain fully supine for at least 1 hour post-dose. IM injections were administered in the gluteus maximus. The dose-normalized relative bioavailability of 1 dose (4 mg total doses) or 2 doses (8 mg total doses) of intranasal naloxone, compared to the 0.4 mg IM dose, was approximately 44% and 43%, respectively. Median Tmax after intranasal administration was 30 minutes after a single 4 mg dose and 20 minutes after double 4 mg doses; these values were not significantly different compared to the Tmax after IM administration (23 minutes). The Cmax and AUC were as follows: for the single 4 mg intranasal dose, Cmax was 4.83 ng/mL and AUC 7.87 ng/mL x hour; for double 4 mg doses, Cmax was 9.7 ng/mL and AUC was 15.3 ng/mL x hour. Comparatively, the Cmax and AUC after IM administration was 0.88 ng/mL and 1.7 ng/mL x hour, respectively. Half-life of intranasal naloxone was approximately 2 hours.
Another study compared the relative bioavailability in healthy subjects of one 4 mg intranasal spray and a single 0.4 mg IM injection to a 2 mg IV infusion. The dose normalized relative bioavailability of the intranasal and IM doses compared with the IV infusion were 40.7% (+/- 17.8) and 95.9% (+/- 28.5), respectively. The 4 mg intranasal dose had a Tmax, Cmax, AUC, and half-life of 32.1 (+/-1.6) minutes, 3.71 (+/-1.55) ng/mL, 6.63 (+/-1.32) ng x hour/mL, and 67.6 (+/-1.2) minutes. The Tmax, Cmax, AUC, and half-life of the 0.4 mg IM dose were 24.4 (+/-2.4) minutes, 0.73 (+/-1.56) ng/mL, 1.6 (+/-1.27) ng x hour/mL, and 75.7 (+/-1.2) minutes, respectively. The Tmax, Cmax, AUC, and half-life of 2 mg IV infusion doses were 4.9 (+/-1.4) minutes, 11.1 (+/-2.15) ng/mL, 8.64 (+/-1.33) ng x hour/mL, and 66.2 (+/-1.2) minutes, respectively.
The pharmacokinetics of 8 mg intranasal naloxone were assessed in 2 studies involving up to 24 healthy adults in each study. In these studies, a single 8 mg naloxone intranasal dose (1 spray) was compared to a single 0.4 mg intramuscular (IM) dose and a single 2 mg intravenous (IV) dose. The dose normalized relative bioavailability of the 8 mg intranasal dose was 42% to 47% of the 0.4 mg IM dose. The dose normalized absolute bioavailability of the 8 mg intranasal dose compared to the 2 mg IV dose was 37%. For the 8 mg intranasal dose, the Cmax was approximately 12 ng/mL and the AUC was about 18 ng/mL x hour. The median Tmax was 15 minutes for both the 8 mg intranasal dose and the 0.4 mg IM dose. The mean half-life of intranasal naloxone was 1.8 hours.

Available data from retrospective cohort studies on oral naloxone use in human pregnancy for opioid use disorder have not identified a drug-associated risk of major birth defects, miscarriages, or other maternal or fetal adverse outcomes. Animal studies have revealed no evidence of teratogenicity. Although there are risks to the fetus of an opioid-dependent mother with use of naloxone, an opioid overdose is a medical emergency and can be fatal for the pregnant woman and fetus if left untreated. Treatment with naloxone for opioid overdose should not be withheld because of potential concerns regarding the effects of naloxone on the fetus. In 1 study evaluating the effects of naloxone on fetal behavior, 54 pregnant women near term received either 0.4 mg of naloxone or placebo. Significant increases were observed in the number, duration, and amplitude of fetal heart rate accelerations, number of fetal body movements, and percentage of time spent breathing in the naloxone group. Significantly more fetuses in the naloxone-treated group were actively awake than those who were not exposed. During a study in which 40 women in labor received 1 mg of morphine, 1 group subsequently received a 0.4 mg IV bolus of naloxone after 1 hour plus a 0.4 to 0.6 mg/hour infusion for 23 hours and the second group received an identical placebo regimen. Despite placental transfer of naloxone, neonatal outcomes were not adversely affected. In 1 newborn, administration of naloxone to treat a flat fetal heart rate was a possible cause of fetal asphyxia leading to fatal respiratory failure. Since naloxone crosses the placenta, evaluate the fetus for signs of withdrawal and distress after naloxone is used. Careful monitoring is needed until the fetus and mother are stabilized.

There is no information regarding the presence of naloxone in human milk or the effects of naloxone on the breast-fed infant or milk production. Studies in breast-feeding mothers have shown that naloxone does not affect prolactin or oxytocin hormone levels. Naloxone is minimally orally bioavailable. Although the effect of naloxone exposure in the nursing infant has not been evaluated, naloxone has been administered to newborns following in utero exposure to narcotics, and no adverse effects have been reported. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for naloxone and any potential adverse effects on the breast-fed infant from naloxone or the underlying maternal condition.